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1.  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
2.  Indigenous Health and Socioeconomic Status in India 
PLoS Medicine  2006;3(10):e421.
Background
Systematic evidence on the patterns of health deprivation among indigenous peoples remains scant in developing countries. We investigate the inequalities in mortality and substance use between indigenous and non-indigenous, and within indigenous, groups in India, with an aim to establishing the relative contribution of socioeconomic status in generating health inequalities.
Methods and Findings
Cross-sectional population-based data were obtained from the 1998–1999 Indian National Family Health Survey. Mortality, smoking, chewing tobacco use, and alcohol use were four separate binary outcomes in our analysis. Indigenous status in the context of India was operationalized through the Indian government category of scheduled tribes, or Adivasis, which refers to people living in tribal communities characterized by distinctive social, cultural, historical, and geographical circumstances.
Indigenous groups experience excess mortality compared to non-indigenous groups, even after adjusting for economic standard of living (odds ratio 1.22; 95% confidence interval 1.13–1.30). They are also more likely to smoke and (especially) drink alcohol, but the prevalence of chewing tobacco is not substantially different between indigenous and non-indigenous groups. There are substantial health variations within indigenous groups, such that indigenous peoples in the bottom quintile of the indigenous-peoples-specific standard of living index have an odds ratio for mortality of 1.61 (95% confidence interval 1.33–1.95) compared to indigenous peoples in the top fifth of the wealth distribution. Smoking, drinking alcohol, and chewing tobacco also show graded associations with socioeconomic status within indigenous groups.
Conclusions
Socioeconomic status differentials substantially account for the health inequalities between indigenous and non-indigenous groups in India. However, a strong socioeconomic gradient in health is also evident within indigenous populations, reiterating the overall importance of socioeconomic status for reducing population-level health disparities, regardless of indigeneity.
Indigenous groups in India were found to have excess mortality rates compared with non-indigenous groups. A socioeconomic gradient within indigenous populations was also found.
Editors' Summary
Background.
In many parts of the world the majority of the population are the descendants of immigrants who arrived there within the last few hundred years. Living alongside of them, and in a minority, are the so-called indigenous (or aboriginal) people who are the descendants of people who lived there in more ancient times. It is estimated that there are 300 million indigenous people worldwide. They are frequently marginalized from the rest of the population, their human rights are often abused, and there are serious concerns about their health and welfare. The state of health of the indigenous people of developed countries such as the US and Australia has often been studied, and we have a fairly clear idea of the kinds of problems these people face. Most indigenous people, however, live in developing countries, and less is known about their health.
India is the second-most populous country in the world, with an estimated 1.1 billion inhabitants. An estimated 90 million indigenous people live in India, where they are often referred to as “scheduled tribes” or Adivasis. They live in many parts of the country but are much more numerous in some Indian states than in others.
Why Was This Study Done?
It has often been said that indigenous people in India have worse health than other Indians, though no figures have been compiled to confirm these claims. The researchers wanted to establish whether it is simply an issue of indigenous people being poorer than other Indians—poverty being well known as a cause of disease—or whether being indigenous is, in itself, a health risk. The researchers also wanted to establish whether there are health inequalities within indigenous groups, and if these differences also followed a socioeconomic patterning.
What Did the Researchers Do and Find?
They used figures collected in the 1998–1999 Indian National Family Health Survey. When this survey was conducted, it was noted whether people were considered to be members of scheduled tribes. The researchers also knew, from the survey, about the income of the families, their death rates, and whether they drank alcohol or smoked or chewed tobacco. They found that indigenous people had higher death rates than other Indians. They made statistical calculations to account for differences in standard of living, and this substantially reduced the difference in death rate among indigenous groups, but an indigenous person was still 1.2 times more likely to die than a non-indigenous person with the same standard of living. Indigenous people were also more likely to drink alcohol and smoke tobacco, and here again, differences in standard of living accounted for a substantial portion of the differences. Importantly, the researchers' analysis showed a strong socioeconomic patterning of health inequalities within the indigenous population groups: the health differences between the poorest and richest indigenous groups were similar in scale to the differences between the poorest and richest non-indigenous groups.
What Do These Findings Mean?
The authors consider their finding that there is a socioeconomic gradient in mortality and health behaviors among indigenous people to be an important result from the study. The socioeconomic marginalization of indigenous people from the rest of Indian society does seem to increase their health risks, and so does their use of alcohol and tobacco. However, if their standard of living can be improved there would be major benefits for their health and welfare.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0030421.
A useful discussion of the term “indigenous people” (with links to documents about international agreements intended to improve their human rights) may be found on Wikipedia. (Wikipedia is an internet encyclopedia that anyone can edit.)
Survival International is a human rights organization that campaigns for the rights of indigenous peoples, helping them preserve their land and culture.
The charity Health Unlimited also works with indigenous people and its Web site includes links to recent studies and conferences.
A news item from the BBC describes a recent investigation into the health of indigenous people worldwide.
The World Health Organization has produced a number of reports on the health of indigenous people
doi:10.1371/journal.pmed.0030421
PMCID: PMC1621109  PMID: 17076556
3.  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
4.  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
5.  The maternal and neonatal outcomes for an urban Indigenous population compared with their non-Indigenous counterparts and a trend analysis over four triennia 
Background
Indigenous Australians experience significantly disproportionate poorer health outcomes compared to their non-Indigenous counterparts. Despite the recognised importance of maternal infant health (MIH), there is surprisingly little empirical research to guide service redesign that successfully addresses the disparities. This paper reports on a service evaluation that also compared key MIH indicators for Indigenous and non-Indigenous mothers and babies over a 12-year period 1998–2009.
Methods
Trend analysis with logistic regression, using the independent variables of ethnicity and triennia, explored changes over time (1998–2009) between two cohorts: 1,523 births to Indigenous mothers and 43,693 births to non-Indigenous mothers. We included bivariate and multivariate analysis on key indicators (e.g. teenage births, preterm birth, low birth weight, smoking) and report odds ratios (ORs), 95% CIs and logistic regression adjusting for important confounders. We excluded transfers in from other areas which are identified within the database.
Results
Bivariate analysis revealed Indigenous women were statistically more likely to have spontaneous onset of labour and a non-instrumental vaginal birth. They were less likely to take epidurals for pain relief in labour, have assisted births, caesarean sections or perineal trauma. Despite better labour outcomes, Indigenous babies were more likely to be born preterm (< 37 weeks) and be low birth weight (< 2500 g); these differences remained significant in multivariate analysis. The trend analysis revealed relatively stable rates for teenage pregnancy, small for gestational age, low birth weight babies, and perinatal mortality for both cohorts, with the gap between cohorts consistent over time. A statistical widening of the gap in preterm birth and smoking rates was found with preterm birth demonstrating a relative increase of 51% over this period.
Conclusions
The comprehensive database from a large urban hospital allowed a thorough examination of outcomes and contributing factors. The gap between both cohorts remains static in several areas but in some cases worsened. Alternative models for delivering care to Indigenous women and their babies have shown improved outcomes, including preterm birth, though not all have been sustained over time and none are available Australia-wide. New models of care, which recognise the heterogeneity of Indigenous communities, incorporate a multiagency approach, and are set within a research framework, are urgently needed.
doi:10.1186/1471-2393-13-167
PMCID: PMC3766203  PMID: 24000821
Aboriginal and Torres Strait Islander; Indigenous Australian; Antenatal; Maternity; Midwifery; Culturally responsive; Model of care; Evaluation
6.  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
7.  Preterm Birth and Childhood Wheezing Disorders: A Systematic Review and Meta-Analysis 
PLoS Medicine  2014;11(1):e1001596.
In a systematic review and meta-analysis, Jasper Been and colleagues investigate the association between preterm birth and the development of wheezing disorders in childhood.
Please see later in the article for the Editors' Summary
Background
Accumulating evidence implicates early life factors in the aetiology of non-communicable diseases, including asthma/wheezing disorders. We undertook a systematic review investigating risks of asthma/wheezing disorders in children born preterm, including the increasing numbers who, as a result of advances in neonatal care, now survive very preterm birth.
Methods and Findings
Two reviewers independently searched seven online databases for contemporaneous (1 January 1995–23 September 2013) epidemiological studies investigating the association between preterm birth and asthma/wheezing disorders. Additional studies were identified through reference and citation searches, and contacting international experts. Quality appraisal was undertaken using the Effective Public Health Practice Project instrument. We pooled unadjusted and adjusted effect estimates using random-effects meta-analysis, investigated “dose–response” associations, and undertook subgroup, sensitivity, and meta-regression analyses to assess the robustness of associations.
We identified 42 eligible studies from six continents. Twelve were excluded for population overlap, leaving 30 unique studies involving 1,543,639 children. Preterm birth was associated with an increased risk of wheezing disorders in unadjusted (13.7% versus 8.3%; odds ratio [OR] 1.71, 95% CI 1.57–1.87; 26 studies including 1,500,916 children) and adjusted analyses (OR 1.46, 95% CI 1.29–1.65; 17 studies including 874,710 children). The risk was particularly high among children born very preterm (<32 wk gestation; unadjusted: OR 3.00, 95% CI 2.61–3.44; adjusted: OR 2.81, 95% CI 2.55–3.12). Findings were most pronounced for studies with low risk of bias and were consistent across sensitivity analyses. The estimated population-attributable risk of preterm birth for childhood wheezing disorders was ≥3.1%.
Key limitations related to the paucity of data from low- and middle-income countries, and risk of residual confounding.
Conclusions
There is compelling evidence that preterm birth—particularly very preterm birth—increases the risk of asthma. Given the projected global increases in children surviving preterm births, research now needs to focus on understanding underlying mechanisms, and then to translate these insights into the development of preventive interventions.
Review Registration
PROSPERO CRD42013004965
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Most pregnancies last around 40 weeks, but worldwide, more than 11% of babies are born before 37 weeks of gestation (the period during which a baby develops in its mother's womb). Preterm birth is a major cause of infant death—more than 1 million babies die annually from preterm birth complications—and the number of preterm births is increasing globally. Multiple pregnancies, infections, and chronic (long-term) maternal conditions such as diabetes can all cause premature birth, but the cause of many preterm births is unknown. The most obvious immediate complication that is associated with preterm birth is respiratory distress syndrome. This breathing problem, which is more common in early preterm babies than in near-term babies, occurs because the lungs of premature babies are structurally immature and lack pulmonary surfactant, a unique mixture of lipids and proteins that coats the inner lining of the lungs and helps to prevent the collapse of the small air sacs in the lungs that absorb oxygen from the air. Consequently, preterm babies often need help with their breathing and oxygen supplementation.
Why Was This Study Done?
Improvements in the management of prematurity mean that more preterm babies survive today than in the past. However, accumulating evidence suggests that early life events are involved in the subsequent development of non-communicable diseases (non-infectious chronic diseases). Given the increasing burden of preterm birth, a better understanding of the long-term effects of preterm birth is essential. Here, the researchers investigate the risks of asthma and wheezing disorders in children who are born preterm by undertaking a systematic review (a study that uses predefined criteria to identify all the research on a given topic) and a meta-analysis (a statistical method for combining the results of several studies). Asthma is a chronic condition that is caused by inflammation of the airways. In people with asthma, the airways can react very strongly to allergens such as animal fur and to irritants such as cigarette smoke. Exercise, cold air, and infections can also trigger asthma attacks, which can sometimes be fatal. The symptoms of asthma include wheezing (a high-pitched whistling sound during breathing), coughing, chest tightness, and shortness of breath. Asthma cannot be cured, but drugs can relieve its symptoms and prevent acute asthma attacks.
What Did the Researchers Do and Find?
The researchers identified 30 studies undertaken between 1995 and the present (a time span chosen to allow for recent changes in the management of prematurity) that investigated the association between preterm birth and asthma/wheezing disorders in more than 1.5 million children. Across the studies, 13.7% of preterm babies developed asthma/wheezing disorders during childhood, compared to only 8.3% of babies born at term. Thus, the risk of preterm babies developing asthma or a wheezing disorder during childhood was 1.71 times higher than the risk of term babies developing these conditions (an unadjusted odds ratio [OR] of 1.71). In analyses that allowed for confounding factors—other factors that affect the risk of developing asthma/wheezing disorders such as maternal smoking—the risk of preterm babies developing asthma or a wheezing disorder during childhood was 1.46 times higher than that of babies born at term (an adjusted OR of 1.46). Notably, compared to children born at term, children born very early (before 32 weeks of gestation) had about three times the risk of developing asthma/wheezing disorders in unadjusted and adjusted analyses. Finally, the population-attributable risk of preterm birth for childhood wheezing disorders was more than 3.1%. That is, if no preterm births had occurred, there would have been more than a 3.1% reduction in childhood wheezing disorders.
What Do These Findings Mean?
These findings strongly suggest that preterm birth increases the risk of asthma and wheezing disorders during childhood and that the risk of asthma/wheezing disorders increases as the degree of prematurity increases. The accuracy of these findings may be affected, however, by residual confounding. That is, preterm children may share other, unknown characteristics that increase their risk of developing asthma/wheezing disorders. Moreover, the generalizability of these findings is limited by the lack of data from low- and middle-income countries. However, given the projected global increases in children surviving preterm births, these findings highlight the need to undertake research into the mechanisms underlying the association between preterm birth and asthma/wheezing disorders and the need to develop appropriate preventative and therapeutic measures.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001596.
The March of Dimes, a nonprofit organization for pregnancy and baby health, provides information on preterm birth (in English and Spanish)
Nemours, another nonprofit organization for child health, also provides information (in English and Spanish) on premature babies and on asthma (including personal stories)
The UK National Health Service Choices website provides information about premature labor and birth and a real story about having a preterm baby; it provides information about asthma in children (including real stories)
The MedlinePlus Encyclopedia has pages on preterm birth, asthma, asthma in children, and wheezing (in English and Spanish); MedlinePlus provides links to further information on premature birth, asthma, and asthma in children (in English and Spanish)
doi:10.1371/journal.pmed.1001596
PMCID: PMC3904844  PMID: 24492409
8.  Indigenous Birth Outcomes in Australia, Canada, New Zealand and the United States – an Overview 
Objective
To review Indigenous infant mortality, stillbirth, birth weight, and preterm birth outcomes in Australia, Canada, New Zealand and the United States.
Methods
Systematic searches of published literature and a review and assessment of existing perinatal surveillance systems were undertaken. Where possible, within country comparisons of Indigenous to non-Indigenous birth outcomes are included.
Results
Indigenous/non-Indigenous infant mortality rate ratios range from 1.6 to 4.0. Stillbirth rates, where data are available, are also uniformly higher for Indigenous people. In all four countries, the disparities in Indigenous/non-Indigenous infant mortality rate ratios are most marked in the post-neonatal period. With few exceptions, the rates of leading causes of infant mortality are higher among Indigenous infants than non-Indigenous infants within all four countries. In most cases, rates of small for gestational age and preterm birth were also elevated for Indigenous compared to non-Indigenous infants.
Conclusions
There are significant disparities in Indigenous/non-Indigenous birth outcomes in Australia, Canada, New Zealand and the United States. These Indigenous/non-Indigenous birth outcome disparities fit the criteria for health inequities, as they are not only unnecessary and avoidable, but also unfair and unjust.
doi:10.2174/1874291201004010007
PMCID: PMC3563669  PMID: 23390467 CAMSID: cams2716
Indigenous; birth outcomes; infant mortality; stillbirth; birth weight; and preterm birth; Canada; Australia; New Zealand; United States
9.  Primary Prevention of Gestational Diabetes Mellitus and Large-for-Gestational-Age Newborns by Lifestyle Counseling: A Cluster-Randomized Controlled Trial 
PLoS Medicine  2011;8(5):e1001036.
In a cluster-randomized trial, Riitta Luoto and colleagues find that counseling on diet and activity can reduce the birthweight of babies born to women at risk of developing gestational diabetes mellitus (GDM), but fail to find an effect on GDM.
Background
Our objective was to examine whether gestational diabetes mellitus (GDM) or newborns' high birthweight can be prevented by lifestyle counseling in pregnant women at high risk of GDM.
Method and Findings
We conducted a cluster-randomized trial, the NELLI study, in 14 municipalities in Finland, where 2,271 women were screened by oral glucose tolerance test (OGTT) at 8–12 wk gestation. Euglycemic (n = 399) women with at least one GDM risk factor (body mass index [BMI] ≥25 kg/m2, glucose intolerance or newborn's macrosomia (≥4,500 g) in any earlier pregnancy, family history of diabetes, age ≥40 y) were included. The intervention included individual intensified counseling on physical activity and diet and weight gain at five antenatal visits. Primary outcomes were incidence of GDM as assessed by OGTT (maternal outcome) and newborns' birthweight adjusted for gestational age (neonatal outcome). Secondary outcomes were maternal weight gain and the need for insulin treatment during pregnancy. Adherence to the intervention was evaluated on the basis of changes in physical activity (weekly metabolic equivalent task (MET) minutes) and diet (intake of total fat, saturated and polyunsaturated fatty acids, saccharose, and fiber). Multilevel analyses took into account cluster, maternity clinic, and nurse level influences in addition to age, education, parity, and prepregnancy BMI. 15.8% (34/216) of women in the intervention group and 12.4% (22/179) in the usual care group developed GDM (absolute effect size 1.36, 95% confidence interval [CI] 0.71–2.62, p = 0.36). Neonatal birthweight was lower in the intervention than in the usual care group (absolute effect size −133 g, 95% CI −231 to −35, p = 0.008) as was proportion of large-for-gestational-age (LGA) newborns (26/216, 12.1% versus 34/179, 19.7%, p = 0.042). Women in the intervention group increased their intake of dietary fiber (adjusted coefficient 1.83, 95% CI 0.30–3.25, p = 0.023) and polyunsaturated fatty acids (adjusted coefficient 0.37, 95% CI 0.16–0.57, p<0.001), decreased their intake of saturated fatty acids (adjusted coefficient −0.63, 95% CI −1.12 to −0.15, p = 0.01) and intake of saccharose (adjusted coefficient −0.83, 95% CI −1.55 to −0.11, p  =  0.023), and had a tendency to a smaller decrease in MET minutes/week for at least moderate intensity activity (adjusted coefficient 91, 95% CI −37 to 219, p = 0.17) than women in the usual care group. In subgroup analysis, adherent women in the intervention group (n = 55/229) had decreased risk of GDM (27.3% versus 33.0%, p = 0.43) and LGA newborns (7.3% versus 19.5%, p = 0.03) compared to women in the usual care group.
Conclusions
The intervention was effective in controlling birthweight of the newborns, but failed to have an effect on maternal GDM.
Trial registration
Current Controlled Trials ISRCTN33885819
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Gestational diabetes mellitus (GDM) is diabetes that is first diagnosed during pregnancy. Like other types of diabetes, it is characterized by high levels of sugar (glucose) in the blood. Blood-sugar levels are normally controlled by insulin, a hormone that the pancreas releases when blood-sugar levels rise after meals. Hormonal changes during pregnancy and the baby's growth demands increase a pregnant woman's insulin needs and, if her pancreas cannot make enough insulin, GDM develops. Risk factors for GDM, which occurs in 2%–14% of pregnant women, include a high body-mass index (a measure of body fat), excessive weight gain or low physical activity during pregnancy, high dietary intake of polyunsaturated fats, glucose intolerance (an indicator of diabetes) or the birth of a large baby in a previous pregnancy, and a family history of diabetes. GDM is associated with an increased rate of cesarean sections, induced deliveries, birth complications, and large-for-gestational-age (LGA) babies (gestation is the time during which the baby develops within the mother). GDM, which can often be controlled by diet and exercise, usually disappears after pregnancy but increases a woman's subsequent risk of developing diabetes.
Why Was This Study Done?
Although lifestyle changes can be used to control GDM, it is not known whether similar changes can prevent GDM developing (“primary prevention”). In this cluster-randomized controlled trial, the researchers investigate whether individual intensified counseling on physical activity, diet, and weight gain integrated into routine maternity care visits can prevent the development of GDM and the occurrence of LGA babies among newborns. In a cluster-randomized controlled trial, groups of patients rather than individual patients are randomly assigned to receive alternative interventions, and the outcomes in different “clusters” are compared. In this trial, each cluster is a municipality in the Pirkanmaa region of Finland.
What Did the Researchers Do and Find?
The researchers enrolled 399 women, each of whom had a normal blood glucose level at 8–12 weeks gestation but at least one risk factor for GDM. Women in the intervention municipalities received intensified counseling on physical activity at 8–12 weeks' gestation, dietary counseling at 16–18 weeks' gestation, and further physical activity and dietary counseling at each subsequent antenatal visits. Women in the control municipalities received some dietary but little physical activity counseling as part of their usual care. 23.3% and 20.2% of women in the intervention and usual care groups, respectively, developed GDM, a nonstatistically significant difference (that is, a difference that could have occurred by chance). However, the average birthweight and the proportion of LGA babies were both significantly lower in the intervention group than in the usual care group. Food frequency questionnaires completed by the women indicated that, on average, those in the intervention group increased their intake of dietary fiber and polyunsaturated fatty acids and decreased their intake of saturated fatty acids and sucrose as instructed during counseling, The amount of moderate physical activity also tended to decrease less as pregnancy proceeded in the intervention group than in usual care group. Finally, compared to the usual care group, significantly fewer of the 24% of women in the intervention group who actually met dietary and physical activity targets (“adherent” women) developed GDM.
What Do These Findings Mean?
These findings indicate that intensified counseling on diet and physical activity is effective in controlling the birthweight of babies born to women at risk of developing GDM and encourages at least some of them to alter their lifestyle. However, the findings fail to show that the intervention reduces the risk of GDM because of the limited power of the study. The power of a study—the probability that it will achieve a statistically significant result—depends on the study's size and on the likely effect size of the intervention. Before starting this study, the researchers calculated that they would need 420 participants to see a statistically significant difference between the groups if their intervention reduced GDM incidence by 40%. This estimated effect size was probably optimistic and therefore the study lacked power. Nevertheless, the analyses performed among adherent women suggest that lifestyle changes might be a way to prevent GDM and so larger studies should now be undertaken to test this potential primary prevention intervention.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001036.
The US National Institute of Diabetes and Digestive and Kidney Diseases provides information for patients on diabetes and on gestational diabetes (in English and Spanish)
The UK National Health Service Choices website also provides information for patients on diabetes and on gestational diabetes, including links to other useful resources
The MedlinePlus Encyclopedia has pages on diabetes and on gestational diabetes; MedlinePlus provides links to additional resources on diabetes and on gestational diabetes (in English and Spanish)
More information on this trial of primary prevention of GDM is available
doi:10.1371/journal.pmed.1001036
PMCID: PMC3096610  PMID: 21610860
10.  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
11.  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
12.  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
13.  Impact of Scotland's Smoke-Free Legislation on Pregnancy Complications: Retrospective Cohort Study 
PLoS Medicine  2012;9(3):e1001175.
An analysis of pregnancy data for the whole of Scotland demonstrates a reduction in small-for-gestational-age births and preterm delivery since the introduction of legislation banning smoking in enclosed public spaces.
Background
Both active smoking and environmental tobacco smoke exposure are associated with pregnancy complications. In March 2006, Scotland implemented legislation prohibiting smoking in all wholly or partially enclosed public spaces. The aim of this study was to determine the impact of this legislation on preterm delivery and small for gestational age.
Methods and Findings
We conducted logistic regression analyses using national administrative pregnancy data covering the whole of Scotland. Of the two breakpoints tested, 1 January 2006 produced a better fit than the date when the legislation came into force (26 March 2006), suggesting an anticipatory effect. Among the 716,941 eligible women who conceived between August 1995 and February 2009 and subsequently delivered a live-born, singleton infant between 24 and 44 wk gestation, the prevalence of current smoking fell from 25.4% before legislation to 18.8% after legislation (p<0.001). Three months prior to the legislation, there were significant decreases in small for gestational age (−4.52%, 95% CI −8.28, −0.60, p = 0.024), overall preterm delivery (−11.72%, 95% CI −15.87, −7.35, p<0.001), and spontaneous preterm labour (−11.35%, 95% CI −17.20, −5.09, p = 0.001). In sub-group analyses, significant reductions were observed among both current and never smokers.
Conclusions
Reductions were observed in the risk of preterm delivery and small for gestational age 3 mo prior to the introduction of legislation, although the former reversed partially following the legislation. There is growing evidence of the potential for tobacco control legislation to have a positive impact on health.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
The risks of smoking during pregnancy, both on mother and fetus, are well established: women who smoke during pregnancy are more likely to have a miscarriage. Smoking can cause placental problems, such as placental abruption, which can result in heavy bleeding during pregnancy, which is dangerous for both mother and baby. Other dangers of smoking during pregnancy include the baby being born too early (premature birth), the baby being below average weight (small for gestational age), birth defects, and infant death. Because of the serious damage to health caused by smoking, in 2005, under the auspices of the World Health Organization, countries adopted the Framework Convention on Tobacco Control to protect present and future generations from the devastating health, social, environmental, and economic consequences of tobacco consumption and exposure to tobacco smoke. Article 8 of the treaty obliges member states who have ratified the treaty—168 so far—to protect all people from exposure to tobacco smoke in indoor workplaces, public transport, and indoor public places. As a result, many countries around the world have banned smoking in public places.
Why Was This Study Done?
Scotland was the first country in the United Kingdom to ban smoking in public places, which was implemented as part of the Smoking, Health and Social Care (Scotland) Bill on 26 March 2006. Previous studies have shown that the introduction of the legislation led directly to a reduction in smoking and also a reduction in environmental tobacco smoke exposure in adults and children. Furthermore, the Scottish legislation has been accompanied by significant reductions in both cardiovascular and respiratory disease. Because of the known risks of smoking during pregnancy, the researchers wanted to investigate whether the change in policy on smoking in public places had positive benefits on the health of mothers and babies. They evaluated this by measuring the rates of preterm delivery and small for gestational age before and after the Scottish legislation went into effect.
What Did the Researchers Do and Find?
The researchers collected information on preterm delivery and small for gestational age in all single babies born live at 22–44 weeks gestation between 1 January 1996 and 31 December 2009 by using the Scottish Morbidity Record (SMR2), which collects relevant information on all women discharged from Scottish maternity hospitals, including maternal and infant characteristics and pregnancy complications. The researchers categorized preterm delivery into mild, moderate, and extreme depending on how much before 37 weeks the baby was born. They defined small for gestational age as the smallest 10% (below the 10th centile) for sex-specific birth weight at delivery, and very small for gestational age as the smallest 3% (below the 3rd centile), for all deliveries in Scotland over the study period. As some people may have stopped smoking in anticipation of the smoking ban, in their statistical model, the researchers included two possible breakpoints for the effect of the legislation—the actual date of implementation and 1 January 2006.
The researchers found that of the 716,968 pregnancies (the number eligible for inclusion in the study), 99.9% of women had their smoking status recorded, and among these 23.9% were current smokers, 57.6% never smokers, and 8.7% former smokers. However, following implementation of the legislation the researchers noted that there was a significant reduction in current smokers to 18.8%. In their statistical model, the researchers found that following 1 January 2006, there was a significant drop in overall preterm deliveries, which remained after adjustment for potential confounding factors. Likewise, there was a significant decrease in the number of infants born small, and very small, for gestational age after 1 January 2006. Furthermore, the researchers found that these significant reductions occurred in both mothers who smoked and those who had never smoked.
What Do These Findings Mean?
These findings suggest that the introduction of national, comprehensive smoke-free legislation in Scotland was associated with significant reductions in preterm delivery and babies being born small for gestational age. These findings are plausible and add to the growing evidence of the wide-ranging health benefits of smoke-free legislation, and support the adoption of such legislation in other countries that have yet to implement smoking bans.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001175.
More information is available on the World Health Organization's Framework Convention for Tobacco Control
More information on the Smoking, Health and Social Care (Scotland) Bill is available
The US Centers for Disease Control and Prevention has more information about the risks of smoking in pregnancy, as does the UK National Health Service's smokefree web page
NHS Health Scotland has a website that summarises all the studies to date evaluating the Scottish smoke-free legislation
doi:10.1371/journal.pmed.1001175
PMCID: PMC3295815  PMID: 22412353
14.  Birthweight, preterm birth and perinatal mortality: A comparison of black babies in Tanzania and the USA 
Objectives
Adverse conditions in Africa produce some of the highest rates of infant mortality in the world. Fetal growth restriction and preterm delivery are commonly regarded as major pathways through which conditions in the developing world affect infant survival. The aim of this article was to compare patterns of birthweight, preterm delivery, and perinatal mortality between black people in Tanzania and the USA.
Design
Registry-based study.
Settings
Referral hospital data from North Eastern Tanzania and US Vital Statistics.
Sample
Consisted of 14 444 singleton babies from a hospital-based registry (1999–2006) and 3 530 335 black singletons from US vital statistics (1995–2000).
Main outcome measures
birthweight, gestational age and perinatal mortality.
Methods
Restricting to babies born with at least 500g, we compared birthweight, gestational age, and perinatal mortality (stillbirths and deaths in the first week) in the two study populations.
Results
Perinatal mortality in the Tanzanian sample was 41/1000, compared with 10/100 among USA blacks. Tanzanian babies were slightly smaller on average (43g), but fewer were preterm (before 37 weeks) (10.0% vs 16.2%). Applying the USA weight-specific mortality rates to Tanzanian babies born at term suggested that birthweight does not play a role in their increased mortality relative to USA blacks.
Conclusions
Higher mortality independent of birthweight and preterm delivery for Tanzanian babies, suggests the need to address the contribution of other pathways that can further reduce the excess perinatal mortality.
doi:10.1111/j.1600-0412.2011.01195.x
PMCID: PMC3655527  PMID: 21615361
birthweight; developing country; fetal development; perinatal mortality; preterm birth
15.  Risk adjusted and population based studies of the outcome for high risk infants in Scotland and Australia 
OBJECTIVES—To compare outcomes of care in selected neonatal intensive care units (NICUs) for very low birthweight (VLBW) or preterm infants in Scotland and Australia (study 1) and perinatal care for all VLBW infants in both countries (study 2).
DESIGN—Study 1: risk adjusted cohort study; study 2: population based cohort study.
SUBJECTS—Study 1: all 2621 infants of < 1500 g birth weight or < 31 weeks' gestation admitted to a volunteer sample of hospitals comprising eight of all 17 Scottish NICUs and six of all 12 tertiary NICUs in New South Wales and Queensland in 1993-1994; study 2: all 5986infants of 500-1499 g birth weight registered as live born in Scotland and Australia in 1993-1994.
MAIN OUTCOMES—Study 1: (a) hospital death; (b) death or cerebral damage, each adjusted for gestation and CRIB (clinical risk index for babies); study 2: neonatal (28 day) mortality.
RESULTS—Study 1. Data were obtained for 1628 admissions in six Australian NICUs, 775 in five Scottish tertiary NICUs, and 148 in three Scottish non-tertiary NICUs. Crude hospital death rates were 13%, 22%, and 22% respectively. Risk adjusted hospital mortality was about 50% higher in Scottish than in Australian NICUs (adjusted mortality ratio 1.46, 95% confidence interval (CI) 1.29 to 1.63,p < 0.001). There was no difference in risk adjusted outcomes between Scottish tertiary and non-tertiary NICUs. After risk adjustment, death or cerebral damage was more common in Scottish than Australian NICUs (odds ratio 1.9, 95% CI 1.5 to 2.5). Both these risk adjusted adverse outcomes remained more common in Scottish than Australian NICUs after excluding all infants < 28 weeks' gestation from the comparison. Study 2. Population based neonatal mortality in infants of 500-1499 g was higher in Scotland (20.3%) than Australia (16.6%) (relative risk 1.22, 95% CI 1.08 to 1.39, p = 0.002). In a post hoc analysis, neonatal mortality was also higher in England and Wales than in Australia.
CONCLUSIONS—Study 1: outcome was better in the Australian NICUs. Study 2: perinatal outcome was better in Australia. Both results may be consistent, at least in part, with differences in the organisation and implementation of neonatal care.


doi:10.1136/fn.82.2.F118
PMCID: PMC1721047  PMID: 10685984
16.  Prevalence and perinatal mortality associated with preterm births in a tertiary medical center in South East Nigeria 
Background
Preterm birth is a high risk condition associated with significant mortality and morbidity in the perinatal, neonatal, and childhood periods, and even in adulthood. Knowledge of the epidemiology of preterm births is necessary for planning appropriate maternal and fetal care.
Objective
The objective of this study was to determine the prevalence, pattern, and perinatal mortality associated with preterm births at the University of Nigeria Teaching Hospital, Enugu, South East Nigeria.
Methods
This was a review of prospectively collected routine delivery data involving preterm deliveries that occurred between 1 January 2009 and 31 December 2013. Data analysis involved descriptive and inferential statistics at 95% level of confidence using SPSS version 17.0 for Windows.
Results
There were 3,760 live births over the 5-year study period out of which 636 were preterm births, giving a prevalence rate of 16.9%. Spontaneous preterm births occurred in approximately 57% of preterm births while provider-initiated births occurred in 43%. The mean gestational age at preterm deliveries was 32.6±3.2 weeks while the mean birth weight was 2.0±0.8 kilograms. Approximately 89% of preterm births involved singleton pregnancies. Sixty-eight percent of preterm births were moderate to late preterm. The male:female ratio of preterm babies born during the period was 1.2:1. The adjusted perinatal mortality rate for preterm babies in the study center was 46.1% (236/512). The stillbirth rate for preterm babies was 22.0% (149/678) and the adjusted early neonatal death rate was 24.0% (87/363).
Conclusion
The prevalence of preterm births and associated perinatal mortality were high which may be a reflection of suboptimal prenatal and newborn care. An urgent improvement in prenatal and newborn care is therefore needed in the study center in order to improve the capacity to prevent or abate preterm labor, and preterm premature rupture of membranes; and to reduce avoidable stillbirths. Further upgrading of personnel and facilities in the newborn special care unit is also required to minimize early neonatal deaths.
doi:10.2147/IJWH.S72229
PMCID: PMC4207576  PMID: 25378955
preterm birth; prevalence; mortality; pattern; Nigeria
17.  A population-based investigation into inequalities amongst Indigenous mothers and newborns by place of residence in the Northern territory, Australia 
Background
Comparisons of birth outcomes between Australian Indigenous and non-Indigenous populations show marked inequalities. These comparisons obscure Indigenous disparities. There is much variation in terms of culture, language, residence, and access to services amongst Australian Indigenous peoples. We examined outcomes by region and remoteness for Indigenous subgroups and explored data for communities to inform health service delivery and interventions.
Methods
Our population-based study examined maternal and neonatal outcomes for 7,560 mothers with singleton pregnancies from Australia’s Northern Territory Midwives’ Data Collection (2003–2005) using uni- and multivariate analyses. Groupings were by Indigenous status; region (Top End (TE)/Central Australia (CA)); Remote/Urban residence; and across two large TE communities.
Results
Of the sample, 34.1% were Indigenous women, of whom 65.6% were remote-dwelling versus 6.7% of non-Indigenous women. In comparison to CA Urban mothers: TE Remote (adjusted odds ratio [aOR] 1.47, 95%CI: 1.13, 1.90) and TE Urban mothers (aOR 1.36 (95% CI: 1.02, 1.80) were more likely, but CA Remote mothers (aOR 0.43; 95% CI: 0.31, 0.58) less likely to smoke during pregnancy; CA Remote mothers giving birth at >32 weeks gestation were less likely to have attended ≥ five antenatal visits (aOR 0.55; 95%CI: 0.36, 0.86); TE Remote (aOR 0.71; 95%CI: 0.53, 0.95) and CA Remote women (aOR 0.68; 95%CI: 0.49, 0.95) who experienced labour had lower odds of epidural/spinal/narcotic pain relief; and TE Remote (aOR 0.47; 95%CI: 0.34, 0.66), TE Urban (aOR 0.67; 95%CI: 0.46, 0.96) and CA Remote mothers (aOR 0.52; 95%CI: 0.35, 0.76) all had lower odds of having a ‘normal’ birth. The aOR for preterm birth for TE Remote newborns was 2.09 (95%CI: 1.20, 3.64) and they weighed 137 g (95%CI: -216 g, -59 g) less than CA Urban babies. There were few significant differences for communities, except for smoking prevalence.
Conclusions
This paper is one of few quantifying inequalities between groups of Australian Indigenous women and newborns at a regional level. Indigenous mothers and newborns do worse on some outcomes if they live remotely, especially if they live in the TE. Smoking prevention and high-quality antenatal care is fundamental to addressing many of the adverse outcomes identified in this paper.
doi:10.1186/1471-2393-12-44
PMCID: PMC3480936  PMID: 22682627
Indigenous; Remote; Maternal; Neonatal; Inequalities
18.  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
19.  National and regional estimates of term and preterm babies born small for gestational age in 138 low-income and middle-income countries in 2010 
The Lancet. Global Health  2013;1(1):e26-e36.
Summary
Background
National estimates for the numbers of babies born small for gestational age and the comorbidity with preterm birth are unavailable. We aimed to estimate the prevalence of term and preterm babies born small for gestational age (term-SGA and preterm-SGA), and the relation to low birthweight (<2500 g), in 138 countries of low and middle income in 2010.
Methods
Small for gestational age was defined as lower than the 10th centile for fetal growth from the 1991 US national reference population. Data from 22 birth cohort studies (14 low-income and middle-income countries) and from the WHO Global Survey on Maternal and Perinatal Health (23 countries) were used to model the prevalence of term-SGA births. Prevalence of preterm-SGA infants was calculated from meta-analyses.
Findings
In 2010, an estimated 32·4 million infants were born small for gestational age in low-income and middle-income countries (27% of livebirths), of whom 10·6 million infants were born at term and low birthweight. The prevalence of term-SGA babies ranged from 5·3% of livebirths in east Asia to 41·5% in south Asia, and the prevalence of preterm-SGA infants ranged from 1·2% in north Africa to 3·0% in southeast Asia. Of 18 million low-birthweight babies, 59% were term-SGA and 41% were preterm. Two-thirds of small-for-gestational-age infants were born in Asia (17·4 million in south Asia). Preterm-SGA babies totalled 2·8 million births in low-income and middle-income countries. Most small-for-gestational-age infants were born in India, Pakistan, Nigeria, and Bangladesh.
Interpretation
The burden of small-for-gestational-age births is very high in countries of low and middle income and is concentrated in south Asia. Implementation of effective interventions for babies born too small or too soon is an urgent priority to increase survival and reduce disability, stunting, and non-communicable diseases.
Funding
Bill & Melinda Gates Foundation by a grant to the US Fund for UNICEF to support the activities of the Child Health Epidemiology Reference Group (CHERG).
doi:10.1016/S2214-109X(13)70006-8
PMCID: PMC4221634  PMID: 25103583
20.  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
21.  Decreased Bone Mineral Density in Adults Born with Very Low Birth Weight: A Cohort Study 
PLoS Medicine  2009;6(8):e1000135.
Petteri Hovi and colleagues evaluate skeletal health in 144 adults born preterm with very low birth weight and show that as adults these individuals have significantly lower bone mineral density than do their term-born peers.
Background
Very-low-birth-weight (VLBW, <1,500 g) infants have compromised bone mass accrual during childhood, but it is unclear whether this results in subnormal peak bone mass and increased risk of impaired skeletal health in adulthood. We hypothesized that VLBW is associated with reduced bone mineral density (BMD) in adulthood.
Methods and Findings
The Helsinki Study of Very Low Birth Weight Adults is a multidisciplinary cohort study representative of all VLBW births within the larger Helsinki area from 1978 to 1985. This study evaluated skeletal health in 144 such participants (all born preterm, mean gestational age 29.3 wk, birth weight 1,127 g, birth weight Z score 1.3), and in 139 comparison participants born at term, matched for sex, age, and birth hospital. BMD was measured by dual energy X-ray absorptiometry at age 18.5 to 27.1 y. Adults born with VLBW had, in comparison to participants born at term, a 0.51-unit (95% confidence interval [CI] 0.28–0.75) lower lumbar spine Z score and a 0.56-unit (95% CI 0.34–0.78) lower femoral neck Z score for areal BMD. These differences remained statistically significant after adjustment for the VLBW adults' shorter height and lower self-reported exercise intensity.
Conclusions
Young adults born with VLBW, when studied close to the age of peak bone mass, have significantly lower BMD than do their term-born peers. This suggests that compromised childhood bone mass accrual in preterm VLBW children translates into increased risk for osteoporosis in adulthood, warranting vigilance in osteoporosis prevention.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Most pregnancies last 40 weeks but some babies arrive earlier than expected. Sadly, babies born before 37 weeks of pregnancy—premature babies—are more likely to die than full-term babies, although recent improvements in neonatal care have increased their chances of survival. Premature babies also often have serious long-term health problems, particularly those born before 32 weeks of pregnancy. Such extremely premature babies have poorly developed internal organs and are usually very small—babies whose birth weight is less than 1,500 g are called very-low-birth-weight (VLBW) babies; the average full-term birth weight is about 3,500 g. Furthermore, their bones are not as well developed as those of full-term babies. The human skeleton initially consists of a soft fibrous material called cartilage. This is gradually transformed into bone by a process called bone mineralization. The last third of pregnancy is a crucial period for bone mineralization although the process continues throughout infancy and childhood. Thus, VLBW babies often have subnormal skeletal mineralization and their accrual of bone mass during childhood is frequently compromised.
Why Was This Study Done?
It is not known whether the childhood bone deficits of VLBW babies persist into adulthood because the first generation of these infants not to die soon after birth is only just reaching adulthood. Peak bone mass is reached in early adulthood (bone mass begins to decrease from the age of 35 years onward) and is an important indicator of whether an individual will develop osteoporosis (thinning of the bones) and be susceptible to bone fractures later in life. If adults with VLBW (about 1% of live births in high-income countries are now VLBW births) do have a subnormal peak bone mass and reduced bone mineral density (BMD), they may be able reduce their risk of developing osteoporosis by eating a healthy diet and exercising regularly. In this study (part of the Helsinki Study of Very Low Birth Weight Adults), the researchers investigate the skeletal health of people who were born with VLBW in the Helsinki area between 1978 and 1985.
What Did the Researchers Do and Find?
The researchers compared the skeletal health of 144 young adults who were born prematurely with VLBW and subnormal BMD with that of 139 age- and sex-matched individuals who were born at term. They measured the BMD of the participants (average age 22.6 years) using “dual energy X-ray absorptiometry” and determined a “Z score” for the spine in the lower back (the lower lumbar spine) and the hip (two sites that are routinely examined in assessments of skeletal health). Z scores indicate whether an individual's BMD is significantly different from the average BMD of healthy age- and sex-matched people; in this study, reduced BMD was defined as a Z score of −1.0 or less. The researchers found that adults born with VLBW had an average Z score of −0.51 at the lower lumbar spine and −0.56 at the hip when compared with the adults born at term. Furthermore, 44% of the VLBW participants but only 26% of the term-born participants had a lumbar spine Z score of −1.0 or less. Adjustment for the shorter height of the VLBW participants slightly reduced these differences in BMD but the differences remained statistically significant.
What Do These Findings Mean?
These findings show that, when studied close to the age of peak bone mass, young adults born with VLBW have a significantly lower BMD than their term-born peers and a 2-fold greater risk of having a lumbar spine Z score of below −1.0; a unit decrease in Z score approximately doubles the risk of bone fractures. Because BMD measurements were only taken at one age, it remains possible, however, that the BMD of the VLBW adults might eventually match that of their full-term peers. Recently born VLBW babies still have a lower than average BMD during their childhood, note the researchers, even though their care has changed since the people included in this study were born. Thus, these findings suggest that people who were VLBW infants should be encouraged to eat food rich in vitamin D and calcium and to do regular weight-bearing exercise throughout their lives to improve their bone health and reduce their risk of developing osteoporosis.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000135.
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 and to information on osteoporosis (in English and Spanish)
The US National Institute of Arthritis and Musculoskeletal and Skin Diseases and the UK National Health Service also provide detailed information on all aspects of osteoporosis
Further details about the Helsinki Study of Very Low Birth Weight Adults are available
doi:10.1371/journal.pmed.1000135
PMCID: PMC2722726  PMID: 19707270
22.  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
23.  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
24.  Preventing preterm births: trends and potential reductions with current interventionsin 39 very high human development index countries 
Lancet  2012;381(9862):223-234.
Summary
Background
Each year,1.1 million babies die from prematurity, andmany survivors are disabled. Worldwide, 15 million babies are preterm(<37 weeks’ gestation),withtwo decades of increasing ratesinalmost all countries with reliable data. Improved care of babies has reduced mortality in high-income countries, although effective interventions have yet to be scaled-up in most low-income countries. A 50% reduction goal for preterm-specific mortality by 2025 has been set in the “Born Too Soon” report. However, for preterm birth prevention,understanding of drivers and potential impact of preventive interventions is limited. We examine trends and estimate the potential reduction in preterm birthsforvery high human development index (VHHDI) countries if current evidence-based interventions were widely implemented. This analysis is to inform a “Born Too Soon” rate reduction target.
Methods
Countries were assessed for inclusion based on availability and quality ofpreterm prevalence data (2000-2010), and trend analyses with projections undertaken. We analysed drivers of rate increases in the USA, 1998-2004. For 39 VHHDI countrieswith >10,000 births, country-by-country analyses were performed based on target population, incremental coverage increase,and intervention efficacy. Cost savings were estimated based on reported costs for preterm care in the USAadjusted usingWorld Bank purchasing power parity.
Findings
From 2010, even if all VHHDI countries achieved annual preterm birth rate reductions of the best performers, (Sweden and Netherlands), 2000-2010 or 2005-2010(Lithuania, Estonia)), rates would experience a relative reduction of<5% by 2015 on average across the 39 countries.Our analysis of preterm birth rise 1998-2004 in USA suggests half the change is unexplained, but important drivers includeinductions/cesareandelivery and ART.For all 39 VHHDI countries, five interventionsmodeling at high coveragepredicted 5%preterm birth rate relative reduction from 9.59 to 9.07% of live births:smoking cessation (0.01 rate reduction), decreasing multiple embryo transfers during assisted reproductive technologies (0.06), cervical cerclage (0.15), progesterone supplementation (0.01), and reduction of non-medically indicated labour induction or caesarean delivery (0.29).These translate to 58,000 preterm births averted and total annual economic cost savings of ~US$ 3 billion.
Interpretation
Even with optimal coverage of current interventions, many being complex to implement, the estimated potential reduction in preterm birth is tiny. Hence we recommenda conservative target of 5% preterm birth rate relative reductionby 2015. Our findings highlight the urgent need for discovery research into underlying mechanisms of preterm birth, and developmentof innovative interventions. Furthermore, the highest preterm birth rates occur in low-income settings where the causes of prematurity may differand have simpler solutions, such as birth spacing and treatment of infections in pregnancy. Urgent focus on these settings also is critical to reduce preterm births worldwide.
doi:10.1016/S0140-6736(12)61856-X
PMCID: PMC3572865  PMID: 23158883
child mortality; newborn mortality; preterm birth; prematurity
25.  Birth outcomes and infant mortality among First Nations Inuit, and non-Indigenous women by northern versus southern residence, Quebec 
Background
In circumpolar countries such as Canada, northern regions represent a unique geographical entity climatically, socioeconomically and environmentally. There is a lack of comparative data on birth outcomes among Indigenous and non-Indigenous subpopulations within northern regions and compared with southern regions.
Methods
A cohort study of all births by maternal mother tongue to residents of northern (2616 First Nations (North American Indians), 2388 Inuit and 5006 non-Indigenous) and southern (2563 First Nations, 810 643 non-Indigenous) Quebec, 1991–2000.
Results
Compared with births to southern non-Indigenous mother tongue women, births to northern women of all three mother tongue groups were at substantially elevated risks of infant death (adjusted OR (aOR) 1.7–2.9), especially postneonatal death (aOR 2.2–4.4) after controlling for maternal education, age, marital status and parity. The risk elevation in perinatal death was greater for southern First Nations (aOR 1.6) than for northern First Nations (aOR 1.2). Infant macrosomia was highly prevalent among First Nations in Quebec, especially in the north (31% vs 24% in the south). Within northern regions, Inuit births were at highest risk of preterm delivery (aOR 1.4) and infant death (aOR 1.6).
Conclusion
All northern infants (First Nations, Inuit or non-Indigenous) were at substantially elevated risk of infant death in Quebec, despite a universal health insurance system. Southern First Nations newborns have not benefited from the more advanced perinatal care facilities in southern regions. Environmental influences may partly account for the very high prevalence of macrosomia among First Nations in northern Quebec.
doi:10.1136/jech.2009.092619
PMCID: PMC3133748  PMID: 21051777 CAMSID: cams1702

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