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1.  Neonatal Mortality Risk Associated with Preterm Birth in East Africa, Adjusted by Weight for Gestational Age: Individual Participant Level Meta-Analysis 
PLoS Medicine  2012;9(8):e1001292.
In an analysis of four datasets from East Africa, Tanya Marchant and colleagues investigate the neonatal mortality risk associated with preterm birth and how this changes with weight for gestational age.
Background
Low birth weight and prematurity are amongst the strongest predictors of neonatal death. However, the extent to which they act independently is poorly understood. Our objective was to estimate the neonatal mortality risk associated with preterm birth when stratified by weight for gestational age in the high mortality setting of East Africa.
Methods and Findings
Members and collaborators of the Malaria and the MARCH Centers, at the London School of Hygiene & Tropical Medicine, were contacted and protocols reviewed for East African studies that measured (1) birth weight, (2) gestational age at birth using antenatal ultrasound or neonatal assessment, and (3) neonatal mortality. Ten datasets were identified and four met the inclusion criteria. The four datasets (from Uganda, Kenya, and two from Tanzania) contained 5,727 births recorded between 1999–2010. 4,843 births had complete outcome data and were included in an individual participant level meta-analysis. 99% of 445 low birth weight (<2,500 g) babies were either preterm (<37 weeks gestation) or small for gestational age (below tenth percentile of weight for gestational age). 52% of 87 neonatal deaths occurred in preterm or small for gestational age babies. Babies born <34 weeks gestation had the highest odds of death compared to term babies (odds ratio [OR] 58.7 [95% CI 28.4–121.4]), with little difference when stratified by weight for gestational age. Babies born 34–36 weeks gestation with appropriate weight for gestational age had just three times the likelihood of neonatal death compared to babies born term, (OR 3.2 [95% CI 1.0–10.7]), but the likelihood for babies born 34–36 weeks who were also small for gestational age was 20 times higher (OR 19.8 [95% CI 8.3–47.4]). Only 1% of babies were born moderately premature and small for gestational age, but this group suffered 8% of deaths. Individual level data on newborns are scarce in East Africa; potential biases arising due to the non-systematic selection of the individual studies, or due to the methods applied for estimating gestational age, are discussed.
Conclusions
Moderately preterm babies who are also small for gestational age experience a considerably increased likelihood of neonatal death in East Africa.
Please see later in the article for the Editors' Summary.
Editors' Summary
Background
Worldwide, every year around 3.3 million babies die within their first month of life and the proportion of under-five child deaths that are now in the neonatal period (the first 28 days of life) has increased in all regions of the world and is currently estimated at 41%. Of these deaths, over 90% occur in low- and middle-income countries, and a third of all neonatal deaths occur in sub-Saharan Africa. Low birth weight (defined as <2,500 g) is one of the biggest risk factors associated with neonatal deaths but it is the causes of low birth weight, rather than the low weight itself that is thought to lead to neonatal deaths. The two main causes of low birth weight are preterm birth (delivery before 37 weeks gestation) and/or restricted growth in the womb (intra-uterine growth retardation), resulting in babies who are small for their dates (defined as being in the lowest 10% of weight expected for gestational age with reference to a US population).
Why Was This Study Done?
Despite growing international attention focused on neonatal mortality in recent years, the relative importance of low birth weight, small for gestational age, and preterm birth in causing newborn deaths remains unclear. So in this study, the researchers investigated these relationships by calculating the risk of neonatal mortality associated with preterm birth after adjusting for weight for gestational age by conducting a meta-analysis (synthesis of the data) using information from studies reporting neonatal mortality conducted in sub-Saharan Africa.
What Did the Researchers Do and Find?
The researchers identified potential African datasets and selected four out of a possible ten to include in their analysis as these studies included three essential birth outcomes: birth weight; gestational age measured using antenatal ultrasound, or neonatal assessment on the day of birth; and neonatal mortality. These four studies were conducted in Kenya, Tanzania, and Uganda, all in East Africa. The researchers analysed each study separately but also conducted a pooled statistical analysis on all four studies. To give a more detailed analysis, the researchers categorized babies into six groups taking into account whether the babies were moderately preterm (born at 34–36 weeks) or very preterm (born before 34 weeks) and whether their weight was appropriate for their gestational age.
The researchers included a total of 4,843 live births in their analysis and found that overall, 9.2% of babies were low birth weight, 4.0% were preterm, and 20.4% were small for gestational age. Amongst low birth weight babies, 26.1% were preterm, 85.0% were small for gestational age, and 98.8% were either preterm or small for gestational age. In their detailed analysis, the researchers found that the odds (chance) of death in the first 28 days of life were seven times higher for babies born low birth weight compared to those with normal birth weight, with low birth weight infants experiencing a neonatal mortality rate of 80.9/1,000 live births. The odds of death were twice as high for babies born small for gestational age compared to those born appropriate for gestational age, giving a neonatal mortality rate of 29.3/1,000 live births. Furthermore, compared to those born at term, the odds of death were over six times higher for babies born moderately preterm and almost 60 times higher for babies born very preterm with almost half of all very preterm babies dying in the first 28 days of life, giving a neonatal mortality rate 473.6/1,000 live births. However, moderately preterm babies who were small for gestational age had a much greater odds of death than moderately preterm babies who were of the appropriate weight for their gestational age.
What Do These Findings Mean?
These findings from East Africa show that babies born either small for gestational age or preterm contributed 52% of neonatal deaths. The detailed analysis suggests that babies born preterm are at the greatest risk of death, but size for gestational age also plays an important role especially in moderately preterm babies. The results from this study emphasize the pressing need to find ways to prevent preterm delivery and intra-uterine growth retardation and also illustrate the importance of measuring and reporting outcomes of individual babies.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001292.
A recent PLOS Medicine study by Oestergaard et al. has the latest global figures on neonatal mortality
UNICEF provides information on neonatal mortality
The World Health Organization (WHO) provides factsheets on the causes of neonatal mortality, including preterm birth
doi:10.1371/journal.pmed.1001292
PMCID: PMC3419185  PMID: 22904691
2.  Post-neonatal Mortality, Morbidity, and Developmental Outcome after Ultrasound-Dated Preterm Birth in Rural Malawi: A Community-Based Cohort Study 
PLoS Medicine  2011;8(11):e1001121.
Using data collected as a follow-up to a randomized trial, Melissa Gladstone and colleagues show that during the first two years of life, infants born preterm in southern Malawi are disadvantaged in terms of mortality, growth, and development.
Background
Preterm birth is considered to be associated with an estimated 27% of neonatal deaths, the majority in resource-poor countries where rates of prematurity are high. There is no information on medium term outcomes after accurately determined preterm birth in such settings.
Methods and Findings
This community-based stratified cohort study conducted between May–December 2006 in Southern Malawi followed up 840 post-neonatal infants born to mothers who had received antenatal antibiotic prophylaxis/placebo in an attempt to reduce rates of preterm birth (APPLe trial ISRCTN84023116). Gestational age at delivery was based on ultrasound measurement of fetal bi-parietal diameter in early-mid pregnancy. 247 infants born before 37 wk gestation and 593 term infants were assessed at 12, 18, or 24 months. We assessed survival (death), morbidity (reported by carer, admissions, out-patient attendance), growth (weight and height), and development (Ten Question Questionnaire [TQQ] and Malawi Developmental Assessment Tool [MDAT]). Preterm infants were at significantly greater risk of death (hazard ratio 1.79, 95% CI 1.09–2.95). Surviving preterm infants were more likely to be underweight (weight-for-age z score; p<0.001) or wasted (weight-for-length z score; p<0.01) with no effect of gestational age at delivery. Preterm infants more often screened positively for disability on the Ten Question Questionnaire (p = 0.002). They also had higher rates of developmental delay on the MDAT at 18 months (p = 0.009), with gestational age at delivery (p = 0.01) increasing this likelihood. Morbidity—visits to a health centre (93%) and admissions to hospital (22%)—was similar for both groups.
Conclusions
During the first 2 years of life, infants who are born preterm in resource poor countries, continue to be at a disadvantage in terms of mortality, growth, and development. In addition to interventions in the immediate neonatal period, a refocus on early childhood is needed to improve outcomes for infants born preterm in low-income settings.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Being born at term in Africa is not necessarily straightforward. In Malawi, 33 of every 1,000 infants born die in the first 28 days after birth; the lifetime risk for a mother dying during or shortly after pregnancy is one in 36. The comparable figures for the United Kingdom are three infants dying per 1,000 births and a lifetime risk of maternal death of one in 4,700. But for a baby, being born preterm is even more risky and the gap between low- and high-income countries widens still further. According to a World Health Organization report in 2010, a baby born at 32 weeks of gestation (weighing around 2,000 g) in Africa has little chance of survival, while the chances of survival for a baby born at 32 weeks in North America or Europe are similar to one born at term. There are very few data on the longer term outcomes of babies born preterm in Africa and there are multiple challenges involved in gathering such information. As prenatal ultrasound is not routinely available, gestational age is often uncertain. There may be little routine follow-up of preterm babies as is commonplace in high-income countries. Data are needed from recent years that take into account both improvements in perinatal care and adverse factors such as a rising number of infants becoming HIV positive around the time of birth.
Why Was This Study Done?
We could improve outcomes for babies born preterm in sub-Saharan Africa if we understood more about what happens to them after birth. We cannot assume that the progress of these babies will be the same as those born preterm in a high-income country, as the latter group will have received different care, both before and after birth. If we can document the problems that these preterm babies face in a low-income setting, we can consider why they happen and what treatments can be realistically tested in this setting. It is also helpful to establish baseline data so that changes over time can be recorded.
The aim of this study was to document four specific outcomes up to the age of two years, on which there were few data previously from rural sub-Saharan Africa: how many babies survived, visits to a health center and admissions to the hospital, growth, and developmental delay.
What Did the Researchers Do and Find?
The researchers examined a group of babies that had been born to mothers who had taken part in a randomized controlled trial of an antibiotic to prevent preterm birth. The trial had previously shown that the antibiotic (azithromycin) had no effect on how many babies were born preterm or on other measures of the infants' wellbeing, and so the researchers followed up babies from both arms of the trial to look at longer term outcomes. From the original group of 2,297 women who took part in the trial, they compared 247 infants born preterm against 593 term infants randomly chosen as controls, assessed at 12, 18, or 24 months. The majority of the preterm babies who survived past a month of age (all but ten) were born after 32 weeks of gestation. Compared to the babies born at term, the infants born preterm were nearly twice as likely to die subsequently in the next two years, were more likely to be underweight (a third were moderately underweight), and to have higher rates of developmental delay. The commonest causes of death were gastroenteritis, respiratory problems, and malaria. Visits to a health center and admissions to hospital were similar in both groups.
What Do these Findings Mean?
This study documents longer term outcomes of babies born preterm in sub-Saharan Africa in detail for the first time. The strengths of the study include prenatal ultrasound dating and correct adjustment of follow-up age (which takes into account being born before term). Because the researchers defined morbidity using routine health center attendances and self-report of illnesses by parents, this outcome does not seem to have been as useful as the others in differentiating between the preterm and term babies. Better means of measuring morbidity are needed in this setting.
In the developed world, there is considerable investment being made to improve care during pregnancy and in the neonatal period. This investment in care may help by predicting which mothers are more likely to give birth early and preventing preterm birth through drug or other treatments. It is to be hoped that some of the benefit will be transferable to low-income countries. A baby born at 26 weeks' gestation and admitted to a neonatal unit in the United Kingdom has a 67% chance of survival; preterm babies born in sub-Saharan Africa face a starkly contrasting future.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001121.
UNICEF presents useful statistics on mother and child outcomes
The World Health Organization has attempted to analyse preterm birth rates worldwide, including mapping the regional distribution and has also produced practical guides on strategies such as Kangaroo Mother Care, which can be used for the care of preterm infants in low resource settings
Healthy Newborn Network has good information on initiatives taking place to improve neonatal outcomes in low income settings
The March of Dimes, a nonprofit organization for pregnancy and baby health, provides information on research being conducted into preterm birth
Tommy's is a nonprofit organization that funds research and provides information on the risks and causes of premature birth
doi:10.1371/journal.pmed.1001121
PMCID: PMC3210771  PMID: 22087079
3.  The Effect of Changing Patterns of Obstetric Care in Scotland (1980–2004) on Rates of Preterm Birth and Its Neonatal Consequences: Perinatal Database Study 
PLoS Medicine  2009;6(9):e1000153.
Jane Norman and colleagues analyzed linked perinatal surveillance data in Scotland and find that between 1980 and 2004 increases in spontaneous and medically induced preterm births contributed equally to the rising rate of preterm births.
Background
Rates of preterm birth are rising worldwide. Studies from the United States and Latin America suggest that much of this rise relates to increased rates of medically indicated preterm birth. In contrast, European and Australian data suggest that increases in spontaneous preterm labour also play a role. We aimed, in a population-based database of 5 million people, to determine the temporal trends and obstetric antecedents of singleton preterm birth and its associated neonatal mortality and morbidity for the period 1980–2004.
Methods and Findings
There were 1.49 million births in Scotland over the study period, of which 5.8% were preterm. We found a percentage increase in crude rates of both spontaneous preterm birth per 1,000 singleton births (10.7%, p<0.01) and medically indicated preterm births (41.2%, p<0.01), which persisted when adjusted for maternal age at delivery. The greater proportion of spontaneous preterm births meant that the absolute increase in rates of preterm birth in each category were similar. Of specific maternal complications, essential and pregnancy-induced hypertension, pre-eclampsia, and placenta praevia played a decreasing role in preterm birth over the study period, with gestational and pre-existing diabetes playing an increasing role. There was a decline in stillbirth, neonatal, and extended perinatal mortality associated with preterm birth at all gestation over the study period but an increase in the rate of prolonged hospital stay for the neonate. Neonatal mortality improved in all subgroups, regardless of obstetric antecedent of preterm birth or gestational age. In the 28 wk and greater gestational groups we found a reduction in stillbirths and extended perinatal mortality for medically induced but not spontaneous preterm births (in the absence of maternal complications) although at the expense of a longer stay in neonatal intensive care. This improvement in stillbirth and neonatal mortality supports the decision making behind the 34% increase in elective/induced preterm birth in these women. Although improvements in neonatal outcomes overall are welcome, preterm birth still accounts for over 66% of singleton stillbirths, 65% of singleton neonatal deaths, and 67% of infants whose stay in the neonatal unit is “prolonged,” suggesting this condition remains a significant contributor to perinatal mortality and morbidity.
Conclusions
In our population, increases in spontaneous and medically induced preterm births have made equal contributions to the rising rate of preterm birth. Despite improvements in related perinatal mortality, preterm birth remains a major obstetric and neonatal problem, and its frequency is increasing.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Most pregnancies last about 40 weeks but increasing numbers of babies are being born preterm, before they reach 37 weeks of gestation (gestation is the period during which a baby develops in its mother). Nowadays in the US, for example, more than half a million babies arrive earlier than expected every year (1 in 8 babies). Although improvements in the care of newborn babies (neonatal care) mean that preterm babies are more likely to survive than in the past, preterm birth remains the single biggest cause of infant death in many developed countries, and many preterm babies who survive have long-term health problems and disabilities, particularly those born before 32 weeks of gestation. Preterm births can be spontaneous or medically induced. At present, it impossible to predict which mothers will spontaneously deliver early and there is no effective way to prevent these preterm births; medically induced early labor is undertaken when either the unborn baby or mother would be at risk if the pregnancy continued to full term.
Why Was This Study Done?
Preterm birth rates need to be reduced, but before this can be done it is important to know how the causes of preterm birth, the numbers of preterm stillbirths, and the numbers of preterm babies who die at birth (neonatal deaths) or soon after (perinatal deaths) are changing with time. If, for example, the rise in preterm births is mainly due to an increase in medically induced labor and if this change in practice has reduced neonatal deaths, it would be unwise to try to reduce the preterm birth rate by discouraging medically induced preterm births. So far, data from the US and Latin America suggest that the increase in preterm births in these countries is solely due to increased rates of medically induced preterm births. However, in Europe and Australia, the rate of spontaneous preterm births also seems to be increasing. In this study, the researchers examine the trends over time and causes of preterm birth and of neonatal death and illness in Scotland over a 25-year period.
What Did the Researchers Do and Find?
By searching a Scottish database of linked maternity records and infant health and death records, the researchers identified 1.49 million singleton births that occurred between 1980 and 2004 of which nearly 90,000 were preterm births. Over the study period, the rates of spontaneous and of medically induced preterm births per 1,000 births increased by 10.7% and 41.2%, respectively, but because there were more spontaneous preterm births than medically induced preterm births, the absolute increase in the rates of each type of birth was similar. Several maternal complications including preeclampsia (a condition that causes high blood pressure) and placenta previa (covering of the opening of the cervix by the placenta) played a decreasing role in preterm births over the study period, whereas gestational and preexisting diabetes played an increasing role. Finally, there was a decline in stillbirths and in neonatal and perinatal deaths among preterm babies, although more babies remained in the hospital longer than 7 days after birth. More specifically, after 28 weeks of gestation, stillbirths and perinatal deaths decreased among medically induced preterm births but not among spontaneous preterm births.
What Do These Findings Mean?
These findings indicate that in Scotland between 1980 and 2004, increases in spontaneous and medically induced preterm births contributed equally to the rising rate of preterm births. Importantly, they also show that the increase in induced preterm births helped to reduce stillbirths and neonatal and perinatal deaths, a finding that supports the criteria that clinicians currently use to decide whether to induce an early birth. Nevertheless, preterm births still account for two-thirds of all stillbirths, neonatal deaths, and extended neonatal stays in hospital and thus cause considerable suffering and greatly increase the workload in neonatal units. The rates of such births consequently need to be reduced and, for Scotland at least, ways will have to be found to reduce the rates of both spontaneous and induced preterm births to achieve this goal while continuing to identify those sick babies who need to be delivered early to give them the best chance of survival.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000153
Tommys is a nonprofit organization that funds research and provides information on the causes and prevention of miscarriage, premature birth, and stillbirth
The March of Dimes, a nonprofit organization for pregnancy and baby health, provides information on preterm birth (in English and Spanish)
The Nemours Foundation, another nonprofit organization for child health, also provides information on premature babies (in English and Spanish)
The US Centers for Disease Control and Prevention provides information on maternal and infant health (in English and Spanish)
The US National Women's Health Information Center has detailed information about pregnancy, including a section on pregnancy complications
MedlinePlus provides links to other information on premature babies and to information on pregnancy (in English and Spanish)
doi:10.1371/journal.pmed.1000153
PMCID: PMC2740823  PMID: 19771156
4.  Birth Outcome in Women with Previously Treated Breast Cancer—A Population-Based Cohort Study from Sweden 
PLoS Medicine  2006;3(9):e336.
Background
Data on birth outcome and offspring health after the appearance of breast cancer are limited. The aim of this study was to assess the risk of adverse birth outcomes in women previously treated for invasive breast cancer compared with the general population of mothers.
Methods and Findings
Of all 2,870,932 singleton births registered in the Swedish Medical Birth Registry during 1973–2002, 331 first births following breast cancer surgery—with a mean time to pregnancy of 37 mo (range 7–163)—were identified using linkage with the Swedish Cancer Registry.
Logistic regression analysis was used. The estimates were adjusted for maternal age, parity, and year of delivery. Odds ratios (ORs) and 95% confidence intervals (CIs) were used to estimate infant health and mortality, delivery complications, the risk of preterm birth, and the rates of instrumental delivery and cesarean section.
The large majority of births from women previously treated for breast cancer had no adverse events. However, births by women exposed to breast cancer were associated with an increased risk of delivery complications (OR 1.5, 95% CI 1.2–1.9), cesarean section (OR 1.3, 95% CI 1.0–1.7), very preterm birth (<32 wk) (OR 3.2, 95% CI 1.7–6.0), and low birth weight (<1500 g) (OR 2.9, 95% CI 1.4–5.8). A tendency towards an increased risk of malformations among the infants was seen especially in the later time period (1988–2002) (OR 2.1, 95% CI 1.2–3.7).
Conclusions
It is reassuring that births overall were without adverse events, but our findings indicate that pregnancies in previously treated breast cancer patients should possibly be regarded as higher risk pregnancies, with consequences for their surveillance and management.
The large majority of births from women previously treated for breast cancer had no adverse events, but such pregnancies might benefit from increased surveillance and management.
Editors' Summary
Background.
More women of all ages are developing breast cancer than ever before. In the US, one woman in eight will now develop this disease during her lifetime. For most of these women, their breast cancer diagnosis will come late in life, but a fifth of breast cancers are diagnosed before the age of 50. These days, the long-term outlook for women with breast cancer is quite good; 80% of women who receive a diagnosis of breast cancer survive more than five years. These figures, together with a trend towards starting families later in life—since the late 1970s birth rates for women in their late 30s and 40s have more than doubled in the US, and in Sweden the average age for having a first baby is now 29 years—mean that many women who have had breast cancer want to have children. One estimate is that up to 7% of women who are fertile after treatment for breast cancer will later have children.
Why Was This Study Done?
Pregnancy seems to have no adverse affects on women who have had breast cancer—there is no evidence that pregnancy can trigger a relapse. However, little is known about whether the chemotherapy and radiotherapy used to treat breast cancer have any long-lasting effects that might result in a poor birth outcome such as stillbirth, low birth weight, premature delivery, or abnormalities in the baby (congenital abnormalities). In this study, the researchers assessed the risk of adverse birth outcomes in women previously treated for breast cancer in Sweden.
What Did the Researchers Do and Find?
Nearly three million singleton births that occurred between 1973 and 2002 are recorded in the Swedish Medical Birth Registry. The researchers linked this information with that in the Swedish Cancer Registry to identify 331 first births after treatment for invasive breast cancer (cancer that has spread from where it started to grow in the breast). The birth registry includes details on maternal age and health, child's birth weight, whether the delivery was preterm, and whether the child had any congenital abnormalities, so the researchers were able to compare birth outcomes in these 331 births with those in the general population. They discovered that most births after breast cancer treatment went smoothly. There was no increase in stillbirths, but there were slightly more delivery complications in the women who had had breast cancer than in the general population, and a slight increase in babies born prematurely or with low birth weight. Finally, a few more babies with congenital abnormalities were born to women after breast cancer treatment than to women in the general population.
What Do These Findings Mean?
Overall, these results should reassure women who are thinking about having children after breast cancer about the health of their future offspring. However, they do suggest that these women may need careful monitoring during late pregnancy and delivery. This result was not predicted by the researchers who performed the study. Before starting the study, they thought that there would be no difference in birth outcomes between patients previously treated for breast cancer and the general population. Furthermore, a recently published similar study in Denmark found no increased risk of preterm birth, low birth weight, or congenital abnormalities after breast cancer. Differences between the two countries in the accuracy of their registries or in the use of chemotherapy and radiotherapy treatments may account for this difference in results. Additional studies are now needed in other populations to resolve this discrepancy and to provide more information about how breast cancer treatment might affect birth outcomes. For example, the current study did not provide any information about whether specific chemotherapy regimens or different types of breast cancer might put women at a higher risk of adverse birth outcomes, or whether the time between the cancer diagnosis and treatment and the pregnancy made a difference.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0030336.
MedlinePlus encyclopedia entry on breast cancer
National Cancer Institute information for patients and physicians on breast cancer, including links to pages on breast cancer and pregnancy
Cancer Research UK's information on breast cancer for patients, and statistics on breast cancer in the UK
• Wikipedia page on breast cancer (note: Wikipedia is a free online encyclopedia that anyone can edit)
Royal College of Obstetricians and Gynaecologists guidelines for physicians on pregnancy and breast cancer
doi:10.1371/journal.pmed.0030336
PMCID: PMC1564170  PMID: 16968117
5.  The APPLe Study: A Randomized, Community-Based, Placebo-Controlled Trial of Azithromycin for the Prevention of Preterm Birth, with Meta-Analysis 
PLoS Medicine  2009;6(12):e1000191.
In a randomized trial in Malawi of azithromycin versus placebo in over 2,000 pregnant women, Jim Neilson and colleagues show no benefit of azithromycin for a number of outcomes including preterm birth and prenatal death.
Background
Premature birth is the major cause of perinatal mortality and morbidity in both high- and low-income countries. The causes of preterm labour are multiple but infection is important. We have previously described an unusually high incidence of preterm birth (20%) in an ultrasound-dated, rural, pregnant population in Southern Malawi with high burdens of infective morbidity. We have now studied the impact of routine prophylaxis with azithromycin as directly observed, single-dose therapy at two gestational windows to try to decrease the incidence of preterm birth.
Methods and Findings
We randomized 2,297 pregnant women attending three rural and one peri-urban health centres in Southern Malawi to a placebo-controlled trial of oral azithromycin (1 g) given at 16–24 and 28–32 wk gestation. Gestational age was determined by ultrasound before 24 wk. Women and their infants were followed up until 6 wk post delivery. The primary outcome was incidence of preterm delivery, defined as <37 wk. Secondary outcomes were mean gestational age at delivery, perinatal mortality, birthweight, maternal malaria, and anaemia. Analysis was by intention to treat. There were no significant differences in outcome between the azithromycin group (n = 1,096) and the placebo group (n = 1,087) in respect of preterm birth (16.8% versus 17.4%), odds ratio (OR) 0.96, 95% confidence interval (0.76–1.21); mean gestational age at delivery (38.5 versus 38.4 weeks), mean difference 0.16 (−0.08 to 0.40); mean birthweight (3.03 versus 2.99 kg), mean difference 0.04 (−0.005 to 0.08); perinatal deaths (4.3% versus 5.0%), OR 0.85 (0.53–1.38); or maternal malarial parasitaemia (11.5% versus 10.1%), OR 1.11 (0.84–1.49) and anaemia (44.1% versus 41.3%) at 28–32 weeks, OR 1.07 (0.88–1.30). Meta-analysis of the primary outcome results with seven other studies of routine antibiotic prophylaxis in pregnancy (>6,200 pregnancies) shows no effect on preterm birth (relative risk 1.02, 95% confidence interval 0.86–1.22).
Conclusions
This study provides no support for the use of antibiotics as routine prophylaxis to prevent preterm birth in high risk populations; prevention of preterm birth requires alternative strategies.
Trial registration
Current Controlled Trials ISRCTN84023116
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Most pregnancies last about 40 weeks. Labor that occurs before 37 weeks of gestation (the period during which a baby develops in its mother) is defined as a preterm birth. In industrialized countries, 5%–10% of all births are preterm. Figures for preterm births are harder to obtain for low-income countries because of uncertainties about gestational dates but, in both rich and poor countries, preterm birth is a major cause of infant death and illness around the time of birth. Babies who are born prematurely also often have long-term health problems and disabilities. There are many reasons why some babies are born prematurely. Structural problems such as a weak cervix (the neck of the womb, which dilates during labor to allow the baby to leave the mother's body) can result in a premature delivery, as can pregnancy-induced diabetes, blood-clotting disorders, bacterial infections in the vagina or the womb, and malaria. However, it is impossible to predict which mothers will spontaneously deliver early.
Why Was This Study Done?
At present there is no effective way to prevent premature births. Because infection is often associated with preterm labor and can occur early in pregnancy but remain undetected, one way to reduce the incidence of preterm births may be to give pregnant women antibiotics even when they have no obvious infection (prophylactic antibiotics). In this study, the researchers test this hypothesis by giving the antibiotic azithromycin to pregnant women living in Southern Malawi in a randomized, placebo-controlled trial. One baby in five is born before 37 weeks gestation in Southern Malawi and the women living in this part of sub-Saharan Africa have a high burden of infection. Azithromycin is a safe antibiotic that can treat many of the bacterial infections that have been implicated in preterm birth. It also has some antimalarial activity. In a randomized, placebo-controlled trial, participants are randomly assigned to receive a drug or identical-looking “dummy” tablets (placebo).
What Did the Researchers Do and Find?
The researchers enrolled more than 2,000 pregnant women into the APPLe study (Azithromycin for the Prevention of Preterm Labor) and determined the gestational age of their unborn babies using ultrasound. Half of the women were given an oral dose of azithromycin at 16–24 weeks and at 28–32 weeks gestation. The remaining women were given a placebo at similar times. The mothers and their babies were followed up until 6 weeks after delivery. There was no significant difference in the primary outcome of the study—the incidence of delivery before 37 weeks gestation—between the two groups of women. Secondary outcomes—including mean gestational age at delivery, mean birth weight, and still births and infant deaths within a week of birth—were also similar in the two groups of women. Finally, the researchers did a meta-analysis (a statistical technique that combines the results of several studies) of their study and seven published studies of routine antibiotic prophylaxis in pregnancy, which indicated that the prophylactic use of antibiotics did not alter the risk of preterm birth.
What Do These Findings Mean?
These findings provide no support for the use of antibiotics as prophylaxis to prevent preterm birth. The women included in this study had an unusually high incidence of preterm delivery and a high burden of infection so these findings may not be generalizable. The results of the meta-analysis, however, also provide no support for prophylactic antibiotics. Given that observational data have associated infection with preterm labor, why are the results of the APPLe trial and the meta-analysis negative? One possibility is that different antibiotics or dosing regimens might be more effective. Another possibility is that infection might be a secondary consequence of some other condition that causes preterm birth rather than the primary cause of early delivery. Whatever the reason for the lack of effect of prophylactic antibiotics, the researchers recommend that pregnant women should not be given antibiotics prophylactically to prevent preterm birth particularly since, in a recent study, the babies of women given antibiotics to halt ongoing preterm labor had an increased risk of developmental problems.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000191.
The March of Dimes, a nonprofit organization for pregnancy and baby health, provides information on preterm birth (in English and Spanish)
The Nemours Foundation, another nonprofit organization for child health, also provides information on premature babies (in English and Spanish)
Tommy's is a nonprofit organization that funds research and provides information on the causes and prevention of miscarriage, premature birth, and stillbirth
The US Centers for Disease Control and Prevention provides information on maternal and infant health (in English and Spanish)
The US National Women's Health Information Center has detailed information about pregnancy (in English and Spanish)
MedlinePlus provides links to other information on premature babies (in English and Spanish)
doi:10.1371/journal.pmed.1000191
PMCID: PMC2776277  PMID: 19956761
6.  Genetic Markers of Adult Obesity Risk Are Associated with Greater Early Infancy Weight Gain and Growth 
PLoS Medicine  2010;7(5):e1000284.
Ken Ong and colleagues genotyped children from the ALSPAC birth cohort and showed an association between greater early infancy gains in weight and length and genetic markers for adult obesity risk.
Background
Genome-wide studies have identified several common genetic variants that are robustly associated with adult obesity risk. Exploration of these genotype associations in children may provide insights into the timing of weight changes leading to adult obesity.
Methods and Findings
Children from the Avon Longitudinal Study of Parents and Children (ALSPAC) birth cohort were genotyped for ten genetic variants previously associated with adult BMI. Eight variants that showed individual associations with childhood BMI (in/near: FTO, MC4R, TMEM18, GNPDA2, KCTD15, NEGR1, BDNF, and ETV5) were used to derive an “obesity-risk-allele score” comprising the total number of risk alleles (range: 2–15 alleles) in each child with complete genotype data (n = 7,146). Repeated measurements of weight, length/height, and body mass index from birth to age 11 years were expressed as standard deviation scores (SDS). Early infancy was defined as birth to age 6 weeks, and early infancy failure to thrive was defined as weight gain between below the 5th centile, adjusted for birth weight. The obesity-risk-allele score showed little association with birth weight (regression coefficient: 0.01 SDS per allele; 95% CI 0.00–0.02), but had an apparently much larger positive effect on early infancy weight gain (0.119 SDS/allele/year; 0.023–0.216) than on subsequent childhood weight gain (0.004 SDS/allele/year; 0.004–0.005). The obesity-risk-allele score was also positively associated with early infancy length gain (0.158 SDS/allele/year; 0.032–0.284) and with reduced risk of early infancy failure to thrive (odds ratio  = 0.92 per allele; 0.86–0.98; p = 0.009).
Conclusions
The use of robust genetic markers identified greater early infancy gains in weight and length as being on the pathway to adult obesity risk in a contemporary birth cohort.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
The proportion of overweight and obese children is increasing across the globe. In the US, the Surgeon General estimates that, compared with 1980, twice as many children and three times the number of adolescents are now overweight. Worldwide, 22 million children under five years old are considered by the World Health Organization to be overweight.
Being overweight or obese in childhood is associated with poor physical and mental health. In addition, childhood obesity is considered a major risk factor for adult obesity, which is itself a major risk factor for cancer, heart disease, diabetes, osteoarthritis, and other chronic conditions.
The most commonly used measure of whether an adult is a healthy weight is body mass index (BMI), defined as weight in kilograms/(height in metres)2. However, adult categories of obese (>30) and overweight (>25) BMI are not directly applicable to children, whose BMI naturally varies as they grow. BMI can be used to screen children for being overweight and or obese but a diagnosis requires further information.
Why Was This Study Done?
As the numbers of obese and overweight children increase, a corresponding rise in future numbers of overweight and obese adults is also expected. This in turn is expected to lead to an increasing incidence of poor health. As a result, there is great interest among health professionals in possible pathways between childhood and adult obesity. It has been proposed that certain periods in childhood may be critical for the development of obesity.
In the last few years, ten genetic variants have been found to be more common in overweight or obese adults. Eight of these have also been linked to childhood BMI and/or obesity. The authors wanted to identify the timing of childhood weight changes that may be associated with adult obesity. Knowledge of obesity risk genetic variants gave them an opportunity to do so now, without following a set of children to adulthood.
What Did the Researchers Do and Find?
The authors analysed data gathered from a subset of 7,146 singleton white European children enrolled in the Avon Longitudinal Study of Parents and Children (ALSPAC) study, which is investigating associations between genetics, lifestyle, and health outcomes for a group of children in Bristol whose due date of birth fell between April 1991 and December 1992. They used knowledge of the children's genetic makeup to find associations between an obesity risk allele score—a measure of how many of the obesity risk genetic variants a child possessed—and the children's weight, height, BMI, levels of body fat (at nine years old), and rate of weight gain, up to age 11 years.
They found that, at birth, children with a higher obesity risk allele score were not any heavier, but in the immediate postnatal period they were less likely to be in the bottom 5% of the population for weight gain (adjusted for birthweight), often termed “failure to thrive.” At six weeks of age, children with a higher obesity risk allele score tended to be longer and heavier, even allowing for weight at birth.
After six weeks of age, the obesity risk allele score was not associated with any further increase in length/height, but it was associated with a more rapid weight gain between birth and age 11 years. BMI is derived from height and weight measurements, and the association between the obesity risk allele score and BMI was weak between birth and age three-and-a-half years, but after that age the association with BMI increased rapidly. By age nine, children with a higher obesity risk allele score tended to be heavier and taller, with more fat on their bodies.
What Do These Findings Mean?
The combined obesity allele risk score is associated with higher rates of weight gain and adult obesity, and so the authors conclude that weight gain and growth even in the first few weeks after birth may be the beginning of a pathway of greater adult obesity risk.
A study that tracks a population over time can find associations but it cannot show cause and effect. In addition, only a relatively small proportion (1.7%) of the variation in BMI at nine years of age is explained by the obesity risk allele score.
The authors' method of finding associations between childhood events and adult outcomes via genetic markers of risk of disease as an adult has a significant advantage: the authors did not have to follow the children themselves to adulthood, so their findings are more likely to be relevant to current populations. Despite this, this research does not yield advice for parents how to reduce their children's obesity risk. It does suggest that “failure to thrive” in the first six weeks of life is not simply due to a lack of provision of food by the baby's caregiver but that genetic factors also contribute to early weight gain and growth.
The study looked at the combined obesity risk allele score and the authors did not attempt to identify which individual alleles have greater or weaker associations with weight gain and overweight or obesity. This would require further research based on far larger numbers of babies and children. The findings may also not be relevant to children in other types of setting because of the effects of different nutrition and lifestyles.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000284.
Further information is available on the ALSPAC study
The UK National Health Service and other partners provide guidance on establishing a healthy lifestyle for children and families in their Change4Life programme
The International Obesity Taskforce is a global network of expertise and the advocacy arm of the International Association for the Study of Obesity. It works with the World Health Organization, other NGOs, and stakeholders and provides information on overweight and obesity
The Centers for Disease Control and Prevention (CDC) in the US provide guidance and tips on maintaining a healthy weight, including BMI calculators in both metric and Imperial measurements for both adults and children. They also provide BMI growth charts for boys and girls showing how healthy ranges vary for each sex at with age
The Royal College of Paediatrics and Child Health provides growth charts for weight and length/height from birth to age 4 years that are based on WHO 2006 growth standards and have been adapted for use in the UK
The CDC Web site provides information on overweight and obesity in adults and children, including definitions, causes, and data
The CDC also provide information on the role of genes in causing obesity.
The World Health Organization publishes a fact sheet on obesity, overweight and weight management, including links to childhood overweight and obesity
Wikipedia includes an article on childhood obesity (note that Wikipedia is a free online encyclopedia that anyone can edit; available in several languages)
doi:10.1371/journal.pmed.1000284
PMCID: PMC2876048  PMID: 20520848
7.  Increased Birth Weight Associated with Regular Pre-Pregnancy Deworming and Weekly Iron-Folic Acid Supplementation for Vietnamese Women 
Background
Hookworm infections are significant public health issues in South-East Asia. In women of reproductive age, chronic hookworm infections cause iron deficiency anaemia, which, upon pregnancy, can lead to intrauterine growth restriction and low birth weight. Low birth weight is an important risk factor for neonatal and infant mortality and morbidity.
Methodology
We investigated the association between neonatal birth weight and a 4-monthly deworming and weekly iron-folic acid supplementation program given to women of reproductive age in north-west Vietnam. The program was made available to all women of reproductive age (estimated 51,623) in two districts in Yen Bai Province for 20 months prior to commencement of birth weight data collection. Data were obtained for births at the district hospitals of the two intervention districts as well as from two control districts where women did not have access to the intervention, but had similar maternal and child health indicators and socio-economic backgrounds. The primary outcome was low birth weight.
Principal Findings
The birth weights of 463 infants born in district hospitals in the intervention (168) and control districts (295) were recorded. Twenty-six months after the program was started, the prevalence of low birth weight was 3% in intervention districts compared to 7.4% in control districts (adjusted odds ratio 0.29, 95% confidence interval 0.10 to 0.81, p = 0.017). The mean birth weight was 124 g (CI 68 - 255 g, p<0.001) greater in the intervention districts compared to control districts.
Conclusions/Significance
The findings of this study suggest that providing women with regular deworming and weekly iron-folic acid supplements before pregnancy is associated with a reduced prevalence of low birth weight in rural Vietnam. The impact of this health system-integrated intervention on birth outcomes should be further evaluated through a more extensive randomised-controlled trial.
Author Summary
Low birth weight is an important risk factor for neonatal and infant morbidity and mortality and may impact on growth and development. Maternal iron deficiency anaemia contributes to intrauterine growth restriction and low birth weight. Hookworm infections and an iron-depleted diet may lead to iron deficiency anaemia, and both are common in many developing countries. A pilot program of deworming and weekly iron-folic acid supplementation for non-pregnant women aiming to prevent iron deficiency was implemented in northern Vietnam. We compared the birth weight of babies born to women who had had access to the intervention to babies born in districts where the intervention had not been implemented. The mean birth weight of the intervention districts' babies was 124 g more than the control districts' babies; the prevalence of low birth weight was also reduced. These results suggest that providing women with deworming and weekly iron-folic acid supplements before pregnancy is associated with increased birth weight in rural Vietnam. This intervention was provided as a health system integrated program which could be replicated in other at-risk rural areas. If so it could increase the impact of prenatal and antenatal programs, improving the health of both women and newborns.
doi:10.1371/journal.pntd.0001608
PMCID: PMC3317901  PMID: 22509421
8.  Pregnancy Weight Gain and Childhood Body Weight: A Within-Family Comparison 
PLoS Medicine  2013;10(10):e1001521.
David Ludwig and colleagues examine the within-family relationship between pregnancy weight gain and the offspring's childhood weight gain, thereby reducing the influence of genes and environment.
Please see later in the article for the Editors' Summary
Background
Excessive pregnancy weight gain is associated with obesity in the offspring, but this relationship may be confounded by genetic and other shared influences. We aimed to examine the association of pregnancy weight gain with body mass index (BMI) in the offspring, using a within-family design to minimize confounding.
Methods and Findings
In this population-based cohort study, we matched records of all live births in Arkansas with state-mandated data on childhood BMI collected in public schools (from August 18, 2003 to June 2, 2011). The cohort included 42,133 women who had more than one singleton pregnancy and their 91,045 offspring. We examined how differences in weight gain that occurred during two or more pregnancies for each woman predicted her children's BMI and odds ratio (OR) of being overweight or obese (BMI≥85th percentile) at a mean age of 11.9 years, using a within-family design. For every additional kg of pregnancy weight gain, childhood BMI increased by 0.0220 (95% CI 0.0134–0.0306, p<0.0001) and the OR of overweight/obesity increased by 1.007 (CI 1.003–1.012, p = 0.0008). Variations in pregnancy weight gain accounted for a 0.43 kg/m2 difference in childhood BMI. After adjustment for birth weight, the association of pregnancy weight gain with childhood BMI was attenuated but remained statistically significant (0.0143 kg/m2 per kg of pregnancy weight gain, CI 0.0057–0.0229, p = 0.0007).
Conclusions
High pregnancy weight gain is associated with increased body weight of the offspring in childhood, and this effect is only partially mediated through higher birth weight. Translation of these findings to public health obesity prevention requires additional study.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Childhood obesity has become a worldwide epidemic. For example, in the United States, the number of obese children has more than doubled in the past 30 years. 7% of American children aged 6–11 years were obese in 1980, compared to nearly 18% in 2010. Because of the rising levels of obesity, the current generation of children may have a shorter life span than their parents for the first time in 200 years.
Childhood obesity has both immediate and long-term effects on health. The initial problems are usually psychological. Obese children often experience discrimination, leading to low self-esteem and depression. Their physical health also suffers. They are more likely to be at risk of cardiovascular disease from high cholesterol and high blood pressure. They may also develop pre-diabetes or diabetes type II. In the long-term, obese children tend to become obese adults, putting them at risk of premature death from stroke, heart disease, or cancer.
There are many factors that lead to childhood obesity and they often act in combination. A major risk factor, especially for younger children, is having at least one obese parent. The challenge lies in unravelling the complex links between the genetic and environmental factors that are likely to be involved.
Why Was This Study Done?
Several studies have shown that a child's weight is influenced by his/her mother's weight before pregnancy and her weight gain during pregnancy. An obese mother, or a mother who puts on more pregnancy weight than average, is more likely to have an obese child.
One explanation for the effects of pregnancy weight gain is that the mother's overeating directly affects the baby's development. It may change the baby's brain and metabolism in such a way as to increase the child's long-term risk of obesity. Animal studies have confirmed that the offspring of overfed rats show these kinds of physiological changes. However, another possible explanation is that mother and baby share a similar genetic make-up and environment so that a child becomes obese from inheriting genetic risk factors, and growing up in a household where being overweight is the norm.
The studies in humans that have been carried out to date have not been able to distinguish between these explanations. Some have given conflicting results. The aim of this study was therefore to look for evidence of links between pregnancy weight gain and children's weight, using an approach that would separate the impact of genetic and environmental factors from a direct effect on the developing baby.
What Did the Researchers Do and Find?
The researchers examined data from the population of the US state of Arkansas recorded between 2003 and 2011. They looked at the health records of over 42,000 women who had given birth to more than one child during this period. This gave them information about how much weight the women had gained during each of their pregnancies. The researchers also looked at the school records of the children, over 91,000 in total, which included the children's body mass index (BMI, which factors in both height and weight). They analyzed the data to see if there was a link between the mothers' pregnancy weight gain and the child's BMI at around 12 years of age. Most importantly, they looked at these links within families, comparing children born to the same mother. The rationale for this approach was that these children would share a similar genetic make-up and would have grown up in similar environments. By taking genetics and environment into account in this manner, any remaining evidence of an impact of pregnancy weight gain on the children's BMI would have to be explained by other factors.
The results showed that the amount of weight each mother gained in pregnancy predicted her children's BMI and the likelihood of her children being overweight or obese. For every additional kg the mother gained during pregnancy, the children's BMI increased by 0.022. The children of mothers who put on the most weight had a BMI that was on average 0.43 higher than the children whose mothers had put on the least weight.
The study leaves some questions unanswered, including whether the mother's weight before pregnancy makes a difference to their children's BMI. The researchers were not able to obtain these measurements, nor the weight of the fathers. There may have also been other factors that weren't measured that might explain the links that were found.
What Do These Findings Mean?
This study shows that mothers who gain excessive weight during pregnancy increase the risk of their child becoming obese. This appears to be partly due to a direct effect on the developing baby.
These results represent a significant public health concern, even though the impact on an individual basis is relatively small. They could contribute to several hundred thousand cases of childhood obesity worldwide. Importantly, they also suggest that some cases could be prevented by measures to limit excessive weight gain during pregnancy. Such an approach could prove effective, as most mothers will not want to damage their child's health, and might therefore be highly motivated to change their behavior. However, because inadequate weight gain during pregnancy can also adversely affect the developing fetus, it will be essential for women to receive clear information about what constitutes optimal weight gain during pregnancy.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001521.
The US Centers for Disease Control and Prevention provide Childhood Obesity Facts
The UK National Health Service article “How much weight will I put on during my pregnancy?” provides information on pregnancy and weight gain and links to related resources
doi:10.1371/journal.pmed.1001521
PMCID: PMC3794857  PMID: 24130460
9.  Clinical Benefits, Costs, and Cost-Effectiveness of Neonatal Intensive Care in Mexico 
PLoS Medicine  2010;7(12):e1000379.
Joshua Salomon and colleagues performed a cost-effectiveness analysis using health and economic outcomes following preterm birth in Mexico and showed that neonatal intensive care provided high value for the money in this setting.
Background
Neonatal intensive care improves survival, but is associated with high costs and disability amongst survivors. Recent health reform in Mexico launched a new subsidized insurance program, necessitating informed choices on the different interventions that might be covered by the program, including neonatal intensive care. The purpose of this study was to estimate the clinical outcomes, costs, and cost-effectiveness of neonatal intensive care in Mexico.
Methods and Findings
A cost-effectiveness analysis was conducted using a decision analytic model of health and economic outcomes following preterm birth. Model parameters governing health outcomes were estimated from Mexican vital registration and hospital discharge databases, supplemented with meta-analyses and systematic reviews from the published literature. Costs were estimated on the basis of data provided by the Ministry of Health in Mexico and World Health Organization price lists, supplemented with published studies from other countries as needed. The model estimated changes in clinical outcomes, life expectancy, disability-free life expectancy, lifetime costs, disability-adjusted life years (DALYs), and incremental cost-effectiveness ratios (ICERs) for neonatal intensive care compared to no intensive care. Uncertainty around the results was characterized using one-way sensitivity analyses and a multivariate probabilistic sensitivity analysis. In the base-case analysis, neonatal intensive care for infants born at 24–26, 27–29, and 30–33 weeks gestational age prolonged life expectancy by 28, 43, and 34 years and averted 9, 15, and 12 DALYs, at incremental costs per infant of US$11,400, US$9,500, and US$3,000, respectively, compared to an alternative of no intensive care. The ICERs of neonatal intensive care at 24–26, 27–29, and 30–33 weeks were US$1,200, US$650, and US$240, per DALY averted, respectively. The findings were robust to variation in parameter values over wide ranges in sensitivity analyses.
Conclusions
Incremental cost-effectiveness ratios for neonatal intensive care imply very high value for money on the basis of conventional benchmarks for cost-effectiveness analysis.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Most pregnancies last about 40 weeks but increasing numbers of babies are being born preterm, before they reach 37 weeks of gestation (the period during which a baby develops in its mother). In developed countries and some middle-income countries such as Mexico, improvements in the care of newborn babies (neonatal intensive care) mean that more preterm babies survive now than in the past. Nevertheless, preterm birth is still a major cause of infant death worldwide that challenges attainment of Target 5 of Millennium Development Goal 4—the reduction of the global under-five mortality rate by two-thirds of the 1990 rate by 2015 (the Millennium Development Goals, which were agreed by world leaders in 2000, aim to reduce world poverty). Furthermore, many preterm babies who survive have long-term health problems and disabilities such as cerebral palsy, deafness, or learning difficulties. The severity of these disabilities and their long-term costs to families and to society depend on the baby's degree of prematurity.
Why Was This Study Done?
Mexico recently reformed its health system in an effort to improve access to care, particularly for the poorest sections of its population, and to improve the quality of its health care. The central component of this health care reform is the System of Social Protection of Health (SSPH). The SSPH contains a family health insurance program—Seguro Popular—that aims to provide the 50 million uninsured people living in Mexico with free access to an explicit set of health care interventions. As with any insurance program, decisions have to be made about which interventions Seguro Poplar should cover. Should neonatal intensive care be covered, for example? Do the benefits of this intervention (increased survival of babies) outweigh the costs of neonatal care and of long-term care for survivors with disabilities? In other words, is neonatal intensive care cost-effective? In this study, the researchers investigate this question by estimating the clinical benefits, costs, and cost-effectiveness of neonatal intensive care in Mexico.
What Did the Researchers Do and Find?
The researchers built a decision analytic model, a mathematical model that combines evidence on the outcomes and costs of alternative treatments to help inform decisions about health care policy. They gathered data about the health outcomes of preterm births in Mexico from registers of births and deaths and from hospital discharge databases, and estimated the costs of neonatal intensive care and long-term care for disabled survivors using data from the Mexican Ministry of Health and the World Health Organization. They then applied their model, which estimates changes in parameters such as life expectancy, lifetime costs, disability-adjusted life years (DALYs; one DALY represents the loss of a year of healthy life), and incremental cost-effectiveness ratios (ICERs; the additional cost expended for each DALY averted) for neonatal intensive care compared to no intensive care, to a group of 2 million infants. Neonatal intensive care for infants born at 24–26, 27–29, and 30–33 weeks gestation prolonged life expectancy by 28, 43, and 34 years and averted 9, 15, and 12 DALYs at incremental costs of US$11,000, US$10,000, and US$3000, respectively, compared to no intensive care. The ICERs of neonatal intensive care for babies born at these times were US$1200, US$700, and US$300 per DALY averted, respectively.
What Do These Findings Mean?
Interventions with ICERs of less than a country's per capita gross domestic product (GDP) are highly cost-effective; those with ICERs of 1–3 times the per capita GDP are potentially cost-effective. Mexico's per capita GDP in 2005 was approximately US$8,200. Thus, neonatal intensive care could provide exceptional value for money in Mexico (and maybe in other middle-income countries), even for very premature babies. The accuracy of these findings inevitably depends on the assumptions used to build the decision analytic model and on the accuracy of the data fed into it, but the findings were little changed by a wide range of alterations that the researchers made to the model. Importantly, however, this cost-effectiveness analysis focuses on health and economic consequences of different intervention choices, and does not capture all aspects of well-being. Decisions regarding neonatal intensive care will need to be based on a full consideration of all relevant factors, including ethical issues, and cost-effectiveness analyses should continue to be updated as new data emerge on health outcomes and costs associated with neonatal intensive care.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000379.
The March of Dimes, a nonprofit organization for pregnancy and baby health, provides information on preterm birth (in English and Spanish)
The Nemours Foundation, another nonprofit organization for child health, also provides information on premature babies (in English and Spanish)
MedlinePlus provides links to other information on premature babies (in English and Spanish)
The United Nations Childrens Fund (UNICEF) works for children's rights, survival, development and protection around the world; it provides information on Millennium Development Goal 4 and its Childinfo website provides detailed statistics about child survival and health (some information in several languages)
A PLoS Medicine Policy Forum by Núria Homedes and Antonio Ugalde discusses health care reforms in Mexico
doi:10.1371/journal.pmed.1000379
PMCID: PMC3001895  PMID: 21179496
10.  Predicting Live Birth, Preterm Delivery, and Low Birth Weight in Infants Born from In Vitro Fertilisation: A Prospective Study of 144,018 Treatment Cycles 
PLoS Medicine  2011;8(1):e1000386.
Using the HFEA database of all 144,018 live births in all IVF cycles in the UK between 2003 and 2007, Scott Nelson and Debbie Lawlor show that couple- and treatment-specific factors can be used to help predict successful outcome following IVF.
Background
The extent to which baseline couple characteristics affect the probability of live birth and adverse perinatal outcomes after assisted conception is unknown.
Methods and Findings
We utilised the Human Fertilisation and Embryology Authority database to examine the predictors of live birth in all in vitro fertilisation (IVF) cycles undertaken in the UK between 2003 and 2007 (n = 144,018). We examined the potential clinical utility of a validated model that pre-dated the introduction of intracytoplasmic sperm injection (ICSI) as compared to a novel model. For those treatment cycles that resulted in a live singleton birth (n = 24,226), we determined the associates of potential risk factors with preterm birth, low birth weight, and macrosomia. The overall rate of at least one live birth was 23.4 per 100 cycles (95% confidence interval [CI] 23.2–23.7). In multivariable models the odds of at least one live birth decreased with increasing maternal age, increasing duration of infertility, a greater number of previously unsuccessful IVF treatments, use of own oocytes, necessity for a second or third treatment cycle, or if it was not unexplained infertility. The association of own versus donor oocyte with reduced odds of live birth strengthened with increasing age of the mother. A previous IVF live birth increased the odds of future success (OR 1.58, 95% CI 1.46–1.71) more than that of a previous spontaneous live birth (OR 1.19, 95% CI 0.99–1.24); p-value for difference in estimate <0.001. Use of ICSI increased the odds of live birth, and male causes of infertility were associated with reduced odds of live birth only in couples who had not received ICSI. Prediction of live birth was feasible with moderate discrimination and excellent calibration; calibration was markedly improved in the novel compared to the established model. Preterm birth and low birth weight were increased if oocyte donation was required and ICSI was not used. Risk of macrosomia increased with advancing maternal age and a history of previous live births. Infertility due to cervical problems was associated with increased odds of all three outcomes—preterm birth, low birth weight, and macrosomia.
Conclusions
Pending external validation, our results show that couple- and treatment-specific factors can be used to provide infertile couples with an accurate assessment of whether they have low or high risk of a successful outcome following IVF.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Worldwide, more than 10% of couples are infertile. Sometimes there is no obvious reason for a couple's inability to have children but, for many couples, problems with their eggs or sperm prevent “fertilization”—the union of an egg and a sperm that leads, eventually, to the birth of a baby. Until recently, little could be done to help infertile couples. Then, on the 25 July 1978, the world's first “test-tube baby” was born. Since then, 4 million babies have been born through in vitro fertilization (IVF). In IVF, mature eggs are collected from the woman (or from an egg donor if the woman cannot make her own eggs) after a course of special hormones, and they are mixed in a dish with her partner's sperm. If her partner has a low sperm count or abnormal sperm, a single sperm can be injected directly into the egg in a procedure called intracytoplasmic sperm injection (ICSI), which became widely available in the mid 1990s, or sperm from a donor can be used. Finally, a number (depending on the country) of embryos (eggs that have begun to divide and develop) are put back into the woman where, hopefully, they will establish a successful pregnancy.
Why Was This Study Done?
Not every attempt at IVF is successful. In the US and the UK, IVF is successful in about a third of women under 35 years old but in only 5%–10% of women over the age of 40. It would be useful to have a way to predict the likelihood of a live birth after IVF for individual couples. Such a “prediction model” would facilitate patient counseling, clinical decision making, and the allocation of IVF resources. In this study, the researchers use information on IVF cycles collected by the Human Fertilisation and Embryology Authority (HFEA), which regulates IVF in the UK, to assess the extent to which the characteristics of infertile couples and the treatment they receive can be used to predict live birth after IVF. They also use these data to identify which factors are associated with preterm delivery, low birthweight, and macrosomia (the birth of an unusually large baby), three undesirable birth characteristics.
What Did the Researchers Do and Find?
Between 2003 and 2007, 163,425 IVF cycles were completed in the UK, 23.4% of which resulted in at least one live birth. The researchers used the data collected by the HFEA on 144,018 of these cycles (the other cycles had missing data) to develop a multivariable logistic regression prediction model (a type of statistical model) for the outcome of IVF. According to this model, a decreased chance of at least one live birth was associated with several factors including increasing maternal age, increasing duration of infertility, and the use of the woman's own oocytes. By contrast, a previous IVF live birth and the use of ICSI were associated with increased chances of success. Importantly, compared with an established multivariable prediction model, which was developed before the introduction of ICSI, the researchers' new prediction model predicted the chance of a live birth following IVF with greater accuracy. Finally, the researchers report that the chances of preterm and low birthweight after IVF were increased if donor eggs were required and ICSI was not used, that an increased risk of macrosomia was associated with increasing maternal age and with a history of previous live births, and that all three undesirable birth characteristics were associated with infertility due to cervical problems.
What Do These Findings Mean?
These findings indicate that couple- and treatment-specific factors can be used to provide infertile couples with an accurate assessment of whether they have a low or high chance of a successful outcome following IVF. The prediction model developed here provides a more accurate assessment of likely outcomes after IVF than a previously established model. Furthermore, because the new model considers the effect of ICSI on outcomes, it should be more useful in contemporary populations than the established model, which does not consider ICSI. However, before this new prediction model is used to guide clinical decisions and to counsel patients, it needs to be validated using independent IVF data. To facilitate the external validation of their model, the researchers are currently generating a free web-based prediction tool and iPhone application (IVFpredict).
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000386.
The Human Fertilisation and Embryology Authority provides information on IVF and IVF statistics for the UK
The UK National Health Service Choices website provides information for patients on infertility and on IVF
The American Pregnancy Association has information for patients on infertility and on IVF
MedlinePlus has links to further resources on infertility and IVF (in English and Spanish)
The history of the development of IVF is described on the Nobel Prize website
The prediction tool that was used in this study is at http://www.IVFpredict.com
doi:10.1371/journal.pmed.1000386
PMCID: PMC3014925  PMID: 21245905
11.  Effect of Facilitation of Local Maternal-and-Newborn Stakeholder Groups on Neonatal Mortality: Cluster-Randomized Controlled Trial 
PLoS Medicine  2013;10(5):e1001445.
Lars Åke Persson and colleagues conduct a cluster randomised control in northern Vietnam to analyze the effect of the activity of local community-based maternal-and-newborn stakeholder groups on neonatal mortality.
Please see later in the article for the Editors' Summary
Background
Facilitation of local women's groups may reportedly reduce neonatal mortality. It is not known whether facilitation of groups composed of local health care staff and politicians can improve perinatal outcomes. We hypothesised that facilitation of local stakeholder groups would reduce neonatal mortality (primary outcome) and improve maternal, delivery, and newborn care indicators (secondary outcomes) in Quang Ninh province, Vietnam.
Methods and Findings
In a cluster-randomized design 44 communes were allocated to intervention and 46 to control. Laywomen facilitated monthly meetings during 3 years in groups composed of health care staff and key persons in the communes. A problem-solving approach was employed. Births and neonatal deaths were monitored, and interviews were performed in households of neonatal deaths and of randomly selected surviving infants. A latent period before effect is expected in this type of intervention, but this timeframe was not pre-specified. Neonatal mortality rate (NMR) from July 2008 to June 2011 was 16.5/1,000 (195 deaths per 11,818 live births) in the intervention communes and 18.4/1,000 (194 per 10,559 live births) in control communes (adjusted odds ratio [OR] 0.96 [95% CI 0.73–1.25]). There was a significant downward time trend of NMR in intervention communes (p = 0.003) but not in control communes (p = 0.184). No significant difference in NMR was observed during the first two years (July 2008 to June 2010) while the third year (July 2010 to June 2011) had significantly lower NMR in intervention arm: adjusted OR 0.51 (95% CI 0.30–0.89). Women in intervention communes more frequently attended antenatal care (adjusted OR 2.27 [95% CI 1.07–4.8]).
Conclusions
A randomized facilitation intervention with local stakeholder groups composed of primary care staff and local politicians working for three years with a perinatal problem-solving approach resulted in increased attendance to antenatal care and reduced neonatal mortality after a latent period.
Trial registration
Current Controlled Trials ISRCTN44599712
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Over the past few years, there has been enormous international effort to meet the target set by Millennium Development Goal 4 to reduce the under-five child mortality rate by two-thirds and to reduce the number of maternal deaths by three-quarters, respectively, from the 1990 level by 2015. There has been some encouraging progress and according to the latest figures from the World Health Organization, in 2011, just under 7 million children aged under 5 years died, a fall of almost 3 million from a decade ago. However, currently, 41% of all deaths among children under the age of 5 years occur around birth and the first 28 days of life (perinatal and neonatal mortality). Simple interventions can substantially reduce neonatal deaths and there have been several international, national, and local efforts to implement effective care packages to help reduce the number of neonatal deaths.
Why Was This Study Done?
In order for these interventions to be most effective, it is important that the local community becomes involved. Community mobilization, especially through local women's groups, can empower women to prioritize specific interventions to help improve their own health and that of their baby. An alternative strategy might be to mobilize people who already have responsibility to promote health and welfare in society, such as primary care staff, village health workers, and elected political representatives. However, it is unclear if the activities of such stakeholder groups result in improved neonatal survival. So in this study from northern Vietnam, the researchers analyzed the effect of the activity of local maternal-and-newborn stakeholder groups on neonatal mortality.
What Did the Researchers Do and Find?
Between 2008 and 2011, the researchers conducted a cluster-randomized controlled trial in 90 communes within the Quang Ninh province of northeast of Vietnam: 44 communes were allocated to intervention and 46 to the control. The local women's union facilitated recruitment to the intervention, local stakeholder groups (Maternal and Newborn Health Groups), which comprised primary care staff, village health workers, women's union representatives, and the person with responsibility for health in the commune. The groups' role was to identify and prioritize local perinatal health problems and implement actions to help overcome these problems.
Over the three-year period, the Maternal and Newborn Health Groups in the 44 intervention communes had 1,508 meetings. Every year 15–27 unique problems were identified and addressed 94–151 times. The problem-solving processes resulted in an annual number of 19–27 unique actions that were applied 297–649 times per year. The top priority problems and actions identified by these groups dealt with antenatal care attendance, post-natal visits, nutrition and rest during pregnancy, home deliveries, and breast feeding. Neonatal mortality in the intervention group did not change over the first two years but showed a significant improvement in the third year. The three leading causes of death were prematurity/low birth-weight (36%), intrapartum-related neonatal deaths (30%), and infections (15%). Stillbirth rates were 7.4 per 1,000 births in the intervention arm and 9.0 per 1,000 births in the control arm. There was one maternal death in the intervention communes and four in the control communes and there was a significant improvement in antenatal care attendance in the intervention arm. However, there were no significant differences between the intervention and control groups of other outcomes, including tetanus immunization, delivery preparedness, institutional delivery, temperature control at delivery, early initiation of breastfeeding, or home visit of a midwife during the first week after delivery.
What Do These Findings Mean?
These findings suggest that local stakeholder groups comprised of primary care staff and local politicians using a problem-solving approach may help to reduce the neonatal mortality rate after three years of implementation (although the time period for an expected reduction in neonatal mortality was not specified before the trial started) and may also increase the rate of antenatal care attendance. However, the intervention had no effect on other important outcomes such as the rate of institutional delivery and breast feeding. This study used a novel approach of community-based activity that was implemented into the public sector system at low cost. A further reduction in neonatal deaths around delivery might be achieved by neonatal resuscitation training and home visits to the mother and her baby.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001445.
The World Health Organization provides comprehensive statistics on neonatal mortality
The Healthy Newborn Network has information on community interventions to help reduce neonatal mortality from around the world
doi:10.1371/journal.pmed.1001445
PMCID: PMC3653802  PMID: 23690755
12.  US Birth Weight/Gestational Age-Specific Neonatal Mortality: 1995–1997 Rates for Whites, Hispanics, and Blacks 
Pediatrics  2003;111(1):e61-e66.
Objective
In recent years, gains in neonatal survival have been most evident among very low birth weight, preterm, and low birth weight (LBW) infants. Most of the improvement in neonatal survival since the early 1980s seems to be the consequence of decreasing birth weight-specific mortality rates, which occurred during a period of increasing preterm and LBW rates. Although the decline in neonatal mortality has been widely publicized in the United States, research suggests that clinicians may still underestimate the chances of survival of an infant who is born too early or too small and may overestimate the eventuality of serious disability. So that clinicians may have current and needed ethnic- and race-specific estimates of the “chances” of early survival for newborn infants, we examined birth weight/gestational age-specific neonatal mortality rates for the 3 largest ethnic/racial groups in the United States: non-Hispanic whites, Hispanics, and non-Hispanic blacks. Marked racial variation in birth weight and gestational age-specific mortality has long been recognized, and growing concerns have been raised about ongoing and increasing racial disparities in pregnancy outcomes. Our purpose for this investigation was to provide an up-to-date national reference for birth weight/gestational age-specific neonatal mortality rates for use by clinicians in care decision making and discussions with parents.
Methods
The National Center for Health Statistics linked live birth-infant death cohort files for 1995–1997 were used for this study. Singleton live births to US resident mothers with a reported maternal ethnicity/race of non-Hispanic white, non-Hispanic black, or Hispanic (n = 10 610 715) were selected for analysis. Birth weight/gestational age-specific neonatal mortality rates were calculated using 250 g/2-week intervals for each ethnic/racial group.
Results
The overall neonatal mortality rates for whites, Hispanics, and blacks were 3.24, 3.45, and 8.16 neonatal deaths per 1000 live births, and the proportion of births <28 weeks was 0.35%, 0.45%, and 1.39%, respectively. Newborns who weighed <1500 g comprised <2.5% of all births in each racial/ethnic group but accounted for >50% of neonatal deaths. For whites, Hispanics, and blacks, >50% of newborns 24 to 25 weeks of gestational age survived. For most combinations of birth weights <3500 g and gestational ages of <37 weeks, the neonatal mortality rate was lowest among blacks, compared with whites or Hispanics. At these same gestational age/birth weight combinations, Hispanics have slightly lower mortality rates than whites. For combinations of birth weights >3500 g and gestational ages of 37 to 41 weeks, Hispanics had the lowest neonatal mortality rate. In these birth weight/gestational age combinations, where approximately two thirds of births occur, blacks had the highest neonatal mortality rate.
Conclusions
Compared with earlier reports, these data suggest that a substantial improvement in birth weight/gestational age-specific neonatal mortality has occurred in the United States. Regardless of ethnicity/race, the risk of a neonatal death does not exceed 50% (the suggested definition for the limit of viability), except for birth weights below 500 g and gestational ages <24 weeks. Notwithstanding, ethnic/racial variations in neonatal mortality rates continue to persist, both in overall rates and within birth weight/gestational age categories. Blacks continue to have higher proportions for preterm and LBW births, compared with either whites or Hispanics. At the same time, blacks experience lower risks of neonatal mortality for preterm and LBW infants, while having higher risks of mortality among term, postterm, normal birth weight, and macrosomic births.
doi:10.1542/peds.111.1.e61
PMCID: PMC1382183  PMID: 12509596
VLBW, very low birth weight; LBW, low birth weight; BG-NMR, birth weight/gestational age-specific neonatal mortality rate; NCHS, National Center for Health Statistics; LMP, last normal menstrual period
13.  Mothers' birth weight and survival of their offspring: population based study. 
BMJ : British Medical Journal  1997;314(7091):1376-1380.
OBJECTIVE: To test the hypothesis that a baby's survival is related to the mother's birth weight. DESIGN: Population based dataset for two generations. SETTING: Population registry in Norway. SUBJECTS: All birth records for women born in Norway since 1967 were linked to births during 1981-94, thereby forming 105104 mother-offspring units. MAIN OUTCOME MEASURES: Perinatal mortality specific for weight for offspring in groups of maternal birth weight (with 500 g categories in both). RESULTS: A mother's birth weight was strongly associated with the weight of her baby. Maternal birth weight was associated with perinatal survival of her baby only for mothers with birth weights under 2000 g. These mothers were more likely to lose a baby in the perinatal period (odds ratio 2.3, 95% confidence interval 1.4 to 3.7). Among mothers with a birth weight over 2000 g there was no overall association between mother's weight and infant survival. There was, however, a strong interaction between mother's birth weight, infant birth weight, and infant survival. Mortality among small babies was much higher for those whose mothers had been large at birth. For example, babies weighing 2500-2999 g had a threefold higher mortality if their mother's birth weight had been high (> or = 4000 g) than if the mother had been small (2500-2999 g). CONCLUSION: Mothers who weighed less than 2000 g at birth have a higher risk of losing their own babies. For mothers who weighed > or = 2000 g their birth weight provides a benchmark for judging the growth of their offspring. Babies who are small relative to their mother's birth weight are at increased risk of mortality.
PMCID: PMC2126647  PMID: 9161309
14.  Maternal Influenza Immunization and Reduced Likelihood of Prematurity and Small for Gestational Age Births: A Retrospective Cohort Study 
PLoS Medicine  2011;8(5):e1000441.
In an analysis of surveillance data from the state of Georgia (US), Saad Omer and colleagues show an association between receipt of influenza vaccination among pregnant women and reduced risk of premature births.
Background
Infections during pregnancy have the potential to adversely impact birth outcomes. We evaluated the association between receipt of inactivated influenza vaccine during pregnancy and prematurity and small for gestational age (SGA) births.
Methods and Findings
We conducted a cohort analysis of surveillance data from the Georgia (United States) Pregnancy Risk Assessment Monitoring System. Among 4,326 live births between 1 June 2004 and 30 September 2006, maternal influenza vaccine information was available for 4,168 (96.3%). The primary intervention evaluated in this study was receipt of influenza vaccine during any trimester of pregnancy. The main outcome measures were prematurity (gestational age at birth <37 wk) and SGA (birth weight <10th percentile for gestational age). Infants who were born during the putative influenza season (1 October–31 May) and whose mothers were vaccinated against influenza during pregnancy were less likely to be premature compared to infants of unvaccinated mothers born in the same period (adjusted odds ratio [OR] = 0.60; 95% CI, 0.38–0.94). The magnitude of association between maternal influenza vaccine receipt and reduced likelihood of prematurity increased during the period of at least local influenza activity (adjusted OR = 0.44; 95% CI, 0.26–0.73) and was greatest during the widespread influenza activity period (adjusted OR = 0.28; 95% CI, 0.11–0.74). Compared with newborns of unvaccinated women, newborns of vaccinated mothers had 69% lower odds of being SGA (adjusted OR = 0.31; 95% CI, 0.13–0.75) during the period of widespread influenza activity. The adjusted and unadjusted ORs were not significant for the pre-influenza activity period.
Conclusions
This study demonstrates an association between immunization with the inactivated influenza vaccine during pregnancy and reduced likelihood of prematurity during local, regional, and widespread influenza activity periods. However, no associations were found for the pre-influenza activity period. Moreover, during the period of widespread influenza activity there was an association between maternal receipt of influenza vaccine and reduced likelihood of SGA birth.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Maternal infections during pregnancy can have harmful effects on both mother and baby. For example, influenza is associated with increased morbidity and mortality among pregnant women compared to women who are not pregnant or who acquire influenza infection after delivery. And some respiratory infections, especially those that can cause maternal pneumonia such as influenza virus, are known to be associated with the baby being small—below the 10th percentile—for gestational age and with an increased risk of preterm birth—birth before 37 weeks of gestation. Previous studies have shown that inactivated influenza vaccination during pregnancy provides protection against influenza virus for both mother and baby. As there has been an increase in the rate of preterm birth the United States from 9.5% in 1981 to 12.8% in 2006, the impact of maternal influenza immunization on birth outcomes has important public health implications and is of particular interest during influenza pandemics.
Why Was This Study Done?
Given that maternal vaccination can protect babies from influenza virus, it is plausible that influenza vaccination in pregnancy could mitigate adverse birth outcomes such as prematurity and the baby being small for gestational age. The researchers of this study set out to evaluate this hypothesis by investigating whether there was an association between women receiving inactivated influenza vaccine during pregnancy and positive birth outcomes for their babies in the population of the state of Georgia, in the United States.
What Did the Researchers Do and Find?
The researchers conducted a retrospective cohort analysis of a large surveillance dataset (the Georgia Pregnancy Risk Assessment Monitoring System) to analyze the relationship between receipt of inactivated influenza vaccine during any trimester of pregnancy by mothers of infants born between June 1, 2004, and September 30, 2006, and their baby being premature or small for gestational age. The study period encompassed the 2004–2005 and 2005–2006 influenza seasons—the two most recent seasons for which the data were available. The researchers did a stratified analysis for the overall study period, and various periods during it, and also weighted their analysis to adjust for possible oversampling. They used logistic regression to evaluate the association of maternal influenza vaccine and (a) prematurity and (b) small for gestational age, and also used linear regression to evaluate the statistical significance of differences between vaccinated and unvaccinated women for mean gestational age at first antenatal visit and mean birth weight.
During the study period, 4,168 mother–baby pairs were included in the analysis. Local influenza activity was detected during 27 weeks (22.1%), and 578 women (14.9% [weighted]) had received the influenza vaccine during pregnancy, giving a vaccination coverage of 19.2% (weighted) among mothers of infants born during the assumed influenza season. In the study sample, 1,547 babies (10.6% [weighted]) were born premature, and 1,186 babies (11.2% [weighted]) were small for gestational age. Infants who were born during the assumed influenza season (October–May) and whose mothers were vaccinated against influenza during pregnancy were less likely to be premature than infants of unvaccinated mothers born in the same period, with an adjusted odds ratio of 0.60. The effect of maternal influenza vaccine on reducing prematurity was the highest for infants born during the period of widespread influenza activity, with 72% lower odds of prematurity in infants of vaccinated mothers than infants of unvaccinated mothers. Compared with newborns of unvaccinated women, babies of vaccinated mothers also had 69% lower odds of being small for gestational age during the period of widespread influenza activity, but the adjusted and unadjusted odd ratios were not significant for the pre-influenza activity period.
What Do These Findings Mean?
These results show that there was an association between maternal immunization with the inactivated influenza vaccine during pregnancy and reduced likelihood of prematurity during local, regional, and widespread influenza activity periods. In addition, during the period of widespread influenza activity there was an negative association between maternal receipt of influenza vaccine and small for gestational age birth.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000441.
More information about influenza vaccination during pregnancy is available from the World Health Organization and the UK National Health Service
More information about the Georgia Pregnancy Risk Assessment Monitoring System is also available
doi:10.1371/journal.pmed.1000441
PMCID: PMC3104979  PMID: 21655318
15.  Cause-specific neonatal mortality in a neonatal care unit in Northern Tanzania: a registry based cohort study 
BMC Pediatrics  2012;12:116.
Background
The current decline in under-five mortality shows an increase in share of neonatal deaths. In order to address neonatal mortality and possibly identify areas of prevention and intervention, we studied causes of admission and cause-specific neonatal mortality in a neonatal care unit at Kilimanjaro Christian Medical Centre (KCMC) in Tanzania.
Methods
A total of 5033 inborn neonates admitted to a neonatal care unit (NCU) from 2000 to 2010 registered at the KCMC Medical Birth Registry and neonatal registry were studied. Clinical diagnosis, gestational age, birth weight, Apgar score and date at admission and discharge were registered. Cause-specific of neonatal deaths were classified by modified Wigglesworth classification. Statistical analysis was performed in SPSS 18.0.
Results
Leading causes of admission were birth asphyxia (26.8%), prematurity (18.4%), risk of infection (16.9%), neonatal infection (15.4%), and birth weight above 4000 g (10.7%). Overall mortality was 10.7% (536 deaths). Leading single causes of death were birth asphyxia (n = 245, 45.7%), prematurity (n = 188, 35.1%), congenital malformations (n = 49, 9.1%), and infections (n = 46, 8.6%). Babies with birth weight below 2500 g constituted 29% of all admissions and 52.1% of all deaths. Except for congenital malformations, case fatality declined with increasing birth weight. Birth asphyxia was the most frequent cause of death in normal birth weight babies (n = 179/246, 73.1%) and prematurity in low birth weight babies (n = 178/188, 94.7%). The majority of deaths (n = 304, 56.7%) occurred within 24 hours, and 490 (91.4%) within the first week.
Conclusions
Birth asphyxia in normal birth weight babies and prematurity in low birth weight babies each accounted for one third of all deaths in this population. The high number of deaths attributable to birth asphyxia in normal birth weight babies suggests further studies to identify causal mechanisms. Strategies directed towards making obstetric and newborn care timely available with proper antenatal, maternal and newborn care support with regular training on resuscitation skills would improve child survival.
doi:10.1186/1471-2431-12-116
PMCID: PMC3469393  PMID: 22871208
Neonatal mortality; Neonatal deaths; Neonatal morbidity; Birth asphyxia; Prematurity; Causes of death
16.  The effects of birth weight and gender on neonatal mortality in north central Nigeria 
BMC Research Notes  2011;4:562.
Background
Worldwide 15.5% of neonates are born with low birth weight, 95.6% of them in the developing countries. Prematurity accounts for 10% of neonatal mortality globally. The purpose of this study was to evaluate the effects of birth weight and gender on neonatal outcome.
Findings
The data of 278 neonates managed in the Special Care Baby Unit (SCBU) of Jos University Teaching Hospital (JUTH) over a 2 year period from July 2006 to June 2008 were analyzed.
One hundred and fifty nine (57.2%) were males and 119(42.8%) females. There were 87(31.3%) preterm and 191 (68.7%) term babies. Twelve of the babies died. Seven (2.52%) and 5 (1.80%) being males and females respectively. The neonatal mortality rate by gender was not significant (p > 0.05). The neonatal mortality was 25.2 deaths per 1000 live births for boys and 18.0 for girls. The mean birth weights of the preterm and term babies were 1.88 ± 0.47 kg and 3.02 ± 0.50 kg respectively, with a mean gestational age of 30.62 ± 3.65 weeks and 38.29 ± 0.99 weeks respectively.
Eighty seven (31.3%) of the babies were of low birth weight, 188(67.6%) were of normal birth weight and 3(1.1%) high birth weight. Of the low birth weight babies, 6(2.2%) were term small for gestational age. Six (2.2%) of the preterm infants had normal birth weight.
Eleven of the babies that died were preterm low birth weight. The overall mortality rate was 4.32%. The birth weight specific mortality rate was 126 per 1000 for the preterm low birth weight and 5 per 1000 for the term babies. Birth weight unlike gender is a significant predictor of mortality, mortality being higher in neonates of <2.5 kg (OR = 0.04; 95% Cl 0.005-0.310, p = 0.002) (p = 0.453). Seven (58.3%) and 4(33.3%) of the pre-terms that died were appropriate and large for gestational age respectively. Gestational age is not a significant predictor of neonatal mortality (p = 0.595). Babies delivered at less than 37 weeks of gestation recorded a higher rate of mortality than those of 37 weeks and above (p = 0.000).
The subjects showed one or more major clinical indications for admission. The major clinical indications for the preterm and term babies were respectively as follows: neonatal sepsis 63(22.7%) and 124(44.6%); neonatal jaundice 32(11.1%) and 71(24.7%); malaria 9(3.1%) and 13(4.5%); birth asphyxia 3(1.0%) and 7(2.4%). Neonatal sepsis was a common denominator among the babies that died.
Conclusion
Birth weight unlike gender is a significant predictor of neonatal outcome
doi:10.1186/1756-0500-4-562
PMCID: PMC3279327  PMID: 22195995
Birth weight; Gender; Gestational age; Neonatal mortality; North central; Nigeria
17.  Disentangling the Effects of Risk Factors and Clinical Care on Subnational Variation in Early Neonatal Mortality in the United States 
PLoS ONE  2012;7(11):e49399.
Objective
Between 1990 and 2010, the U.S ranking in neonatal mortality slipped from 29th to 45th among countries globally. Substantial subnational variation in newborn mortality also exists. Our objective is to measure the extent to which trends and subnational variation in early neonatal mortality reflect differences in the prevalence of risk factors (gestational age and birth weight) compared to differences in clinical care.
Methods
Observational study using linked birth and death data for all births in the United States between 1996 and 2006. We examined health service area (HSA) level variation in the expected early neonatal mortality rate, based on gestational age (GA) and birth-weight (BW), and GA-BW adjusted mortality as a proxy for clinical care. We analyzed the relationship between selected health system indicators and GA-BW-adjusted mortality.
Results
The early neonatal death (ENND) rate declined 12% between 1996 and 2006 (2.39 to 2.10 per 1000 live births). This occurred despite increases in risk factor prevalence. There was significant HSA-level variation in the expected ENND rate (Rate Ratio: 0.73–1.47) and the GA-BW adjusted rate (Rate ratio: 0.63–1.68). Accounting for preterm volume (defined as <34 weeks), the number of neonatologist and NICU beds, 25.2% and 58.7% of the HSA-level variance in outcomes was explained among all births and very low birth weight babies, respectively.
Conclusion
Improvements in mortality could be realized through the expansion or reallocation of clinical neonatal resources, particularly in HSAs with a high volume of preterm births; however, prevention of preterm births and low-birth weight babies has a greater potential to improve newborn survival in the United States.
doi:10.1371/journal.pone.0049399
PMCID: PMC3498121  PMID: 23166659
18.  Recognition and home care of low birth weight neonates: a qualitative study of knowledge, beliefs and practices of mothers in Iganga-Mayuge Health and Demographic Surveillance Site, Uganda 
BMC Public Health  2014;14:546.
Background
Neonatal mortality has remained persistently high worldwide. In Uganda, neonatal deaths account for 50% of all infant deaths. Low birth weight is associated with a higher risk of death during the neonatal period. Failure to recognize low birth weight and inappropriate home care practices increase the risk of morbidity and mortality in this high risk group. This study explored mothers’ knowledge, beliefs and practices in recognising and providing home care for low birth weight babies.
Methods
The study was carried out in Eastern Uganda. In-depth interviews were conducted with sixteen mothers of small babies who delivered in health facilities (10) or at home (6) two months prior to the study. Interviews were conducted in mothers’ homes using the local language. Interviewer notes and audio recordings were transcribed and translated to English. Content analysis was done using Atlas-ti software.
Results
Recognition of low birth weight by mothers when a baby is not weighed was difficult. Mothers were aware of the causes of low birth weight though some mothers believed in the influence of supernatural powers. Mothers who delivered in hospital had better knowledge of appropriate home care practices for low birth weight babies compared to mothers who delivered at home or in a lower level health facility. Practices related to cord care and keeping the baby warm were good while poor practices were noted concerning initiation and exclusive breast feeding, and bathing the baby. Low birth weight was not appreciated as a danger sign in newborns and therefore mothers did not seek health care. Some mothers who initiated good care practices for low birth weight newborns in the facilities did not sustain them at home.
Conclusions
Recognition of low birth weight is still poor. This leads to inappropriate home care practices for these high risk newborns. Mothers’ knowledge and care practices can be improved through health education, and this should be extended to the community to reach mothers that deliver at home. Mechanisms to support mothers to sustain good practices should be put in place by taking advantage of existing village health teams and social support.
doi:10.1186/1471-2458-14-546
PMCID: PMC4064282  PMID: 24888464
19.  Proteomic Profiling of the Amniotic Fluid to Detect Inflammation, Infection, and Neonatal Sepsis 
PLoS Medicine  2007;4(1):e18.
Background
Proteomic analysis of amniotic fluid shows the presence of biomarkers characteristic of intrauterine inflammation. We sought to validate prospectively the clinical utility of one such proteomic profile, the Mass Restricted (MR) score.
Methods and Findings
We enrolled 169 consecutive women with singleton pregnancies admitted with preterm labor or preterm premature rupture of membranes. All women had a clinically indicated amniocentesis to rule out intra-amniotic infection. A proteomic fingerprint (MR score) was generated from fresh samples of amniotic fluid using surface-enhanced laser desorption ionization (SELDI) mass spectrometry. Presence or absence of the biomarkers of the MR score was interpreted in relationship to the amniocentesis-to-delivery interval, placental inflammation, and early-onset neonatal sepsis for all neonates admitted to the Newborn Special Care Unit (n = 104). Women with “severe” amniotic fluid inflammation (MR score of 3 or 4) had shorter amniocentesis-to-delivery intervals than women with “no” (MR score of 0) inflammation or even “minimal” (MR score of 1 or 2) inflammation (median [range] MR 3–4: 0.4 d [0.0–49.6 d] versus MR 1–2: 3.8 d [0.0–151.2 d] versus MR 0: 17.0 d [0.1–94.3 d], p < 0.001). Nonetheless, a “minimal” degree of inflammation was also associated with preterm birth regardless of membrane status. There was a significant association between the MR score and severity of histological chorioamnionitis (r = 0.599, p < 0.001). Furthermore, neonatal hematological indices and early-onset sepsis significantly correlated with the MR score even after adjusting for gestational age at birth (OR for MR 3–4: 3.3 [95% CI, 1.1 to 9.2], p = 0.03). When compared with other laboratory tests routinely used to diagnose amniotic fluid inflammation and infection, the MR score had the highest accuracy to detect inflammation (white blood cell count > 100 cells/mm3), whereas the combination of Gram stain and MR score was best for rapid prediction of intra-amniotic infection (positive amniotic fluid culture).
Conclusions
High MR scores are associated with preterm delivery, histological chorioamnionitis, and early-onset neonatal sepsis. In this study, proteomic analysis of amniotic fluid was shown to be the most accurate test for diagnosis of intra-amniotic inflammation, whereas addition of the MR score to the Gram stain provides the best combination of tests to rapidly predict infection.
Proteomic analysis of amniotic fluid in addition to a Gram stain provides the best combination of tests to rapidly predict intrauterine infection.
Editors' Summary
Background.
A preterm delivery, or premature birth, is normally defined as one that occurs before 37 weeks after the last menstrual cycle (an average pregnancy lasts around 40 weeks). Premature birth is fairly common, with around 12% of births in the US fitting this definition. However, it has serious consequences, being responsible for around 70% of infant deaths and other adverse outcomes for the baby. It is not clear in all cases what directly causes premature birth or how to identify cases in which mother and child are at greater risk of serious outcomes. Evidence from case-control and other studies strongly suggests that infections of the uterus, placenta, or genital tract are associated with, and are likely to directly cause, premature deliveries. Such infections, even if they are “subclinical” (that is, they do not directly cause signs or symptoms that the doctor or patient would notice) cause inflammation in the affected tissues. Hence, it's possible that particular proteins or other molecules could provide a “signature” that would allow the inflammation to be picked up at an early stage.
Why Was This Study Done?
If inflammation could be picked up early, this might help identify mothers at risk of having a preterm delivery, and even to pinpoint cases of very severe inflammation where the baby is more at risk of poor outcomes. The researchers involved in this study had already done previous work looking at protein profiles in the amniotic fluid (the liquid directly surrounding the developing fetus). They identified a set of four protein “markers” that were closely associated with inflammation in the amniotic fluid, and developed a score based on those proteins, which they termed the “Mass Restricted” (MR) score. The researchers showed that this score could accurately identify women at risk of preterm delivery. However, before using the protein marker score in clinical practice it is very important to really be sure it is a reliable diagnostic test for preterm birth and adverse outcomes resulting from preterm birth. Therefore the researchers wanted to find out whether MR scores were associated with the outcome of pregnancy; the presence of infection in the placenta, as detected through microscopic analysis of tissue; and sepsis (severe infection) in the newborn baby.
What Did the Researchers Do and Find?
The study was based on findings from pregnant women presenting at the Yale-New Haven Hospital with symptoms of premature labor, who were all followed up to the point of delivery of the baby. In all cases the decisions about how to manage the pregnancy (for example, whether to deliver the baby or attempt to delay birth) were made by the woman and her physician, not by any procedures laid out in the research study. A total of 169 women were recruited into the study and had a sample of amniotic fluid taken as part of their routine clinical management. The researchers then analyzed this fluid to calculate the protein MR score, to look for evidence of bacterial infection, and also carried out standard laboratory tests. After childbirth the placenta was examined under the microscope to look for any evidence of inflammation. Finally, all babies were checked for any evidence of sepsis. The researchers found that, in line with findings from their previous studies, women with a higher MR score gave birth sooner. There also seemed to be a close agreement between the MR score and evidence of inflammation in the placenta, once it was analyzed under the microscope after birth. Furthermore, mothers with a high MR score were more likely to give birth to babies with suspected or confirmed sepsis. The researchers then compared the usefulness of the MR score against other potential tests for inflammation. Of all the tests compared, the MR score seemed to be the most accurate in predicting inflammation.
What Do These Findings Mean?
This study showed that the MR score was closely associated with a number of different indicators of poor outcome in preterm birth. These outcomes included sooner deliveries, sepsis in the baby, and inflammation in the placenta. In future, the MR score may provide a useful test for recognizing women at risk of preterm delivery and babies at risk of poor outcome. However, further evaluation of the test will still need to be done before it could become a standard procedure in the clinic.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0040018.
Information from the US National Institutes of Health on premature babies
The March of Dimes is a US charity that funds research into prematurity
Information from Wikipedia about proteomics the area of research used to develop the protein score examined here (note: Wikipedia is an online encyclopedia that anyone can edit)
doi:10.1371/journal.pmed.0040018
PMCID: PMC1769412  PMID: 17227133
20.  Induction of Labor versus Expectant Management in Women with Preterm Prelabor Rupture of Membranes between 34 and 37 Weeks: A Randomized Controlled Trial 
PLoS Medicine  2012;9(4):e1001208.
In a randomized controlled trial David van der Ham and colleagues investigate induction of labor versus expectant management for women with preterm prelabor rupture of membranes.
Background
At present, there is insufficient evidence to guide appropriate management of women with preterm prelabor rupture of membranes (PPROM) near term.
Methods and Findings
We conducted an open-label randomized controlled trial in 60 hospitals in The Netherlands, which included non-laboring women with >24 h of PPROM between 34+0 and 37+0 wk of gestation. Participants were randomly allocated in a 1∶1 ratio to induction of labor (IoL) or expectant management (EM) using block randomization. The main outcome was neonatal sepsis. Secondary outcomes included mode of delivery, respiratory distress syndrome (RDS), and chorioamnionitis. Patients and caregivers were not blinded to randomization status. We updated a prior meta-analysis on the effect of both interventions on neonatal sepsis, RDS, and cesarean section rate.
From 1 January 2007 to 9 September 2009, 776 patients in 60 hospitals were eligible for the study, of which 536 patients were randomized. Four patients were excluded after randomization. We allocated 266 women (268 neonates) to IoL and 266 women (270 neonates) to EM. Neonatal sepsis occurred in seven (2.6%) newborns of women in the IoL group and in 11 (4.1%) neonates in the EM group (relative risk [RR] 0.64; 95% confidence interval [CI] 0.25 to 1.6). RDS was seen in 21 (7.8%, IoL) versus 17 neonates (6.3%, EM) (RR 1.3; 95% CI 0.67 to 2.3), and a cesarean section was performed in 36 (13%, IoL) versus 37 (14%, EM) women (RR 0.98; 95% CI 0.64 to 1.50). The risk for chorioamnionitis was reduced in the IoL group. No serious adverse events were reported.
Updating an existing meta-analysis with our trial results (the only eligible trial for the update) indicated RRs of 1.06 (95% CI 0.64 to 1.76) for neonatal sepsis (eight trials, 1,230 neonates) and 1.27 (95% CI 0.98 to 1.65) for cesarean section (eight trials, 1,222 women) for IoL compared with EM.
Conclusions
In women whose pregnancy is complicated by late PPROM, neither our trial nor the updated meta-analysis indicates that IoL substantially improves pregnancy outcomes compared with EM.
Trial registration
Current Controlled Trials ISRCTN29313500
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Most pregnancies last around 40 weeks, but in industrialized countries, 5%–10% of babies are born before 37 weeks of gestation (gestation is the period during which a baby develops in its mother's womb). Premature birth is a major cause of infant death in many developed countries, and preterm babies can also have short- and/or long-term health problems such as breathing problems, increased susceptibility to life-threatening infections, and learning and developmental disabilities. There are many reasons why some babies are born prematurely, but preterm prelabor rupture of the membranes (PPROM) accounts for 30%–40% of preterm deliveries. Inside the womb, the baby is held in a fluid-filled bag called the amniotic sac. The amniotic fluid cushions the baby, helps some of its organs develop, and protects both mother and baby from infection. The membranes that form the sac usually break at the start of labor (“water breaking”), but in PPROM, the membranes break before the baby is fully grown. PPROM increases the mother's risk of a womb infection called chorioamnionitis and the baby's risk of neonatal sepsis (blood infection), and can trigger early labor.
Why Was This Study Done?
There is currently no consensus on how to manage women whose membranes rupture between 34 and 37 weeks' gestation. Some guidelines recommend immediate induction of labor if PPROM occurs at or beyond 34 weeks' gestation. Others recommend that labor not be induced unless the mother develops signs of infection such as a high temperature or has not delivered her baby spontaneously by 37 weeks' gestation (expectant management). Before 34 weeks' gestation, expectant management is generally recommended. In this randomized controlled trial, the researchers compare the effects of induction of labor and of expectant management on the rate of neonatal sepsis (the proportion of babies that develop neonatal sepsis; the trial's primary outcome) and on secondary outcomes such as the rates of neonatal respiratory distress syndrome (RDS), cesarean section (surgical delivery), and chorioamnionitis in women with PPROM between 34 and 37 weeks' gestation. The researchers also undertake a meta-analysis of published trials on the effect of both interventions on pregnancy outcomes. A randomized controlled trial compares the effects of different interventions in groups of individuals chosen through the play of chance; meta-analysis is a statistical approach that combines the results of several trials.
What Did the Researchers Do and Find?
In the PPROM Expectant Management versus Induction of Labor (PRROMEXIL) trial, 532 non-laboring women with PPROM between 34 and 37 weeks' gestation were randomly assigned to either immediate induction of labor or expectant management. Neonatal sepsis occurred in seven babies born to women in the induction of labor group and in 11 babies born to women in the expectant management group. This difference was not statistically significant. That is, it could have happened by chance. Similarly, although more babies born to women in the induction of labor group than in the expectant management group developed RDS (21 and 17 babies, respectively), this difference was not significant. Cesarean section rates were similar in both intervention groups, but the risk of chorioamnionitis was slightly reduced in the induction of labor group compared to the expectant management group. Finally, the researchers' meta-analysis (which included these new results) found no significant differences in the risk of neonatal sepsis, RDS, or cesarean section associated with the two interventions.
What Do These Findings Mean?
These findings show that, compared to expectant management, induction of labor did not reduce the incidence of neonatal sepsis in pregnancies complicated by PPROM between 34 and 37 weeks' gestation. However, because fewer babies than expected born to the women in the expectant management group developed neonatal sepsis, this trial was underpowered. That is, too few women were enrolled in the trial to enable the detection of a small difference between the interventions in the neonatal sepsis rate. These findings also show that induction of labor did not substantially affect most of the secondary outcomes measured by the researchers. Given these results and those of their meta-analysis, the researchers conclude that, in women whose pregnancy is complicated by PPROM late in pregnancy, induction of labor does not substantially improve the outcome for either the woman or her baby compared to expectant management.
Additional Information
Please access these web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001208.
The March of Dimes, a nonprofit organization for pregnancy and baby health, provides information on preterm birth (in English and Spanish); its News Moms Need blog contains a post on PPROM
Tommy's is a nonprofit organization that funds research and provides information on the causes and prevention of miscarriage, premature birth, and stillbirth
The Royal College of Obstetricians and Gynaecologists guidelines on the diagnosis, investigation, and management of PPROM are available (in English and Russian)
Information about the PPROMEXIL trial is available
Personal stories about PPROM are available on the Austprem web site, a non-profit organization that provides information about prematurity and support for parents of premature babies in Australia
MedlinePlus provides links to other information on premature babies (in English and Spanish)
doi:10.1371/journal.pmed.1001208
PMCID: PMC3335867  PMID: 22545024
21.  Neonatal Mortality Levels for 193 Countries in 2009 with Trends since 1990: A Systematic Analysis of Progress, Projections, and Priorities 
PLoS Medicine  2011;8(8):e1001080.
Mikkel Oestergaard and colleagues develop annual estimates for neonatal mortality rates and neonatal deaths for 193 countries for 1990 to 2009, and forecasts into the future.
Background
Historically, the main focus of studies of childhood mortality has been the infant and under-five mortality rates. Neonatal mortality (deaths <28 days of age) has received limited attention, although such deaths account for about 41% of all child deaths. To better assess progress, we developed annual estimates for neonatal mortality rates (NMRs) and neonatal deaths for 193 countries for the period 1990–2009 with forecasts into the future.
Methods and Findings
We compiled a database of mortality in neonates and children (<5 years) comprising 3,551 country-years of information. Reliable civil registration data from 1990 to 2009 were available for 38 countries. A statistical model was developed to estimate NMRs for the remaining 155 countries, 17 of which had no national data. Country consultation was undertaken to identify data inputs and review estimates. In 2009, an estimated 3.3 million babies died in the first month of life—compared with 4.6 million neonatal deaths in 1990—and more than half of all neonatal deaths occurred in five countries of the world (44% of global livebirths): India 27.8% (19.6% of global livebirths), Nigeria 7.2% (4.5%), Pakistan 6.9% (4.0%), China 6.4% (13.4%), and Democratic Republic of the Congo 4.6% (2.1%). Between 1990 and 2009, the global NMR declined by 28% from 33.2 deaths per 1,000 livebirths to 23.9. The proportion of child deaths that are in the neonatal period increased in all regions of the world, and globally is now 41%. While NMRs were halved in some regions of the world, Africa's NMR only dropped 17.6% (43.6 to 35.9).
Conclusions
Neonatal mortality has declined in all world regions. Progress has been slowest in the regions with high NMRs. Global health programs need to address neonatal deaths more effectively if Millennium Development Goal 4 (two-thirds reduction in child mortality) is to be achieved.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Every year, more than 8 million children die before their fifth birthday. Most of these deaths occur in developing countries and most are caused by preventable or treatable diseases. In 2000, world leaders set a target of reducing child mortality to one-third of its 1990 level by 2015 as Millennium Development Goal 4 (MDG4). This goal, together with seven others, is designed to help improve the social, economic, and health conditions in the world's poorest countries. In recent years, progress towards reducing child mortality has accelerated but remains insufficient to achieve MDG4. In particular, progress towards reducing neonatal deaths—deaths during the first 28 days of life—has been slow and neonatal deaths now account for a greater proportion of global child deaths than in 1990. Currently, nearly 41% of all deaths among children under the age of 5 years occur during the neonatal period. The major causes of neonatal deaths are complications of preterm delivery, breathing problems during or after delivery (birth asphyxia), and infections of the blood (sepsis) and lungs (pneumonia). Simple interventions such as improved hygiene at birth and advice on breastfeeding can substantially reduce neonatal deaths.
Why Was This Study Done?
If MDG4 is to be met, more must be done to prevent deaths among newborn babies. To improve survival rates and to monitor the effects of public-health interventions in this vulnerable group, accurate, up-to-date estimates of national neonatal mortality rates (NMRs, the number of neonatal deaths per 1,000 live births) are essential. Although infant (under-one) and under-five mortality rates are estimated annually for individual countries by the United Nations Interagency Group for Child Mortality Estimation, annual NMR trend estimates have not been produced before. In many developed countries, child mortality rates can be calculated directly from vital civil registration data—records of all births and deaths. But many developing countries lack vital registration systems and child mortality has to be estimated using data collected in household surveys such as the Demographic and Health Surveys (a project that helps developing countries collect data on health and population trends). In this study, the researchers estimate annual national NMRs and numbers of neonatal deaths for the past 20 years using the available data.
What Did the Researchers Do and Find?
The researchers used civil registration systems, household surveys, and other sources to compile a database of deaths among neonates and children under 5 years old for 193 countries between 1990 and 2009. They estimated NMRs for 38 countries from reliable vital registration data and developed a statistical model to estimate NMRs for the remaining 155 countries (in which 92% of global live births occurred). In 2009, 3.3 million babies died during their first month of life compared to 4.6 million in 1990. More than half the neonatal deaths in 2009 occurred in five countries—India, Nigeria, Pakistan, China, and the Democratic Republic of Congo. India had the largest number of neonatal deaths throughout the study. Between 1990 and 2009, although the global NMR decreased from 33.2 to 23.9 deaths per 1,000 live births (a decrease of 28%), NMRs increased in eight countries, five of which were in Africa. Moreover, in Africa as a whole, the NMR only decreased by 17.6%, from 43.6 per 1,000 live births in 1990 to 35.9 per 1,000 live births in 2009.
What Do These Findings Mean?
These and other findings suggest that neonatal mortality has declined in all world regions since 1990 but that progress has been slowest in the regions with high NMRs such as Africa. Although there is considerable uncertainty around the estimates calculated by the researchers, these findings nevertheless highlight the slow progress in reducing the neonatal mortality risk over the past 20 years and suggest that the relative contribution of neonatal deaths to child deaths will increase into the future. Thus, if MDG4 is to be achieved, it is essential that national governments and international health bodies invest in improved methods for the measurement of neonatal deaths and stillbirths and increase their investment in the provision of care at birth and during the first few weeks of life.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001080.
The United Nations Children's Fund (UNICEF) works for children's rights, survival, development, and protection around the world; it provides information on Millennium Development Goal 4, and its Childinfo Web site provides detailed statistics about child survival and health, including a description of the United Nations Interagency Group for Child Mortality Estimation and a link to its database, and information on newborn care (some information in several languages)
The World Health Organization also has information about the Millennium Development Goal 4, provides information on newborn mortality, and provides the latest estimates of child mortality
Further information about the Millennium Development Goals is available
Information is also available about the Demographic and Health Surveys
doi:10.1371/journal.pmed.1001080
PMCID: PMC3168874  PMID: 21918640
22.  Maternal Overweight and Obesity and Risks of Severe Birth-Asphyxia-Related Complications in Term Infants: A Population-Based Cohort Study in Sweden 
PLoS Medicine  2014;11(5):e1001648.
Martina Persson and colleagues use a Swedish national database to investigate the association between maternal body mass index in early pregnancy and severe asphyxia-related outcomes in infants delivered at term.
Please see later in the article for the Editors' Summary
Background
Maternal overweight and obesity increase risks of pregnancy and delivery complications and neonatal mortality, but the mechanisms are unclear. The objective of the study was to investigate associations between maternal body mass index (BMI) in early pregnancy and severe asphyxia-related outcomes in infants delivered at term (≥37 weeks).
Methods and Findings
A nation-wide Swedish cohort study based on data from the Medical Birth Register included all live singleton term births in Sweden between 1992 and 2010. Logistic regression analyses were used to obtain odds ratios (ORs) with 95% CIs for Apgar scores between 0 and 3 at 5 and 10 minutes, meconium aspiration syndrome, and neonatal seizures, adjusted for maternal height, maternal age, parity, mother's smoking habits, education, country of birth, and year of infant birth. Among 1,764,403 term births, 86% had data on early pregnancy BMI and Apgar scores. There were 1,380 infants who had Apgar score 0–3 at 5 minutes (absolute risk  = 0.8 per 1,000) and 894 had Apgar score 0–3 at 10 minutes (absolute risk  = 0.5 per 1,000). Compared with infants of mothers with normal BMI (18.5–24.9), the adjusted ORs (95% CI) for Apgar scores 0–3 at 10 minutes were as follows: BMI 25–29.9: 1.32 (1.10–1.58); BMI 30–34.9: 1.57 (1.20–2.07); BMI 35–39.9: 1.80 (1.15–2.82); and BMI ≥40: 3.41 (1.91–6.09). The ORs for Apgar scores 0–3 at 5 minutes, meconium aspiration, and neonatal seizures increased similarly with maternal BMI. A study limitation was lack of data on effects of obstetric interventions and neonatal resuscitation efforts.
Conclusion
Risks of severe asphyxia-related outcomes in term infants increase with maternal overweight and obesity. Given the high prevalence of the exposure and the severity of the outcomes studied, the results are of potential public health relevance and should be confirmed in other populations. Prevention of overweight and obesity in women of reproductive age is important to improve perinatal health.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Economic, technologic, and lifestyle changes over the past 30 years have created an abundance of cheap, accessible, high-calorie food. Combined with fewer demands for physical activity, this situation has lead to increasing body mass throughout most of the world. Consequently, being overweight or obese is much more common in many high-income and low-and middle-income countries compared to 1980. Worldwide estimates put the percentage of overweight or obese adults as increasing by over 10%, between 1980 and 2008.
As being overweight becomes a global epidemic, its prevalence in women of reproductive age has also increased. Pregnant women who are overweight or obese are a cause for concern because of the possible associated health risks to both the infant and mother. Research is necessary to more clearly define these risks.
Why Was This Study Done?
In this study, the researchers investigated the complications associated with excess maternal weight that could hinder an infant from obtaining enough oxygen during delivery (neonatal asphyxia). All fetuses experience a loss of oxygen during contractions, however, a prolonged loss of oxygen can impact an infant's long-term development. To explore this risk, the researchers relied on a universal scoring system known as the Apgar score. An Apgar score is routinely recorded at one, five, and ten minutes after birth and is calculated from an assessment of heart rate, respiratory effort, and color, along with reflexes and muscle tone. An oxygen deficit during delivery will have an impact on the score. A normal score is in the range of 7–10. Body mass index (BMI) a calculation that uses height and weight, was used to assess the weight status (i.e., normal, overweight, obese) of the mother during pregnancy.
What Did the Researchers Do and Find?
Using the Swedish medical birth registry (a database including nearly all the births occurring in Sweden since 1973) the researchers selected records for single births that took place between 1992 to 2010. The registry also incorporates prenatal care data and researchers further selected for records that included weight and height measurement taken during the first prenatal visit. BMI was calculated using the weight and height measurement. Based on BMI ranges that define weight groups as normal, overweight, and obesity grades I, II, and III, the researchers analyzed and compared the number of low Apgar scoring infants (Apgar 0–3) in each group. Mothers with normal weight gave birth to the majority of infants with Apgar 0–3. In comparison the proportion of low Apgar scores were greater in babies of overweight and obese mothers. The researchers found that the rates of low Apgar scores increased with maternal BMI: the authors found that rates of low Apgar score at 5 minutes increased from 0.4 per 1,000 among infants of underweight women (BMI <18.5) to 2.4 per 1,000 among infants of women with obesity class III (BMI ≥40). Furthermore, overweight (BMI 25.0–29.9) was associated with a 55% increased risk of low Apgar scores at 5 minutes; obesity grade I (BMI 30–34.9) and grade II (BMI 35.0–39.9) with an almost 2-fold and a more than 2-fold increased risk, respectively; and obesity grade ΙΙΙ (BMI ≥40.0) with a more than 3-fold increase in risk. Finally, maternal overweight and obesity also increase the risks for seizures and meconium aspiration in the neonate.
What Do These Findings Mean?
These findings suggest that the risk of experiencing an oxygen deficit increases for the babies of women who are overweight or obese. Given the high prevalence of overweight and obesity in many countries worldwide, these findings are important and suggest that preventing women of reproductive age from becoming overweight or obese is therefore important to the health of their children.
A limitation of this study is the lack of data on the effects of clinical interventions and neonatal resuscitation efforts that may have been performed at the time of birth. Also Apgar scoring is based on five variables and a low score is not the most direct way to determine if the infant has experienced an oxygen deficit. However, these findings suggest that early detection of perinatal asphyxia is particularly relevant among infants of overweight and obese women although more studies are necessary to confirm the results in other populations.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001648.
The US National Institutes of Health explains and calculates body mass index
The NIH also defines the Apgar scoring system
The United Kingdom's National Health Service has information for pregnant woman who are overweight
The UK-based Overseas Development Institute discusses how changes in diet have led to a worldwide health crisis in its “Future Diets” publication
Information about the Swedish health care system is available
Information in English is available from the National Board of Health and Welfare in Sweden
doi:10.1371/journal.pmed.1001648
PMCID: PMC4028185  PMID: 24845218
23.  Fetal Growth and Risk of Stillbirth: A Population-Based Case–Control Study 
PLoS Medicine  2014;11(4):e1001633.
Radek Bukowski and colleagues conducted a case control study in 59 US hospitals to determine the relationship between fetal growth and stillbirth, and find that both restrictive and excessive growth could play a role.
Please see later in the article for the Editors' Summary
Background
Stillbirth is strongly related to impaired fetal growth. However, the relationship between fetal growth and stillbirth is difficult to determine because of uncertainty in the timing of death and confounding characteristics affecting normal fetal growth.
Methods and Findings
We conducted a population-based case–control study of all stillbirths and a representative sample of live births in 59 hospitals in five geographic areas in the US. Fetal growth abnormalities were categorized as small for gestational age (SGA) (<10th percentile) or large for gestational age (LGA) (>90th percentile) at death (stillbirth) or delivery (live birth) using population, ultrasound, and individualized norms. Gestational age at death was determined using an algorithm that considered the time-of-death interval, postmortem examination, and reliability of the gestational age estimate. Data were weighted to account for the sampling design and differential participation rates in various subgroups. Among 527 singleton stillbirths and 1,821 singleton live births studied, stillbirth was associated with SGA based on population, ultrasound, and individualized norms (odds ratio [OR] [95% CI]: 3.0 [2.2 to 4.0]; 4.7 [3.7 to 5.9]; 4.6 [3.6 to 5.9], respectively). LGA was also associated with increased risk of stillbirth using ultrasound and individualized norms (OR [95% CI]: 3.5 [2.4 to 5.0]; 2.3 [1.7 to 3.1], respectively), but not population norms (OR [95% CI]: 0.6 [0.4 to 1.0]). The associations were stronger with more severe SGA and LGA (<5th and >95th percentile). Analyses adjusted for stillbirth risk factors, subset analyses excluding potential confounders, and analyses in preterm and term pregnancies showed similar patterns of association. In this study 70% of cases and 63% of controls agreed to participate. Analysis weights accounted for differences between consenting and non-consenting women. Some of the characteristics used for individualized fetal growth estimates were missing and were replaced with reference values. However, a sensitivity analysis using individualized norms based on the subset of stillbirths and live births with non-missing variables showed similar findings.
Conclusions
Stillbirth is associated with both growth restriction and excessive fetal growth. These findings suggest that, contrary to current practices and recommendations, stillbirth prevention strategies should focus on both severe SGA and severe LGA pregnancies.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Pregnancy is usually a happy time, when the parents-to-be anticipate the arrival of a new baby. But, sadly, about 20% of pregnancies end in miscarriage—the early loss of a fetus (developing baby) that is unable to survive independently. Other pregnancies end in stillbirth—fetal death after 20 weeks of pregnancy (in the US; after 24 weeks in the UK). Stillbirths, like miscarriages, are common. In the US, for example, one in every 160 pregnancies ends in stillbirth. How women discover that their unborn baby has died varies. Some women simply know something is wrong and go to hospital to have their fears confirmed. Others find out when a routine check-up detects no fetal heartbeat. Most women give birth naturally after their baby has died, but if the mother's health is at risk, labor may be induced. Common causes of stillbirth include birth defects and infections. Risk factors for stillbirth include being overweight and smoking during pregnancy.
Why Was This Study Done?
Stillbirths are often associated with having a “small for gestational age” (SGA) fetus. Gestation is the period during which a baby develops in its mother's womb. Gestational age is estimated from the date of the woman's last menstrual period and/or from ultrasound scans. An SGA fetus is lighter than expected for its age based on observed distributions (norms) of fetal weights for gestational age. Although stillbirth is clearly associated with impaired fetal growth, the exact relationship between fetal growth and stillbirth remains unclear for two reasons. First, studies investigating this relationship have used gestational age at delivery rather than gestational age at death as an estimate of fetal age, which overestimates the gestational age of stillbirths and leads to errors in estimates of the proportions of SGA and “large for gestational age” (LGA) stillbirths. Second, many characteristics that affect normal fetal growth are also associated with the risk of stillbirth, and this has not been allowed for in previous studies. In this population-based case–control study, the researchers investigate the fetal growth abnormalities associated with stillbirth using a new approach to estimate gestational age and accounting for the effect of characteristics that affect both fetal growth and stillbirth. A population-based case–control study compares the characteristics of patients with a condition in a population with those of unaffected people in the same population.
What Did the Researchers Do and Find?
The researchers investigated all the stillbirths and a sample of live births that occurred over 2.5 years at 59 hospitals in five US regions. They used a formula developed by the Stillbirth Collaborative Research Network to calculate the gestational age at death of the stillbirths. They categorized fetuses as SGA if they had a weight for gestational age within the bottom 10% (below the 10th percentile) of the population and as LGA if they had a weight for gestational age above the 90th percentile at death (stillbirth) or delivery (live birth) using population, ultrasound, and individualized norms of fetal weight for gestational age. Population norms incorporate weights for gestational age from normal pregnancies and from pregnancies complicated by growth abnormalities, whereas the other two norms include weights for gestational age from normal pregnancies only. Having an SGA fetus was associated with a 3- to 4-fold increased risk of stillbirth compared to having a fetus with “appropriate” weight for gestational age based on all three norms. LGA was associated with an increased risk of stillbirth based on the ultrasound and individualized norms but not the population norms. Being more severely SGA or LGA (below the 5th percentile or above the 95th percentile) was associated with an increased risk of stillbirth.
What Do These Findings Mean?
These findings indicate that, when the time of death is accounted for and norms for weight for gestational age only from uncomplicated pregnancies are used, stillbirth is associated with both restricted and excessive fetal growth. Overall, abnormal fetal growth was identified in 25% of stillbirths using population norms and in about 50% of stillbirths using ultrasound or individualized norms. Although the accuracy of these findings is likely to be affected by aspects of the study design, these findings suggest that, contrary to current practices, strategies designed to prevent stillbirth should focus on identifying both severely SGA and severely LGA fetuses and should use norms for the calculation of weight for gestational age based on normal pregnancies only. Such an approach has the potential to identify almost half of the pregnancies likely to result in stillbirth.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001633.
The March of Dimes, a nonprofit organization for pregnancy and baby health, provides information on stillbirth
Tommy's, a UK nonprofit organization that funds research into stillbirth, premature birth, and miscarriage and provides information for parents-to-be, also provides information on stillbirth (including personal stories)
The UK National Health Service Choices website provides information about stillbirth (including a video about dealing with grief after a stillbirth)
MedlinePlus provides links to other resources about stillbirth (in English and Spanish)
Information about the Stillbirth Collaborative Research Network is available
doi:10.1371/journal.pmed.1001633
PMCID: PMC3995658  PMID: 24755550
24.  Effects on birth weight and perinatal mortality of maternal dietary supplements in rural Gambia: 5 year randomised controlled trial . 
BMJ : British Medical Journal  1997;315(7111):786-790.
OBJECTIVE: To test the efficacy in terms of birth weight and infant survival of a diet supplement programme in pregnant African women through a primary healthcare system. DESIGN: 5 year controlled trial of all pregnant women in 28 villages randomised to daily supplementation with high energy groundnut biscuits (4.3 MJ/day) for about 20 weeks before delivery (intervention) or after delivery (control). SETTING: Rural Gambia. SUBJECTS: Chronically undernourished women (twin bearers excluded), yielding 2047 singleton live births and 35 stillbirths. MAIN OUTCOME MEASURES: Birth weight; prevalence of low birth weight (< 2500 g); head circumference; birth length; gestational age; prevalence of stillbirths; neonatal and postneonatal mortality. RESULTS: Supplementation increased weight gain in pregnancy and significantly increased birth weight, particularly during the nutritionally debilitating hungry season (June to October). Weight gain increased by 201 g (P < 0.001) in the hungry season, by 94 g (P < 0.01) in the harvest season (November to May), and by 136 g (P < 0.001) over the whole year. The odds ratio for low birthweight babies in supplemented women was 0.61 (95% confidence interval 0.47 to 0.79, P < 0.001). Head circumference was significantly increased (P < 0.01), but by only 3.1 mm. Birth length and duration of gestation were not affected. Supplementation significantly reduced perinatal mortality: the odds ratio was 0.47 (0.23 to 0.99, P < 0.05) for stillbirths and 0.54 (0.35 to 0.85, P < 0.01) for all deaths in first week of life. Mortality after 7 days was unaffected. CONCLUSION: Prenatal dietary supplementation reduced retardation in intrauterine growth when effectively targeted at genuinely at-risk mothers. This was associated with a substantial reduction in the prevalence of stillbirths and in early neonatal mortality. The intervention can be successfully delivered through a primary healthcare system.
PMCID: PMC2127544  PMID: 9345173
25.  Birth Size and Breast Cancer Risk: Re-analysis of Individual Participant Data from 32 Studies 
PLoS Medicine  2008;5(9):e193.
Background
Birth size, perhaps a proxy for prenatal environment, might be a correlate of subsequent breast cancer risk, but findings from epidemiological studies have been inconsistent. We re-analysed individual participant data from published and unpublished studies to obtain more precise estimates of the magnitude and shape of the birth size–breast cancer association.
Methods and Findings
Studies were identified through computer-assisted and manual searches, and personal communication with investigators. Individual participant data from 32 studies, comprising 22,058 breast cancer cases, were obtained. Random effect models were used, if appropriate, to combine study-specific estimates of effect. Birth weight was positively associated with breast cancer risk in studies based on birth records (pooled relative risk [RR] per one standard deviation [SD] [= 0.5 kg] increment in birth weight: 1.06; 95% confidence interval [CI] 1.02–1.09) and parental recall when the participants were children (1.02; 95% CI 0.99–1.05), but not in those based on adult self-reports, or maternal recall during the woman's adulthood (0.98; 95% CI 0.95–1.01) (p for heterogeneity between data sources = 0.003). Relative to women who weighed 3.000–3.499 kg, the risk was 0.96 (CI 0.80–1.16) in those who weighed < 2.500 kg, and 1.12 (95% CI 1.00–1.25) in those who weighed ≥ 4.000 kg (p for linear trend = 0.001) in birth record data. Birth length and head circumference from birth records were also positively associated with breast cancer risk (pooled RR per one SD increment: 1.06 [95% CI 1.03–1.10] and 1.09 [95% CI 1.03–1.15], respectively). Simultaneous adjustment for these three birth size variables showed that length was the strongest independent predictor of risk. The birth size effects did not appear to be confounded or mediated by established breast cancer risk factors and were not modified by age or menopausal status. The cumulative incidence of breast cancer per 100 women by age 80 y in the study populations was estimated to be 10.0, 10.0, 10.4, and 11.5 in those who were, respectively, in the bottom, second, third, and top fourths of the birth length distribution.
Conclusions
This pooled analysis of individual participant data is consistent with birth size, and in particular birth length, being an independent correlate of breast cancer risk in adulthood.
Editors' Summary
Background.
Last year, more than one million women discovered that they had breast cancer. In the US, nearly 200,000 women will face the same diagnosis this year and 40,000 will die because of breast cancer. Put another way, about one in eight US women will have breast cancer during her lifetime. Like all cancers, breast cancer begins when cells acquire genetic changes that allow them to divide uncontrollably and to move around the body (metastasize). This uncontrolled division leads to the formation of a lump that can be detected by mammography (a breast X-ray) or by manual examination of the breasts. Breast cancer is treated by surgical removal of the lump or, if the cancer has started to spread, by removal of the whole breast (mastectomy). Surgery is usually followed by radiotherapy, chemotherapy, and other treatments designed to kill any remaining cancer cells. Unlike some cancers, the outlook for women with breast cancer is good. In the US, for example, nearly 90% of affected women are still alive five years after their diagnosis.
Why Was This Study Done?
Scientists have identified several factors that increase a woman's risk of developing breast cancer by comparing the characteristics of populations of women with and without breast cancer. Well-established risk factors include increasing age, not having children, and having a late menopause, but another potential risk factor for breast cancer is birth size. A baby's weight, length, and head circumference at birth (three related measures of birth size) depend on the levels of hormones (including estrogen, a hormone that often affects breast cancer growth) and other biological factors to which the baby is exposed during pregnancy—its prenatal environment. The idea that prenatal environment might also affect breast cancer risk in later life was first proposed in 1990, but the findings of studies that have tried to investigate this possibility have been inconsistent. Here, the researchers re-analyze individual participant data from a large number of studies into women's health conducted in Europe, Northern America, and China to get more precise information about the association between birth size and breast cancer risk.
What Did the Researchers Do and Find?
The researchers identified 32 published and unpublished studies that had collected information on birth size and on the occurrence of breast cancer. They then obtained the individual participant data from these studies, which involved more than 22,000 women who had developed breast cancer and more than 600,000 women who had not. Their analyses of these data show that birth weight was positively associated with breast cancer risk in those studies where this measurement was recorded at birth or based on parental recall during the study participant's childhood (but not in those studies in which birth weight was self-reported or maternally recalled during the participant's adulthood). For example, women with recorded birth weights of more than 4 kg or more had a 12% higher chance of developing breast cancer than women who weighed 3–3.5 kg at birth. Birth length and head circumference were also positively associated with breast cancer risk, but birth length was the strongest single predictor of risk. Finally, the amount by which birth size affected breast cancer risk was not affected by allowing for other established risk factors.
What Do These Findings Mean?
These findings provide strong evidence that birth size—in particular, birth length—is a marker of a woman's breast cancer risk in adulthood although the mechanisms underlying this association are unclear. The researchers note that the observed effect of birth size on breast cancer risk is of a similar magnitude to that of other more established risk factors and estimate that 5% of all breast cancers in developed countries could be caused by a high birth size. Because practically all the studies included in this pooled analysis were done in developed countries, these findings may not hold for developing countries. Further investigations into how the prenatal environment may affect breast cancer risk might identify new ways to prevent this increasingly common cancer.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0050193.
This study is further discussed in a PLoS Medicine Perspective by Trichopoulos and Lagiou
The US National Cancer Institute provides detailed information for patients and health professionals on all aspects of breast cancer, including information on risk factors for breast cancer (in English and Spanish)
The MedlinePlus Encyclopedia provides information for patients about breast cancer; Medline Plus also provides links to many other breast cancer resources (in English and Spanish)
The UK charity Cancerbackup also provides detailed information about breast cancer
Cancer Research UK is the UK's leading charity dedicated to cancer research
doi:10.1371/journal.pmed.0050193
PMCID: PMC2553821  PMID: 18828667

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