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1.  Racial variation in the association between gestational age and perinatal mortality: prospective study 
BMJ : British Medical Journal  2007;334(7598):833.
Objectives To determine if the risks of perinatal mortality and antepartum stillbirth associated with post term birth increase earlier during pregnancy in South Asian and black women than in white women, and to investigate differences in the factors associated with antepartum stillbirth between the racial groups.
Design Prospective study using logistic regression analysis.
Setting 15 maternity units in northwest London from 1988 to 2000.
Participants 197 061 nulliparous women self reported as white, South Asian, or black, who delivered a single baby weighing at least 500 g at 24-43 completed weeks' gestation.
Main outcome measures Gestation specific perinatal mortality, antepartum stillbirth rates, and independent factors for antepartum stillbirth by racial groups.
Results The crude gestation specific perinatal mortality patterns for the three racial groups differed (P<0.001). The perinatal mortality rate among black women was lower than among white women before 32 weeks but was higher thereafter. Perinatal mortality was highest among South Asian women at all gestational ages and increased the fastest at term. After adjusting for the confounders of antepartum stillbirth (placental abruption, congenital abnormality, low birth weight, birth weight <10th centile, meconium passage, fever, maternal body mass index ≥30, and maternal age ≥30), the excess mortality among black women after 32 weeks was not significant. After adjusting for confounding, South Asian women still had a significantly higher risk of antepartum stillbirth (odds ratio 1.8, 95% confidence interval 1.2 to 2.7).
Conclusions The risk of perinatal mortality increased earlier in gestation among South Asian women than among white women. The most important factor associated with antepartum stillbirth among white women was placental abruption, but among South Asian and black women it was birth weight below 2000 g.
doi:10.1136/bmj.39132.482025.80
PMCID: PMC1853199  PMID: 17337455
2.  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
3.  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
4.  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
5.  Community Mobilization in Mumbai Slums to Improve Perinatal Care and Outcomes: A Cluster Randomized Controlled Trial 
PLoS Medicine  2012;9(7):e1001257.
David Osrin and colleagues report findings from a cluster-randomized trial conducted in Mumbai slums; the trial aimed to evaluate whether facilitator-supported women's groups could improve perinatal outcomes.
Introduction
Improving maternal and newborn health in low-income settings requires both health service and community action. Previous community initiatives have been predominantly rural, but India is urbanizing. While working to improve health service quality, we tested an intervention in which urban slum-dweller women's groups worked to improve local perinatal health.
Methods and Findings
A cluster randomized controlled trial in 24 intervention and 24 control settlements covered a population of 283,000. In each intervention cluster, a facilitator supported women's groups through an action learning cycle in which they discussed perinatal experiences, improved their knowledge, and took local action. We monitored births, stillbirths, and neonatal deaths, and interviewed mothers at 6 weeks postpartum. The primary outcomes described perinatal care, maternal morbidity, and extended perinatal mortality. The analysis included 18,197 births over 3 years from 2006 to 2009. We found no differences between trial arms in uptake of antenatal care, reported work, rest, and diet in later pregnancy, institutional delivery, early and exclusive breastfeeding, or care-seeking. The stillbirth rate was non-significantly lower in the intervention arm (odds ratio 0.86, 95% CI 0.60–1.22), and the neonatal mortality rate higher (1.48, 1.06–2.08). The extended perinatal mortality rate did not differ between arms (1.19, 0.90–1.57). We have no evidence that these differences could be explained by the intervention.
Conclusions
Facilitating urban community groups was feasible, and there was evidence of behaviour change, but we did not see population-level effects on health care or mortality. In cities with multiple sources of health care, but inequitable access to services, community mobilization should be integrated with attempts to deliver services for the poorest and most vulnerable, and with initiatives to improve quality of care in both public and private sectors.
Trial registration
Current Controlled Trials ISRCTN96256793
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Substantial progress is being made to reduce global child mortality (deaths of children before the age of 5 years) and maternal mortality (deaths among women because of complications of pregnancy and childbirth)—two of the Millennium Development Goals agreed by world leaders in 2000 to end extreme poverty. Even so, worldwide, in 2010, 7.6 million children died before their fifth birthday and there were nearly 360,000 maternal deaths. Almost all child and maternal deaths occur in developing countries—a fifth of under-five deaths and more than a quarter of neonatal deaths (deaths during the first month of life, which account for two-fifths of all child deaths) occur in India alone. Moreover, most child and maternal deaths are caused by avoidable conditions. Specifically, the major causes of neonatal death—complications of preterm delivery, breathing problems during or after delivery, and infections of the blood (sepsis) and lungs (pneumonia)—and of maternal deaths—hemorrhage (abnormal bleeding), sepsis, unsafe abortion, obstructed labor, and hypertensive diseases of pregnancy—could all be largely prevented by improved access to reproductive health services and skilled health care workers.
Why Was This Study Done?
Experts believe that improvements to maternal and newborn health in low-income settings require both health service strengthening and community action. That is, the demand for better services, driven by improved knowledge about maternal and newborn health (perinatal issues), has to be increased in parallel with the supply of those services. To date, community mobilization around perinatal issues has largely been undertaken in rural settings but populations in developing countries are becoming increasingly urban. In India, for example, 30% of the population now lives in cities. In this cluster randomized controlled trial (a study in which groups of people are randomly assigned to receive alternative interventions and the outcomes in the differently treated “clusters” are compared), City Initiative for Newborn Health (CINH) researchers investigate the effect of an intervention designed to help women's groups in the slums of Mumbai work towards improving local perinatal health. The CINH aims to improve maternal and newborn health in slum communities by improving public health care provision and by working with community members to improve maternal and newborn care practices and care-seeking behaviors.
What Did the Researchers Do and Find?
The researchers enrolled 48 Mumbai slum communities of at least 1,000 households into their trial. In each of the 24 intervention clusters, a facilitator supported local women's groups through a 36-meeting learning cycle during which group members discussed their perinatal experiences, improved their knowledge, and took action. To measure the effect of the intervention, the researchers monitored births, stillbirths, and neonatal deaths in all the clusters and interviewed mothers 6 weeks after delivery. During the 3-year trial, there were 18,197 births in the participating settlements. The women in the intervention clusters were enthusiastic about acquiring new knowledge and made substantial efforts to reach out to other women but were less successful in undertaking collective action such as negotiations with civic authorities for more amenities. There were no differences between the intervention and control communities in the uptake of antenatal care, reported work, rest, and diet in late pregnancy, institutional delivery, or in breast feeding and care-seeking behavior. Finally, the combined rate of stillbirths and neonatal deaths (the extended perinatal mortality rate) was the same in both arms of the trial, as was maternal mortality.
What Do These Findings Mean?
These findings indicate that it is possible to facilitate the discussion of perinatal health care by urban women's groups in the challenging conditions that exist in the slums of Mumbai. However, they fail to show any measureable effect of community mobilization through the facilitation of women's groups on perinatal health at the population level. The researchers acknowledge that more intensive community activities that target the poorest, most vulnerable slum dwellers might produce measurable effects on perinatal mortality, and they conclude that, in cities with multiple sources of health care and inequitable access to services, it remains important to integrate community mobilization with attempts to deliver services to the poorest and most vulnerable, and with initiatives to improve the quality of health care in both the public and private sector.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001257.
The United Nations Childrens Fund (UNICEF) works for children's rights, survival, development, and protection around the world; it provides information on the reduction of child mortality (Millennium Development Goal 4); its Childinfo website provides information about all the Millennium Development Goals and detailed statistics about on child survival and health, newborn care, and maternal health (some information in several languages)
The World Health Organization also has information about Millennium Development Goal 4 and Millennium Development Goal 5, the reduction of maternal mortality, provides information on newborn infants, and provides estimates of child mortality rates (some information in several languages)
Further information about the Millennium Development Goals is available
Information on the City Initiative for Newborn Health and its partners and a detailed description of its trial of community mobilization in Mumbai slums to improve care during pregnancy, delivery, postnatally and for the newborn are available
Further information about the Society for Nutrition, Education and Health Action (SNEHA) is available
doi:10.1371/journal.pmed.1001257
PMCID: PMC3389036  PMID: 22802737
6.  Preeclampsia as a Risk Factor for Diabetes: A Population-Based Cohort Study 
PLoS Medicine  2013;10(4):e1001425.
Denice Feig and colleagues assess the association between gestational diabetes, gestational hypertension, and preeclampsia and the development of future diabetes in a database analysis of pregnant women in Ontario, Canada.
Background
Women with preeclampsia (PEC) and gestational hypertension (GH) exhibit insulin resistance during pregnancy, independent of obesity and glucose intolerance. Our aim was to determine whether women with PEC or GH during pregnancy have an increased risk of developing diabetes after pregnancy, and whether the presence of PEC/GH in addition to gestational diabetes (GDM) increases the risk of future (postpartum) diabetes.
Methods and Findings
We performed a population-based, retrospective cohort study for 1,010,068 pregnant women who delivered in Ontario, Canada between April 1994 and March 2008. Women were categorized as having PEC alone (n = 22,933), GH alone (n = 27,605), GDM alone (n = 30,852), GDM+PEC (n = 1,476), GDM+GH (n = 2,100), or none of these conditions (n = 925,102). Our main outcome was a new diagnosis of diabetes postpartum in the following years, up until March 2011, based on new records in the Ontario Diabetes Database. The incidence rate of diabetes per 1,000 person-years was 6.47 for women with PEC and 5.26 for GH compared with 2.81 in women with neither of these conditions. In the multivariable analysis, both PEC alone (hazard ratio [HR] = 2.08; 95% CI 1.97–2.19) and GH alone (HR = 1.95; 95% CI 1.83–2.07) were risk factors for subsequent diabetes. Women with GDM alone were at elevated risk of developing diabetes postpartum (HR = 12.77; 95% CI 12.44–13.10); however, the co–presence of PEC or GH in addition to GDM further elevated this risk (HR = 15.75; 95% CI 14.52–17.07, and HR = 18.49; 95% CI 17.12–19.96, respectively). Data on obesity were not available.
Conclusions
Women with PEC/GH have a 2-fold increased risk of developing diabetes when followed up to 16.5 years after pregnancy, even in the absence of GDM. The presence of PEC/GH in the setting of GDM also raised the risk of diabetes significantly beyond that seen with GDM alone. A history of PEC/GH during pregnancy should alert clinicians to the need for preventative counseling and more vigilant screening for diabetes.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Diabetes is a chronic disease that occurs either when the pancreas does not produce enough insulin (a hormone that regulates blood sugar), known as type 1 diabetes, or when the body cannot effectively use the insulin it produces—type 2 diabetes. Raised blood sugar, is a common effect of uncontrolled diabetes and over time leads to serious complications and even death. Worryingly, the global burden of type 2 diabetes is increasing worldwide, and the World Health Organization estimates that 90% of the 347 million people with diabetes currently have type 2 diabetes. Previous studies have shown that type 2 diabetes can be prevented or delayed in high risk groups by a range of lifestyle and treatment interventions and so it is important to identify potential high risk groups to screen for type 2 diabetes.
Why Was This Study Done?
Gestational diabetes (a form of diabetes that is related to pregnancy) is a major risk factor for developing type 2 diabetes. Therefore, diabetes prevention strategies should target women with gestational diabetes. Likewise, other common disorders of pregnancy possibly associated with insulin resistance, such as preeclampsia (a condition in which affected women have high blood pressure, fluid retention, and protein in their urine) and gestational hypertension (high blood pressure associated with pregnancy), may lead to the future development of type 2 diabetes. So women with these conditions may also benefit from diabetes prevention strategies. Therefore, in this large database study from Ontario, Canada, the researchers examined whether pregnant women with preeclampsia or gestational hypertension had an increased risk of developing diabetes in the years following pregnancy even if they did not have gestational diabetes.
What Did the Researchers Do and Find?
The researchers used a comprehensive Canadian health database to identify all women age 15 to 50 years of age who delivered in an Ontario hospital between April 1994 and March 2008. They then identified women who had preeclampsia, gestational hypertension, or gestational diabetes through hospital records and outpatient information. The researchers then used records from the Ontario Diabetes Database to record whether these women went on to develop diabetes in the period from 180 days after delivery until March 2011.
Using these methods, the researchers identified 1,010,068 pregnant women suitable for analysis, of whom 22,933 had only preeclampsia, 27,605 had only gestational hypertension, and 30,852 had only gestational diabetes: 2,100 women had both gestational diabetes and gestational hypertension and 1,476 women had gestational diabetes and preeclampsia. Overall, 35,077 women developed diabetes (3.5%) in the follow-up period (median of 8.5 years) at a median age of 37 years. In a modeling analysis, the researchers found that women with gestational diabetes had a 15-fold increased rate of developing diabetes compared to women without gestational diabetes, gestational hypertension, and preeclampsia, while women with gestational diabetes plus either preeclampsia or gestational hypertension had a 20- to 21-fold increased rate. These results were slightly reduced after adjusting for age, income quintile, hypertension prior to pregnancy, and co-morbidity, giving a hazard ratio (HR) of 1.95 for gestational hypertension alone, an HR of 2.08 for preeclampsia alone, an HR of 12.77 for gestational diabetes alone, an HR of 18.49 for gestational diabetes plus gestational hypertension and finally, an HR of 15.75 for gestational diabetes plus preeclampsia.
These Findings Mean?
These findings suggest that both preeclampsia and gestational hypertension without gestational diabetes are associated with a 2-fold increased incidence of diabetes in the years following pregnancy after controlling for several important variables. When combined with gestational diabetes, these conditions were associated with a further elevation in diabetes incidence additional to the 13-fold increased incidence resulting from gestational diabetes alone. A limitation of this study was the lack of information on obesity and body mass index, factors which are also associated with increased risk of developing diabetes. Nevertheless, these findings highlight a possible new risk factor for diabetes, and suggest that clinicians should be aware of the need for preventative measures and vigilant screening for diabetes in women with a history of preeclampsia or gestational hypertension.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001425.
NHS Choices has information about preeclampsia, gestational diabetes, and gestational hypertension
Living with diabetes is a useful resource for patients with diabetes
The Preeclampsia Foundation has more information about preeclampsia
doi:10.1371/journal.pmed.1001425
PMCID: PMC3627640  PMID: 23610560
7.  Cesarean Section and Rate of Subsequent Stillbirth, Miscarriage, and Ectopic Pregnancy: A Danish Register-Based Cohort Study 
PLoS Medicine  2014;11(7):e1001670.
Louise Kenny and colleagues conduct a population-based cohort study in Denmark to assess the likelihood of stillbirth, miscarriage, and ectopic pregnancy following cesarean section compared to women who gave birth by vaginal delivery.
Please see later in the article for the Editors' Summary
Background
With cesarean section rates increasing worldwide, clarity regarding negative effects is essential. This study aimed to investigate the rate of subsequent stillbirth, miscarriage, and ectopic pregnancy following primary cesarean section, controlling for confounding by indication.
Methods and Findings
We performed a population-based cohort study using Danish national registry data linking various registers. The cohort included primiparous women with a live birth between January 1, 1982, and December 31, 2010 (n = 832,996), with follow-up until the next event (stillbirth, miscarriage, or ectopic pregnancy) or censoring by live birth, death, emigration, or study end. Cox regression models for all types of cesarean sections, sub-group analyses by type of cesarean, and competing risks analyses for the causes of stillbirth were performed. An increased rate of stillbirth (hazard ratio [HR] 1.14, 95% CI 1.01, 1.28) was found in women with primary cesarean section compared to spontaneous vaginal delivery, giving a theoretical absolute risk increase (ARI) of 0.03% for stillbirth, and a number needed to harm (NNH) of 3,333 women. Analyses by type of cesarean section showed similarly increased rates for emergency (HR 1.15, 95% CI 1.01, 1.31) and elective cesarean (HR 1.11, 95% CI 0.91, 1.35), although not statistically significant in the latter case. An increased rate of ectopic pregnancy was found among women with primary cesarean overall (HR 1.09, 95% CI 1.04, 1.15) and by type (emergency cesarean, HR 1.09, 95% CI 1.03, 1.15, and elective cesarean, HR 1.12, 95% CI 1.03, 1.21), yielding an ARI of 0.1% and a NNH of 1,000 women for ectopic pregnancy. No increased rate of miscarriage was found among women with primary cesarean, with maternally requested cesarean section associated with a decreased rate of miscarriage (HR 0.72, 95% CI 0.60, 0.85). Limitations include incomplete data on maternal body mass index, maternal smoking, fertility treatment, causes of stillbirth, and maternally requested cesarean section, as well as lack of data on antepartum/intrapartum stillbirth and gestational age for stillbirth and miscarriage.
Conclusions
This study found that cesarean section is associated with a small increased rate of subsequent stillbirth and ectopic pregnancy. Underlying medical conditions, however, and confounding by indication for the primary cesarean delivery account for at least part of this increased rate. These findings will assist women and health-care providers to reach more informed decisions regarding mode of delivery.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Globally, increasing numbers of babies are being delivered by cesarean section (a surgical operation in which the baby is delivered through a cut made in the mother's abdomen and womb) instead of naturally through their mother's vagina. In England in 2010, for example, nearly 25% of all babies were delivered by cesarean section (also called C-section) compared to only 2% in the 1950s; in China and some parts of South America cesarean rates are now between 40% and 50%. A cesarean section is usually performed when a vaginal birth would endanger the life of the mother or her unborn child because, for example, the baby is in the wrong position. Some cesareans are performed as emergency procedures, but others are planned in advance when the need for the operation becomes clear during pregnancy (an elective cesarean). Some planned cesarean sections are also undertaken because the mother has requested a cesarean delivery in the absence of any medical reasons for such a delivery.
Why Was This Study Done?
Cesarean sections save lives but do they have any negative impacts on the outcome of subsequent pregnancies? With so many cesarean sections being undertaken, it is important to be sure that the procedure does not increase the rates of subsequent miscarriage, stillbirth, or ectopic pregnancy. Miscarriage—the loss of a fetus (developing baby) that is unable to survive independently—is the commonest complication of early pregnancy, affecting about one in five women who know they are pregnant. Stillbirth is fetal death after about 20–24 weeks of pregnancy; the exact definition of stillbirth varies between countries. About four million stillbirths occur each year worldwide. Ectopic pregnancy—development of the fetus outside the womb—occurs in 1%–2% of all pregnancies. In this population-based cohort study, the researchers investigate the rates of subsequent stillbirth, miscarriage, and ectopic pregnancy following a cesarean section among women living in Denmark. A population-based cohort study determines the baseline characteristics of the individuals in a population, and then follows the population over time to see whether specific characteristics are associated with specific outcomes.
What Did the Researchers Do and Find?
The researchers obtained data for 832,996 women from Danish national registers about their first live birth (including whether they had a cesarean) then followed the women (again using the registers) until they had a stillbirth, miscarriage, or ectopic pregnancy, or a second live birth. The researchers used these data and statistical models to estimate the risk of stillbirth, miscarriage, and ectopic pregnancy following a cesarean compared to a spontaneous vaginal delivery after controlling for the possibility that the cesarean was performed because of an indication that might increase the risk of a subsequent event (confounding). Women who had had a cesarean had a 14% increased risk of a stillbirth in their next pregnancy compared to women who had had a vaginal delivery, corresponding to an absolute risk increase of 0.03%. In other words, 3,333 women would need to have a cesarean to result in one extra stillbirth in subsequent pregnancy (a “number needed to harm” of 3,333). Compared to vaginal delivery, having a cesarean increased the risk of a subsequent ectopic pregnancy by 9% (an absolute risk increase of 0.1% and a number needed to harm of 1,000) but did not increase the rate of subsequent miscarriages.
What Do These Findings Mean?
These findings show that, among women living in Denmark, cesarean section is associated with a slightly increased rate of subsequent stillbirth and ectopic pregnancy. Part of this increase can be accounted for by underlying medical conditions and by confounding by the indication for the primary cesarean section. The accuracy of these findings may be affected by limitations in the study such as incomplete data on some factors (for example, the smoking history of the mother) that might have affected the risk of stillbirth, miscarriage, and ectopic pregnancy, and by misclassification or underreporting of the study outcomes. Given the global increase in cesarean rates, these findings suggest that cesarean delivery is not associated with an increased rate of subsequent stillbirth, miscarriage, or ectopic pregnancy, an important finding for both expectant mothers and health-care professionals that nonetheless needs to be confirmed in further large-scale studies. Finally, these findings highlight the need for women to consider all their options thoroughly before requesting a cesarean section on non-medical grounds.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001670.
The American Congress of Obstetricians and Gynecologists provides patient fact sheets on cesarean birth, miscarriage, and ectopic pregnancy
The US-based non-profit Nemours Foundation provides information about cesarean sections, miscarriage and stillbirth, and ectopic pregnancy (in English and Spanish)
The UK National Health Service Choices website provides information for patients about cesarean section, miscarriage, stillbirth, and ectopic pregnancy
MedlinePlus provides links to additional resources about cesarean section, miscarriage, stillbirth, and ectopic pregnancy (in English and Spanish)
The UK non-profit organization Healthtalkonline provides personal stories about cesarean delivery, miscarriage, and stillbirth
doi:10.1371/journal.pmed.1001670
PMCID: PMC4077571  PMID: 24983970
8.  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
9.  Pregnancy and Infant Outcomes among HIV-Infected Women Taking Long-Term ART with and without Tenofovir in the DART Trial 
PLoS Medicine  2012;9(5):e1001217.
Diana Gibb and colleagues investigate the effect of in utero tenofovir exposure by analyzing the pregnancy and infant outcomes of HIV-infected women enrolled in the DART trial.
Background
Few data have described long-term outcomes for infants born to HIV-infected African women taking antiretroviral therapy (ART) in pregnancy. This is particularly true for World Health Organization (WHO)–recommended tenofovir-containing first-line regimens, which are increasingly used and known to cause renal and bone toxicities; concerns have been raised about potential toxicity in babies due to in utero tenofovir exposure.
Methods and Findings
Pregnancy outcome and maternal/infant ART were collected in Ugandan/Zimbabwean HIV-infected women initiating ART during The Development of AntiRetroviral Therapy in Africa (DART) trial, which compared routine laboratory monitoring (CD4; toxicity) versus clinically driven monitoring. Women were followed 15 January 2003 to 28 September 2009. Infant feeding, clinical status, and biochemistry/haematology results were collected in a separate infant study. Effect of in utero ART exposure on infant growth was analysed using random effects models.
382 pregnancies occurred in 302/1,867 (16%) women (4.4/100 woman-years [95% CI 4.0–4.9]). 226/390 (58%) outcomes were live-births, 27 (7%) stillbirths (≥22 wk), and 137 (35%) terminations/miscarriages (<22 wk). Of 226 live-births, seven (3%) infants died <2 wk from perinatal causes and there were seven (3%) congenital abnormalities, with no effect of in utero tenofovir exposure (p>0.4). Of 219 surviving infants, 182 (83%) enrolled in the follow-up study; median (interquartile range [IQR]) age at last visit was 25 (12–38) months. From mothers' ART, 62/9/111 infants had no/20%–89%/≥90% in utero tenofovir exposure; most were also zidovudine/lamivudine exposed. All 172 infants tested were HIV-negative (ten untested). Only 73/182(40%) infants were breast-fed for median 94 (IQR 75–212) days. Overall, 14 infants died at median (IQR) age 9 (3–23) months, giving 5% 12-month mortality; six of 14 were HIV-uninfected; eight untested infants died of respiratory infection (three), sepsis (two), burns (one), measles (one), unknown (one). During follow-up, no bone fractures were reported to have occurred; 12/368 creatinines and seven out of 305 phosphates were grade one (16) or two (three) in 14 children with no effect of in utero tenofovir (p>0.1). There was no evidence that in utero tenofovir affected growth after 2 years (p = 0.38). Attained height- and weight for age were similar to general (HIV-uninfected) Ugandan populations. Study limitations included relatively small size and lack of randomisation to maternal ART regimens.
Conclusions
Overall 1-year 5% infant mortality was similar to the 2%–4% post-neonatal mortality observed in this region. No increase in congenital, renal, or growth abnormalities was observed with in utero tenofovir exposure. Although some infants died untested, absence of recorded HIV infection with combination ART in pregnancy is encouraging. Detailed safety of tenofovir for pre-exposure prophylaxis will need confirmation from longer term follow-up of larger numbers of exposed children.
Trial registration
www.controlled-trials.com ISRCTN13968779
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Currently, about 34 million people (mostly in low- and middle-income countries) are infected with HIV, the virus that causes AIDS. At the beginning of the epidemic, more men than women were infected with HIV but now about half of all people living with HIV/AIDS are women, most of who became infected through unprotected sex with an infected partner. In sub-Saharan Africa alone, 12 million women are HIV-positive. Worldwide, HIV/AIDS is the leading cause of death among women of child-bearing age. Moreover, most of the 400,000 children who become infected with HIV every year acquire the virus from their mother during pregnancy or birth, or through breastfeeding, so-called mother-to-child transmission (MTCT). Combination antiretroviral therapy (ART)—treatment with cocktails of powerful antiretroviral drugs—reduces HIV-related illness and death among women, and ART given to HIV-positive mothers during pregnancy and delivery and to their newborn babies greatly reduces MTCT.
Why Was This Study Done?
Because of ongoing international efforts to increase ART coverage, more HIV-positive women in Africa have access to ART now than ever before. However, little is known about pregnancy outcomes among HIV-infected African women taking ART throughout pregnancy for their own health or about the long-term outcomes of their offspring. In particular, few studies have examined the effect of taking tenofovir (an antiretroviral drug that is now recommended as part of first-line ART) throughout pregnancy. Tenofovir readily crosses from mother to child during pregnancy and, in animal experiments, high doses of tenofovir given during pregnancy caused bone demineralization (which weakens bones), kidney problems, and impaired growth among offspring. In this study, the researchers analyze data collected on pregnancy and infant outcomes among Ugandan and Zimbabwean HIV-positive women who took ART throughout pregnancy in the Development of AntiRetroviral Therapy in Africa (DART) trial. This trial was designed to test whether ART could be safely and effectively delivered in Africa without access to the expensive laboratory tests that are routinely used to monitor ART toxicity and efficacy in developed countries.
What Did the Researchers Do and Find?
The pregnancy outcomes of 302 women who became pregnant during the DART trial and information on birth defects among their babies were collected as part of the DART protocol; information on the survival, growth, and development of the infants born to these women was collected in a separate infant study. Most of the women who became pregnant were taking tenofovir-containing ART before and throughout their pregnancies. 58% of the pregnancies resulted in a live birth, 7% resulted in a stillbirth (birth of a dead baby at any time from 22 weeks gestation to the end of pregnancy), and 35% resulted in a termination or miscarriage (before 22 weeks gestation). Of the 226 live births, seven infants died within 2 weeks and seven had birth defects. Similar proportions of the infants exposed and not exposed to tenofovir during pregnancy died soon after birth or had birth defects. Of the 182 surviving infants who were enrolled in the infant study, 14 subsequently died at an average age of 9 months, giving a 1-year mortality of 5%. None of the surviving children who were tested (172 infants) were HIV infected. No bone fractures or major kidney problems occurred during follow-up and prebirth exposure to tenofovir in utero had no effect on growth or weight gain at 2 years (in contrast to a previous US study).
What Do These Findings Mean?
By showing that prebirth tenofovir exposure does not affect pregnancy outcomes or increase birth defects, growth abnormalities, or kidney problems, these findings support the use of tenofovir-containing ART during pregnancy among HIV-positive African women, and suggest that it could also be used to prevent women of child-bearing age acquiring HIV-infection heterosexually. Notably, the observed 5% 1-year infant mortality is similar to the 2%–4% infant mortality normally seen in the region. The absence of HIV infection among the infants born to the DART participants is also encouraging. However, this is a small study (only 111 infants were exposed to tenofovir throughout pregnancy) and women were not randomly assigned to receive tenofovir-containing ART. Consequently, more studies are needed to confirm that tenofovir exposure during pregnancy does not affect pregnancy outcomes or have any long-term effects on infants. Such studies are essential because the use of tenofovir as a treatment for women who are HIV-positive is likely to increase and tenofovir may also be used in the future to prevent HIV acquisition in HIV-uninfected women.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001217.
Information is available from the US National Institute of Allergy and infectious diseases on all aspects of HIV infection and AIDS
NAM/aidsmap provides basic information about HIV/AIDS, and summaries of recent research findings on HIV care and treatment (in several languages)
Information is available from Avert, an international AIDS nonprofit on many aspects of HIV/AIDS, including detailed information on HIV/AIDS treatment and care, women, HIV and AIDS, children, HIV and AIDS, and on HIV/AIDS and pregnancy (some information in English and Spanish); personal stories of women living with HIV are available
More information about the DART trial is available
Additional patient stories about living with HIV/AIDS are available through the nonprofit website Healthtalkonline
doi:10.1371/journal.pmed.1001217
PMCID: PMC3352861  PMID: 22615543
10.  Haematological Safety of Perinatal Zidovudine in Pregnant HIV-1–Infected Women in Thailand: Secondary Analysis of a Randomized Trial 
PLoS Clinical Trials  2007;2(4):e11.
Objectives:
To respond to the primary safety objective of the Perinatal HIV Prevention Trial 1 (PHPT-1) by studying the evolution of haematological parameters according to zidovudine exposure duration in HIV-1−infected pregnant women.
Design:
Multicenter, randomized, double-blind, controlled trial of different durations of zidovudine prophylaxis.
Setting:
27 hospitals in Thailand.
Participants:
1,436 HIV-infected pregnant women in PHPT-1.
Intervention:
Zidovudine prophylaxis initiation at 28 or 35 wk gestation.
Outcome measures:
Haemoglobin level, leucocytes, total lymphocyte counts, and absolute neutrophil counts were measured at 26, 32, and 35 wk and at delivery. The evolution of haematological parameters was estimated between 26 and 35 wk (zidovudine/placebo) and between 35 wk and delivery to compare a long versus short zidovudine exposure. For each parameter, linear mixed models were adjusted on baseline sociodemographic variables, HIV clinical stage, CD4 count, and viral load.
Results:
Between 26 and 35 wk, haemoglobin, leucocytes, and absolute neutrophil counts decreased in zidovudine-exposed compared to unexposed women (mean difference [95% CI] −0.4 [−0.5 to −0.3], −423 [−703 to −142], −485 [−757 to −213], respectively). However, between 35 wk and delivery, the haematological parameters increased faster in women exposed to long rather than short durations of zidovudine (0.1 [0.0 to 0.1]; 105 [18 to 191]; 147 [59 to 234], respectively). At delivery, the differences were not statistically significant, except for mean haemoglobin level, which remained slightly lower in the long zidovudine treatment group (difference: 0.2 g/dl). Zidovudine had no negative impact on the absolute lymphocyte counts.
Conclusion:
Zidovudine initiated at 28 wk gestation rather than 35 wk had a transient negative impact on the evolution of haematological parameters, which was largely reversed by delivery despite continuation of zidovudine. This result provides reassurance about the safety of early initiation of zidovudine prophylaxis during pregnancy to maximize prevention of perinatal HIV.
Editorial Commentary
Background: Pregnant women who are infected with HIV are at high risk of passing on the virus to their unborn baby during pregnancy, labour, and breastfeeding. Around 15%–30% of babies born to HIV-positive women will themselves become infected, if the woman avoids breast-feeding but does not use any other means of preventing the virus from being passed on. However, if a drug, zidovudine (AZT), is given during pregnancy the chance of HIV being passed on to a baby drops from around 23% to around 8%. In some settings it may not be realistic to give the standard course of zidovudine, from 28 weeks of pregnancy, because of its cost and complexity. A number of trials have therefore looked at whether standard-course and short-course zidovudine are equivalent at reducing the risk of passing on HIV from mother to baby. One trial, the Perinatal HIV Prevention Trial-1 (PHPT-1) found that the short treatment course was substantially less effective at preventing HIV from being passed on from mother to baby. Current international guidance therefore recommends starting zidovudine at 28 weeks of pregnancy. However, zidovudine does have several side effects, including anemia; it can also cause a drop in the levels of certain types of white blood cell, and is thought to be toxic to bone marrow. The researchers who had carried out the PHPT-1 trial therefore wanted to do a subsequent analysis of data from that trial to find out whether there were any differences in these safety outcomes between standard and short course zidovudine.
What the trial shows: In total 1,436 women were recruited into the trial and assigned to receive either zidovudine from 28 weeks of pregnancy until delivery (standard course; 769 women), or from 35 weeks to delivery (short course; 667). Blood tests were performed at 26, 32, and 35 weeks of pregnancy and then at delivery, and the main outcomes assessed in this secondary analysis were the hemoglobin levels (to check for anemia), and levels of white blood cells, including the levels of two particular types (neutrophils and lymphocytes). The researchers found that standard-course zidovudine resulted in a drop at 35 weeks in the levels of hemoglobin and white blood cells, relative to short-course zidovudine. However, by the time of delivery these levels had recovered and no significant differences could be observed between the two arms of the trial. Women receiving standard-course zidovudine were more likely to experience severe anemia, which although a rare event in both arms of the trial, could have serious outcomes.
Strengths and limitations: The original trial from which these data were collected was a relatively large, randomized study and in which there was a low rate of loss to follow up. Although no formal sample size calculation was performed for the analyses presented here, the study probably had sufficient power to detect small differences in the outcomes assessed. A key limitation of this study is that the analyses presented here are a secondary exploration of data from the PHPT-1 trial and should therefore be seen as hypotheses to test in further studies, rather than as definitive conclusions.
Contribution to the evidence: The analyses presented here add to the findings of the parent trial, PHPT-1, by providing additional data about the toxicity of zidovudine. Other trials have not clearly established whether there are differences between short- and standard-course zidovudine in terms of their toxicity. The findings support current guidelines recommending standard-course zidovudine therapy for HIV-positive pregnant women. It is also crucial that efforts are made to ensure women worldwide can get access to facilities for monitoring the status of their HIV infection, and then receive highly active antiretroviral therapy when it is needed.
doi:10.1371/journal.pctr.0020011
PMCID: PMC1863515  PMID: 17476315
11.  Consequences of Gestational Diabetes in an Urban Hospital in Viet Nam: A Prospective Cohort Study 
PLoS Medicine  2012;9(7):e1001272.
Jane Hirst and colleagues determined the prevalence and outcome of gestational diabetes mellitus in urban Vietnam and found that choice of criteria greatly affected prevalence, and has implications for the ability of the health system to cope with the number of cases.
Background
Gestational diabetes mellitus (GDM) is increasing and is a risk for type 2 diabetes. Evidence supporting screening comes mostly from high-income countries. We aimed to determine prevalence and outcomes in urban Viet Nam. We compared the proposed International Association of the Diabetes and Pregnancy Study Groups (IADPSG) criterion, requiring one positive value on the 75-g glucose tolerance test, to the 2010 American Diabetes Association (ADA) criterion, requiring two positive values.
Methods and Findings
We conducted a prospective cohort study in Ho Chi Minh City, Viet Nam. Study participants were 2,772 women undergoing routine prenatal care who underwent a 75-g glucose tolerance test and interview around 28 (range 24–32) wk. GDM diagnosed by the ADA criterion was treated by local protocol. Women with GDM by the IADPSG criterion but not the ADA criterion were termed “borderline” and received standard care. 2,702 women (97.5% of cohort) were followed until discharge after delivery. GDM was diagnosed in 164 participants (6.1%) by the ADA criterion, 550 (20.3%) by the IADPSG criterion. Mean body mass index was 20.45 kg/m2 in women with out GDM, 21.10 in women with borderline GDM, and 21.81 in women with GDM, p<0.001. Women with GDM and borderline GDM were more likely to deliver preterm, with adjusted odds ratios (aORs) of 1.49 (95% CI 1.16–1.91) and 1.52 (1.03–2.24), respectively. They were more likely to have clinical neonatal hypoglycaemia, aORs of 4.94 (3.41–7.14) and 3.34 (1.41–7.89), respectively. For large for gestational age, the aORs were 1.16 (0.93–1.45) and 1.31 (0.96–1.79), respectively. There was no significant difference in large for gestational age, death, severe birth trauma, or maternal morbidity between the groups. Women with GDM underwent more labour inductions, aOR 1.51 (1.08–2.11).
Conclusions
Choice of criterion greatly affects GDM prevalence in Viet Nam. Women with GDM by the IADPSG criterion were at risk of preterm delivery and neonatal hypoglycaemia, although this criterion resulted in 20% of pregnant women being positive for GDM. The ability to cope with such a large number of cases and prevent associated adverse outcomes needs to be demonstrated before recommending widespread screening.
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 usually controlled by insulin, which is made by the pancreas. 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, usually in mid-pregnancy. Risk factors for GDM include a high body mass index (a measure of body fat), excessive weight gain or lack of physical activity during pregnancy, and glucose intolerance (an indicator of diabetes that is measured using the “oral glucose tolerance test”). GDM increases the risk of premature delivery, induced delivery, and having a large-for-gestational-age baby (gestation is the time during which the baby develops within the mother). It also increases the baby's risk of having low blood sugar (neonatal hypoglycemia). GDM, which can often be controlled by exercise and diet, usually disappears after pregnancy but increases the risk of diabetes developing later in both mother and baby.
Why Was This Study Done?
The prevalence (occurrence) of diabetes is increasing rapidly, particularly in low/middleincome countries as they become more affluent. Because GDM increases the subsequent risk of diabetes, some experts believe that screening for GDM should be included in prenatal care as part of diabetes preventative strategies. However, most of the evidence supporting GDM screening comes from high-income countries, so in this prospective cohort study (a study that analyses associations between the baseline characteristics of a group of patients and outcomes), the researchers investigate the prevalence of GDM (diagnosed using the oral glucose tolerance test) and the consequences of GDM among women attending an urban hospital in Viet Nam, a low/middle-income country. An oral glucose tolerance test measures a patient's blood-sugar level after an overnight fast, and one and two hours after consuming a sugary drink. The International Association of the Diabetes and Pregnancy Study Groups (IADPSG) and the American Diabetes Association (ADA) guidelines state, respectively, that one and two of these blood-sugar measurements must be abnormally high for a diagnosis of GDM. In this study, the researchers use both guidelines to diagnose GDM.
What Did the Researchers Do and Find?
Nearly 3,000 women who attended the hospital for routine prenatal care had a glucose tolerance test at around 28 weeks' gestation and were followed until discharge after delivery. Women who had GDM diagnosed by the ADA criterion were referred for dietary advice and glucose monitoring. Those diagnosed by the IADPSG criterion only were described as having “borderline” GDM and received standard prenatal care. GDM was diagnosed in 6.1% and 20.3% of the women using the ADA and IADPSG criteria, respectively. After allowing for other factors that might have affected outcomes, compared to women without GDM, women with GDM or borderline GDM were more likely to deliver prematurely, and their babies were more likely to have neonatal hypoglycemia. Also, women with GDM (but not borderline GDM) were more likely to have their labor induced than women without GDM.
What Do These Findings Mean?
These findings show that the criterion used to diagnose GDM markedly affected the prevalence of GDM among pregnant women attending this Vietnamese hospital—the use of the IADPSG criterion more than tripled the prevalence of GDM and meant that a fifth of the study participants were diagnosed as having GDM. Importantly, the findings also show that GDM diagnosed using the IADPSG criterion was associated with an increased risk of preterm delivery and neonatal hypoglycemia. Although these findings may not be generalizable to other settings within Viet Nam or to other countries, they highlight the need to demonstrate that sufficient resources are available to cope with an increased GDM burden before recommending widespread screening using the IADPSG criterion. Moreover, because the long-term significance of GDM diagnosed using the IADPSG criterion is not known, all the potential benefits and harms and the costs of screening and treating GDM in low-income settings need to be further investigated before any recommendation for “universal” GDM screening is made.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10. 1371/journal.pmed.1001272.
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 about diabetes and about gestational diabetes, including links to other useful resources
The American Diabetes Association also provides detailed information for patients and professionals about all aspects of diabetes, including gestational diabetes (in English and Spanish)
The International Association of the Diabetes and Pregnancy Study Groups (IADPSG) 2010 recommendations on the diagnosis and classification of gestational diabetes are available
The charity Diabetes UK provides detailed information for patients and carers, including information on gestational diabetes; its blog includes a personal story about gestational diabetes, and its website includes a selection of other stories from people with diabetes; the charity Healthtalkonline also has an interview describing a personal experience of gestational diabetes
MedlinePlus provides links to additional resources on diabetes and on gestational diabetes (in English and Spanish)
doi:10.1371/journal.pmed.1001272
PMCID: PMC3404117  PMID: 22911157
12.  The impact of close surveillance on pregnancy outcome among women with a prior history of antepartum complications attributed to thrombosis: a cohort study 
Background
There is limited evidence, so far, as to the optimal management of women with a prior obstetric history of antepartum complications attributed to thrombosis. We aimed to investigate the contribution of close antepartum surveillance on pregnancy outcome among women with prior antepartum complications attributed to thrombosis.
Methods
The study was conducted on all women who were delivered, conceived and delivered again between January 2000 and January 2006 at a university teaching hospital. Women included were managed in previous pregnancy at a low risk setting and had unpredicted antepartum complications occurring at a gestational age of 23 weeks or more. Antepartum complications considered were intrauterine fetal death, neonates who were small for gestational age, severe pre-eclampsia and placental abruption. All women were tested for the presence of thrombophilia after delivery. In the following pregnancy, only women found to have any thrombophilia (thrombophilic group) were treated with enoxaparin. Both the thrombophilic group and the non-thrombophilic group (tested negatively for thrombophilia) were managed and observed closely at our high-risk pregnancy clinic.
Results
Ninety-seven women, who conceived at least once after the diagnosis of the relevant antepartum complications, were included in this study. Forty-nine had any thrombophilia and 48 tested negatively. Composite antepartum complications (all antepartum complications considered) were reduced significantly after close antepartum surveillance in both groups. Mean birth weight and mean gestational age improved significantly and were comparable between the groups.
Conclusion
Close antepartum surveillance may contribute to improvement in the perinatal outcomes of women with prior antepartum complications attributed to thrombosis.
doi:10.1186/1477-7827-6-55
PMCID: PMC2603012  PMID: 19025596
13.  Implementation and evaluation of a harm-reduction model for clinical care of substance using pregnant women 
Background
Methamphetamine (MA) use during pregnancy is associated with many pregnancy complications, including preterm birth, small for gestational age, preeclampsia, and abruption. Hawaii has lead the nation in MA use for many years, yet prior to 2007, did not have a comprehensive plan to care for pregnant substance-using women. In 2006, the Hawaii State Legislature funded a pilot perinatal addiction clinic. The Perinatal Addiction Treatment Clinic of Hawaii was built on a harm-reduction model, encompassing perinatal care, transportation, child-care, social services, family planning, motivational incentives, and addiction medicine. We present the implementation model and results from our first one hundred three infants (103) seen over 3 years of operation of the program.
Methods
Referrals came from community health centers, hospitals, addiction treatment facilities, private physician offices, homeless outreach services and self-referral through word-of-mouth and bus ads. Data to describe sample characteristics and outcome was obtained prospectively and retrospectively from chart abstraction and delivery data. Drug use data was obtained from the women's self-report and random urine toxicology during the pregnancy, as well as urine toxicology at the time of birth on mothers, and urine and meconium toxicology on the infants. Post-partum depression was measured in mothers with the Edinburgh Post-Partum depression scale. Data from Path clinic patients were compared with a representative cohort of women delivering at Kapiolani Medical Center for Women and Children during the same time frame, who were enrolled in another study of pregnancy outcomes. Ethical approval for this study was obtained through the University of Hawaii Committee for Human Studies.
Results
Between April 2007 and August 2010, 213 women with a past or present history of addiction were seen, 132 were pregnant and 97 delivered during that time. 103 live-born infants were delivered. There were 3 first-trimester Spontaneous Abortions, two 28-week intrauterine fetal deaths, and two sets of twins and 4 repeat pregnancies. Over 50% of the women had lost custody of previous children due to substance use. The majority of women who delivered used methamphetamine (86%), either in the year before pregnancy or during pregnancy. Other drugs include marijuana (59.8%), cocaine (33%), opiates (9.6%), and alcohol (15.2%). Of the women served, 85% smoked cigarettes upon enrollment. Of the 97 women delivered during this period, all but 4 (96%) had negative urine toxicology at the time of delivery. Of the 103 infants, 13 (12.6%) were born preterm, equal to the state and national average, despite having many risk factors for prematurity, including poverty, poor diet, smoking and polysubstance use. Overwhelmingly, the women are parenting their children, > 90% retained custody at 8 weeks. Long-term follow-up showed that women who maintained custody chose long-acting contraceptive methods; while those who lost custody had a very high (> 50%) repeat pregnancy rate at 9 months post delivery.
Conclusion
Methamphetamine use during pregnancy doesn't exist is isolation. It is often combined with a multitude of other adverse circumstances, including poverty, interpersonal violence, psychiatric comorbidity, polysubstance use, nutritional deficiencies, inadequate health care and stressful life experiences. A comprehensive harm reduction model of perinatal care, which aims to ameliorate some of these difficulties for substance-using women without mandating abstinence, provides exceptional birth outcomes and can be implemented with limited resources.
doi:10.1186/1477-7517-9-5
PMCID: PMC3292917  PMID: 22260315
Methamphetamines; Harm Reduction; Pregnancy; Birth Outcomes; Tobacco
14.  Planned Vaginal Birth or Elective Repeat Caesarean: Patient Preference Restricted Cohort with Nested Randomised Trial 
PLoS Medicine  2012;9(3):e1001192.
A study conducted in Australia provides new data on the outcomes for mother and baby associated with either planned vaginal birth, or elective repeat caesarean section following a previous caesarean section.
Background
Uncertainty exists about benefits and harms of a planned vaginal birth after caesarean (VBAC) compared with elective repeat caesarean (ERC). We conducted a prospective restricted cohort study consisting of a patient preference cohort study, and a small nested randomised trial to compare benefits and risks of a planned ERC with planned VBAC.
Methods and findings
2,345 women with one prior caesarean, eligible for VBAC at term, were recruited from 14 Australian maternity hospitals. Women were assigned by patient preference (n = 2,323) or randomisation (n = 22) to planned VBAC (1,225 patient preference, 12 randomised) or planned ERC (1,098 patient preference, ten randomised). The primary outcome was risk of fetal death or death of liveborn infant before discharge or serious infant outcome. Data were analysed for the 2,345 women (100%) and infants enrolled.
The risk of fetal death or liveborn infant death prior to discharge or serious infant outcome was significantly lower for infants born in the planned ERC group compared with infants in the planned VBAC group (0.9% versus 2.4%; relative risk [RR] 0.39; 95% CI 0.19–0.80; number needed to treat to benefit 66; 95% CI 40–200). Fewer women in the planned ERC group compared with women in the planned VBAC had a major haemorrhage (blood loss ≥1,500 ml and/or blood transfusion), (0.8% [9/1,108] versus 2.3% [29/1,237]; RR 0.37; 95% CI 0.17–0.80).
Conclusions
Among women with one prior caesarean, planned ERC compared with planned VBAC was associated with a lower risk of fetal and infant death or serious infant outcome. The risk of major maternal haemorrhage was reduced with no increase in maternal or perinatal complications to time of hospital discharge. Women, clinicians, and policy makers can use this information to develop health advice and make decisions about care for women who have had a previous caesarean.
Trial registration
Current Controlled Trials ISRCTN53974531
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Rates of caesarean section are rising around the world, particularly in high- and middle-income countries, where most women have a choice of how their baby is delivered. Historically, the obstetrician in charge of the woman's care made the decision on whether to perform an elective (planned) caesarean section based on medical criteria. For women who have had a previous caesarean section, typically, their options for mode of childbirth are either a trial of vaginal birth or an elective repeat caesarean section. The proportion of women attempting a vaginal birth after a previous caesarean section has been declining in many countries partly due to the variable chance of achieving a successful vaginal birth (reported between 56% and 80%) and partly because of negative reports of the risk of complications, both to the mother and the baby, of a having a vaginal delivery following a caesarean section. Consequently, the rates of repeat caesarean section have risen sharply, for example, currently 83% in Australia and almost 90% in the US.
Why Was This Study Done?
Both elective repeat caesarean section and subsequent vaginal delivery after a previous caesarean section have clinical risks and benefits. Most obviously, having a surgical procedure puts the woman having the repeat caesarean section at risk of surgical complications, especially if performed under a general anesthetic, and her baby may be at risk of respiratory complications. However, subsequent vaginal delivery following a previous caesarean section may put the mother at risk of bleeding severely enough to need a blood transfusion (more than 1,500 ml blood loss) and she may also be at increased risk of rupturing her uterus; and her baby may have an increased risk of dying or of becoming brain damaged due to lack of oxygen.
However, to date there have been no randomized controlled trials of elective repeat caesarean section versus vaginal delivery following a previous caesarean section to compare the health outcomes of mother and baby and a recent systematic review could draw no conclusions. So the researchers conducted this prospective cohort study based on patient preference (with a few women agreeing to be randomized to mode of delivery), to compare the health outcomes for mother and baby for elective repeat caesarean section versus vaginal delivery in women following a previous caesarean section.
What Did the Researchers Do and Find?
Between 2002 and 2007, the researchers recruited 2,345 suitable women (that is, women who had one previous caesarean section, were currently 37 weeks pregnant with a single baby, and who were clinically able to have a vaginal delivery) from 14 maternity hospitals throughout Australia. A few women (22) agreed to be randomized to either mode of delivery but most women chose her preferred option. Then, depending on the woman's preferences for mode of birth, participating obstetricians either scheduled a date for an elective caesarean section (1,098 women) or assessed on-going suitability for the woman to have a planned vaginal delivery (1,225 women). However only 535 (43.2%) women who chose to have a vaginal birth were able to deliver this way because of failure to progress in labor or fetal distress: 334 of these women (27.0%) had to have an elective caesarean section and 368 women had to have an emergency caesarean section.
Although no women died, women who had a planned caesarean section experienced less severe bleeding than women who delivered vaginally. There were no infant deaths in those born by elective caesarean section but two unexplained stillbirths in the planned vaginal delivery group. There was also a reduced risk of nonfatal serious outcome before discharge from hospital for infants delivered by in the elective caesarean section. The researchers calculated that one infant death or near death would be prevented for every 66 elective caesarean sections performed in women who had a previous caesarean section.
What Do These Findings Mean?
These findings show that in women who had delivered by a previous caesarean section delivering their next baby by planned caesarean section was associated with less infant death and better health outcomes for the mother before she was discharged from the hospital compared to women who had a subsequent vaginal delivery. This information can be used by women, clinicians, and policy makers in helping to make decisions about the mode of subsequent deliveries and best care for women who have had a previous caesarean section.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001192.
This study is linked to a PLoS Medicine Research Article by Fitzpatrick and colleagues and a PLoS Medicine Perspective by Catherine Spong
The American Congress of Obstetricians and Gynecologists has information sheets for patients on caesarean sections and on vaginal birth after caesarean delivery
Childbirth Connection, a US-based not-for-profit organization, provides information about caesarean sections and about vaginal birth after caesarean
The National Childbirth Trust, a UK charity, provides information for parents on all aspects of pregnancy and birth, including caesarean sections and vaginal birth after caesarean delivery
The UK charity Healthtalkonline has personal stories from women making decisions about birth after a caesarean section
doi:10.1371/journal.pmed.1001192
PMCID: PMC3302845  PMID: 22427749
15.  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
16.  First versus Second Trimester Ultrasound: The Effect on Pregnancy Dating and Perinatal Outcomes 
Objective
To examine the effect of first trimester obstetric ultrasound (OBUS) on the measurement of the effect of complications ascribed to postterm pregnancies.
Study Design
We conducted a retrospective cohort study of all term, singleton pregnancies delivered at our institution who had an OBUS at ≤24 weeks of gestation. Those women who underwent an OBUS at ≤12 weeks of gestation (OBUS12) were compared to those who had an OBUS at 13–24 weeks of gestation (OBUS13–24). The primary outcome measures were the rates of postterm pregnancies greater than 41 or 42 weeks’ gestation. Secondary outcomes were the differences between the postterm and term gestations in maternal and neonatal outcomes.
Results
In the OBUS12 group, the rate of postterm pregnancy ≥42 weeks was lower (2.7%) as compared to the OBUS13–24 group (3.7%, p=0.022). With regards to reaching 41 weeks of gestation, the OBUS12 group was again lower (18.2%) as compared to the OBUS13–24 group (22.1%, p<0.001). There were also fewer postterm inductions at ≥42 weeks in the OBUS12 group (1.8%) as compared to the OBUS13–24 group (2.6%, p=0.017). When comparing perinatal outcomes between those women who reached 41 weeks of gestation and those prior to 41 weeks of gestation, the OBUS12 group demonstrated greater differences between these two groups.
Conclusion
Our findings suggest that earlier obstetric ultrasound, which leads to better pregnancy dating, reduces the rate of estimated postterm pregnancies. This may, in turn, reduce unnecessary intervention and lead to better identification of postterm pregnancies at greater risk of complications.
doi:10.1016/j.ajog.2008.03.034
PMCID: PMC2603611  PMID: 18538160
pregnancy dating; ultrasound; complications of pregnancy; post-term; post-dates
17.  Costs and consequences of treatment for mild gestational diabetes mellitus – evaluation from the ACHOIS randomised trial 
Background
Recommended best practice is that economic evaluation of health care interventions should be integral with randomised clinical trials. We performed a cost-consequence analysis of treating women with mild gestational diabetes mellitus by dietary advice, blood glucose monitoring and insulin therapy as needed compared with routine pregnancy care, using patient-level data from a multi-centre randomised clinical trial.
Methods
Women with a singleton pregnancy who had mild gestational diabetes diagnosed by an oral glucose-tolerance test between 24 and 34 weeks' gestation and their infants were included. Clinical outcomes and outpatient costs derived from all women and infants in the trial. Inpatient costs derived from women and infants attending the hospital contributing the largest number of enrolments (26.1%), and charges to women and their families derived from a subsample of participants from that hospital (in 2002 Australian dollars). Occasions of service and health outcomes were adjusted for maternal age, ethnicity and parity. Analysis of variance was used with bootstrapping to confirm results. Primary clinical outcomes were serious perinatal complications; admission to neonatal nursery; jaundice requiring phototherapy; induction of labour and caesarean delivery. Economic outcome measures were outpatient and inpatient costs, and charges to women and their families.
Results
For every 100 women with a singleton pregnancy and positive oral glucose tolerance test who were offered treatment for mild gestational diabetes mellitus in addition to routine obstetric care, $53,985 additional direct costs were incurred at the obstetric hospital, $6,521 additional charges were incurred by women and their families, 9.7 additional women experienced induction of labour, and 8.6 more babies were admitted to a neonatal nursery. However, 2.2 fewer babies experienced serious perinatal complication and 1.0 fewer babies experienced perinatal death. The incremental cost per additional serious perinatal complication prevented was $27,503, per perinatal death prevented was $60,506 and per discounted life-year gained was $2,988.
Conclusion
It is likely that the general public in high-income countries such as Australia would find reductions in perinatal mortality and in serious perinatal complications sufficient to justify additional health service and personal monetary charges. Over the whole lifespan, the incremental cost per extra life-year gained is highly favourable.
Trial Registration
Australian Clinical Trials Registry ACTRN12606000294550
doi:10.1186/1471-2393-7-27
PMCID: PMC2241640  PMID: 17963528
18.  Causes of perinatal death at a tertiary care hospital in Northern Tanzania 2000–2010: a registry based study 
Background
Perinatal mortality reflects maternal health as well as antenatal, intrapartum and newborn care, and is an important health indicator. This study aimed at classifying causes of perinatal death in order to identify categories of potentially preventable deaths.
Methods
We studied a total of 1958 stillbirths and early neonatal deaths above 500 g between July 2000 and October 2010 registered in the Medical Birth Registry and neonatal registry at Kilimanjaro Christian Medical Centre (KCMC) in Northern Tanzania. The deaths were classified according to the Neonatal and Intrauterine deaths Classification according to Etiology (NICE).
Results
Overall perinatal mortality was 57.7/1000 (1958 out of 33 929), of which 1219 (35.9/1000) were stillbirths and 739 (21.8/1000) were early neonatal deaths. Major causes of perinatal mortality were unexplained asphyxia (n=425, 12.5/1000), obstetric complications (n=303, 8.9/1000), maternal disease (n=287, 8.5/1000), unexplained antepartum stillbirths after 37 weeks of gestation (n= 219, 6.5/1000), and unexplained antepartum stillbirths before 37 weeks of gestation (n=184, 5.4/1000). Obstructed/prolonged labour was the leading condition (251/303, 82.8%) among the obstetric complications. Preeclampsia/eclampsia was the leading cause (253/287, 88.2%) among the maternal conditions. When we excluded women who were referred for delivery at KCMC due to medical reasons (19.1% of all births and 36.0% of all deaths), perinatal mortality was reduced to 45.6/1000. This reduction was mainly due to fewer deaths from obstetric complications (from 8.9 to 2.1/1000) and maternal conditions (from 8.5 to 5.5/1000).
Conclusion
The distribution of causes of death in this population suggests a great potential for prevention. Early identification of mothers at risk of pregnancy complications through antenatal care screening, teaching pregnant women to recognize signs of pregnancy complications, timely access to obstetric care, monitoring of labour for fetal distress, and proper newborn resuscitation may reduce some of the categories of deaths.
doi:10.1186/1471-2393-12-139
PMCID: PMC3533832  PMID: 23199181
Perinatal mortality; Perinatal deaths; Maternal disease; Obstetric complication; NICE classification
19.  An Imbalance between Angiogenic and Anti-angiogenic Factors precedes Fetal Death in a subset of patients: Results of a Longitudinal Study 
OBJECTIVE
Fetal death at the time of diagnosis has higher maternal plasma concentrations of the anti-angiogenic factor, soluble vascular endothelial growth factor receptor (sVEGFR)-1, than that of women with normal pregnancy. An important question is whether these changes are the cause or consequence of fetal death. To address this issue, we conducted a longitudinal nested case-control study and measured the maternal plasma concentrations of selective angiogenic and anti-angiogenic factors before the diagnosis of a fetal death. The anti-angiogenic factors studied included sVEGFR-1, soluble endoglin (sEng), and the angiogenic factor, placental growth factor (PlGF).
Methods
A retrospective longitudinal nested case-control study was conducted. It included 143 singleton pregnancies in the following groups: (1) patients with uncomplicated pregnancies who delivered a term infant with an appropriate weight for gestational age (n=124); and (2) patients who had a fetal death (n=19). Samples were collected at each prenatal visit, scheduled at 4-week intervals from the first trimester until delivery. Plasma concentrations of sVEGFR-1, sEng, and PlGF were determined by specific and sensitive ELISA. A linear mixed-effects model was used for analysis.
Results
1) Linear mixed-effects model analyses indicated that the average profiles of analyte concentrations as a function of gestational age for sVEGFR-1, sEng and PlGF were different between women destined to have a fetal death and those with normal pregnancy outcome after adjusting for covariates (p<0.05); 2) Plasma sVEGFR-1 concentrations in patients destined to have a fetal death were significantly lower between 7 and 11 weeks of gestation and became significantly higher than those of women with a normal pregnancy between 23 and 35 weeks of gestation (p<0.05); 3) Similarly, plasma sEng concentrations of women destined to have a fetal death were lower at 7 weeks of gestation (p=0.04) and became significantly higher than those of women destined to have a normal pregnancy between 23 and 41 weeks of gestation (p<0.05); 4) In contrast, plasma PlGF concentrations were higher among patients destined to develop a fetal death between 7 and 13 weeks of gestation and became significantly lower than those in the control group between 22 and 40 weeks of gestation (p<0.05); 5) The ratio of PlGF/sVEGFR-1 x sEng was significantly higher in women destined to have a fetal death between 7 and 13 weeks of gestation (89%–765%) and significantly lower (45%–76%) than those in normal pregnant women between 20 and 41 weeks of gestation (p<0.05); 6) Similar results were obtained when patients with a fetal death were stratified into those who were diagnosed before or after 37 weeks.
Conclusions
1) Patient destined to have a fetal death, compared to normal pregnancy, was characterized by higher plasma concentrations of PlGF during the first trimester, and this profile changed into an anti-angiogenic one during the second and third trimesters.
doi:10.3109/14767051003681121
PMCID: PMC3023956  PMID: 20459337
soluble VEGF receptor-1 (sVEGFR-1); sFlt-1; soluble endoglin (sEng); placental growth factor (PLGF); mixed- effect model; fetal demise; stillbirth; pregnancy; anti-angiogenic state
20.  Stillbirths and hospital early neonatal deaths at Queen Elizabeth Central Hospital, Blantyre-Malawi 
Background
Much of the data on still births and early neonatal deaths from resource-limited settings are obtained via maternal recall from national or community level surveys. While this approach results in useful information to be obtained, often such data suffer from significant recall bias and misclassification. In order to determine the prevalence of stillbirths (SB), early hospital neonatal death (EHND) and associated factors in Blantyre, Malawi, a prospective study of pregnant and post-natal women was conducted at the Queen Elizabeth Central Hospital (QECH), Malawi.
Methods
A prospective observational study was conducted between February 1, 2004 and October 30, 2005. Consecutive women attending the hospital for delivery were recruited. Data were collected on the health status of the fetus on admission to labor ward and immediately after delivery, whether alive or dead. Gestational age (GA) and birth weight (BW) and sex of the newborn were also noted. Similar data were also collected on the live births that died in the delivery room or nursery. Data were analyzed using SPSS (Statistical Package for the Social Sciences) statistical package.
Results
A total of 10,700 deliveries were conducted during the 12 months study period and of these deliveries, 845 (7.9%) were SB and EHND. Stillbirths comprised 3.4% of all deliveries; 20.2% of the ante-partum deaths occurred before the mother was admitted to the labor ward while a slightly higher proportion (22.7%) of fetal loss occurred during the process of labor and delivery. Fifty-sex percent of the perinatal deaths (PD) were EHND. The mean gestational age for the perinatal deaths was 34.7 weeks and mean birth weight was 2,155 g (standard deviation = 938 g). The majority, 468 (57.8%) of the perinatal deaths were males and 350 (43.2%) were females. Many of the perinatal deaths (57.9%) were deliveries between gestational ages of 20 and 37 weeks. Most (62.7%) of the mothers with a perinatal death had experienced a previous similar incident.
Conclusion
About 3.4% of all pregnant mothers past 20 weeks of gestation ended up in delivering a stillbirth; another 4.4% of the live births died before discharge from hospital, thus, 7.9% of pregnancy loss after 20 weeks (or 500 g estimated weight) of gestation. This is a higher loss when compared to international and regional data. We recommend attention be given to these unfavorable outcomes and preventive measures or intervention for preventable causes be considered seriously. These measures could include the provision of emergency obstetric care, improving access to deliveries by health professionals and resourcing of health facilities such that neonatal viability is promoted.
doi:10.1186/1755-7682-2-25
PMCID: PMC2746193  PMID: 19719841
21.  Risk factors for antepartum stillbirth and the influence of maternal age in New South Wales Australia: A population based study 
Background
Maternal age is a known risk factor for stillbirth and delayed childbearing is a societal norm in developed country settings. The timing and reasons for age being a risk factor are less clear. This study aimed to document the gestational specific risk of maternal age throughout pregnancy and whether the underlying causes of stillbirth differ for older women.
Methods
Using linkage of state maternity and perinatal death data collections the authors assessed risk factors for antepartum stillbirth in New South Wales Australia for births between 2002 – 2006 (n = 327,690) using a Cox proportional hazards model. Gestational age specific risk was calculated for different maternal age groups. Deaths were classified according to the Perinatal Mortality Classifications of the Perinatal Society of Australia and New Zealand.
Results
Maternal age was a significant independent risk factor for antepartum stillbirth (35 – 39 years HR 1.4 95% CI 1.12 – 1.75; ≥ 40 years HR 2.41 95% CI 1.8 – 3.23). Other significant risk factors were smoking HR 1.82 (95% CI 1.56 –2.12) nulliparity HR 1.23 (95% CI 1.08 – 1.40), pre-existing hypertension HR 2.77 (95% CI 1.94 – 3.97) and pre-existing diabetes HR 2.65 (95% CI 1.63 – 4.32). For women aged 40 or over the risk of antepartum stillbirth beyond 40 weeks was 1 in 455 ongoing pregnancies compared with 1 in 1177 ongoing pregnancies for those under 40. This risk was increased in nulliparous women to 1 in 247 ongoing pregnancies. Unexplained stillbirths were the most common classification for all women, stillbirths classified as perinatal infection were more common in the women aged 40 or above.
Conclusions
Women aged 35 or older in a first pregnancy should be counselled regarding stillbirth risk at the end of pregnancy to assist with informed decision making regarding delivery. For women aged 40 or older in their first pregnancy it would be reasonable to offer induction of labour by 40 weeks gestation.
doi:10.1186/1471-2393-13-12
PMCID: PMC3552834  PMID: 23324309
Stillbirth; Maternal age; Risk factors; Population-based; Data linkage
22.  Cervical assessment by ultrasound for preventing preterm delivery 
Background
Measurement of cervical length (CL) by transvaginal ultrasound (TVU) is predictive of preterm birth (PTB). It is unclear if this screening test is effective for prevention of PTB.
Objectives
To assess the effectiveness of antenatal management based on TVU CL screening for preventing PTB.
Search methods
We searched the Cochrane Pregnancy and Childbirth Group’s Trials Register (September 2008), MEDLINE (1966 to September 2008), and reviewed the reference list of all articles. We updated the search of the Cochrane Pregnancy and Childbirth Group’s Trials Register on 27 January 2012 and added the results to the awaiting classification section.
Selection criteria
Published and unpublished randomized controlled trials including pregnant women between the gestational ages of 14 to 32 weeks screened with TVU CL for risk of PTB. This review focuses exclusively on studies based on knowledge versus no knowledge of TVU CL results.
Data collection and analysis
All potential studies identified as in the search were assessed for inclusion by three independent review authors. We also analyzed studies for quality measures and extracted data.
Main results
Of 12 trials identified, five were eligible for inclusion (n = 507). Three included singleton gestations with preterm labor (PTL); one included singleton gestations with preterm prelabour rupture of membranes (PPROM); and one included twin gestations without or with PTL.
In the three trials of singleton gestations with PTL, 290 women were randomized; 147 to knowledge and 143 to no knowledge of TVU CL. Knowledge of TVU CL results was associated with a non-significant decrease in PTB at less than 37 weeks (22.3% versus 34.7%, respectively; risk ratio 0.59, 95% confidence interval (CI) 0.26 to 1.32). Delivery occurred at a later gestational age in the knowledge versus no knowlege groups (mean difference 0.64 weeks (CI 0.03 to 1.25)). All other outcomes for which there were available data (PTB at less than 34 or 28 weeks; birthweight less than 2500 grams; perinatal death; maternal hospitalization; tocolysis; and steroids for fetal lung maturity) were similar in the two groups.
The trial of singleton gestations with PPROM (n = 92) evaluated as its primary outcome safety of TVU CL in this population, and not its effect on management. The incidence of maternal and neonatal infections was similar in the TVU CL and no TVU CL groups.
In the trial of twin gestations with or without PTL (n = 125), PTB at less than 36, 34, or 30 weeks, gestational age at delivery, and other perinatal and maternal outcomes were similar in the TVU CL and the no TVU CL groups. Life table analysis revealed significantly less preterm birth at less than 35 weeks in the TVU CL group compared to the no TVU CL group (P = 0.02).
Authors’ conclusions
Currently there is insufficient evidence to recommend routine screening of asymptomatic or symptomatic pregnant women with TVU CL. Since there is a non-significant association between knowledge of TVU CL results and a lower incidence of PTB at less than 37 weeks in symptomatic women, we encourage further research. Future studies should look at specific populations separately (eg singleton versus twins; symptoms of PTL or no such symptoms), report on all pertinent maternal and perinatal outcomes, and include cost-effectiveness analyses. Most importantly, future studies should include a clear protocol for management of women based on TVU CL results, so that it can be easily evaluated and replicated.
[Note: The two citations in the awaiting classification section of the review may alter the conclusions of the review once assessed.]
doi:10.1002/14651858.CD007235.pub2
PMCID: PMC4239539  PMID: 19588421
Cervical Length Measurement [*methods]; Cervix Uteri [*ultrasonography]; Pregnancy, Multiple; Premature Birth [*prevention & control; ultrasonography]; Randomized Controlled Trials as Topic; Twins; Female; Humans; Pregnancy
23.  Lesser than diabetes hyperglycemia in pregnancy is related to perinatal mortality: a cohort study in Brazil 
Background
Gestational diabetes related morbidity increases along the continuum of the glycemic spectrum. Perinatal mortality, as a complication of gestational diabetes, has been little investigated. In early studies, an association was found, but in more recent ones it has not been confirmed. The Brazilian Study of Gestational Diabetes, a cohort of untreated pregnant women enrolled in the early 1990's, offers a unique opportunity to investigate this question. Thus, our objective is to evaluate whether perinatal mortality increases in a continuum across the maternal glycemic spectrum.
Methods
We prospectively enrolled and followed 4401 pregnant women attending general prenatal care clinics in six Brazilian state capitals, without history of diabetes outside of pregnancy, through to birth, and their offspring through the early neonatal period. Women answered a structured questionnaire and underwent a standardized 2-hour 75-g oral glucose tolerance test (OGTT). Obstetric care was maintained according to local protocols. We obtained antenatal, delivery and neonatal data from hospital records. Odds ratios (OR) were estimated using logistic regression.
Results
We ascertained 97 perinatal deaths (67 fetal and 31 early neonatal). Odds of dying increased according to glucose levels, statistically significantly so only for women delivering at gestational age ≥34 weeks (p < 0.05 for glycemia-gestational age interaction). ORs for a 1 standard deviation difference in glucose, when analyzed continuously, were for fasting 1.47 (95% CI 1.12, 1.92); 1-h 1.55 (95% CI 1.15, 2.07); and 2-h 1.53 (95% CI 1.15, 2.02). The adjusted OR for IADPSG criteria gestational diabetes was 2.21 (95% CI 1.15, 4.27); and for WHO criteria gestational diabetes, 3.10 (95% CI 1.39, 6.88).
Conclusions
In settings of limited detection and treatment of gestational diabetes mellitus, women across a spectrum of lesser than diabetes hyperglycemia, experienced a continuous rise in perinatal death with increasing levels of glycemia after 34 weeks of pregnancy. Current GDM diagnostic criteria identified this increased risk of mortality.
doi:10.1186/1471-2393-11-92
PMCID: PMC3241204  PMID: 22078268
24.  Very advanced maternal age and morbidity in Victoria, Australia: a population based study 
Background
In Australia, approximately 0.1% of births occur to women 45 years or older and this rate has been increasing in recent years. There are however, few population based studies examining perinatal outcomes among this age group. The aim of this study was to determine the maternal and perinatal outcomes of pregnancies in women aged 45 years or older compared to women aged 30–34 years.
Methods
Data on births at 20 or more weeks’ gestation were obtained from the Victorian Perinatal Data Collection for the years 2005 and 2006. We examined selected maternal and perinatal outcomes for women of very advanced maternal age (VAMA) aged 45 years or older (n = 217) and compared them to women aged 30–34 years (n = 48,909). Data were summarised using numbers and percentages. Categorical data were analysed by Chi-square tests and Fisher’s exact test. Comparisons are presented using unadjusted odds ratios, 95 percent confidence intervals (CIs) and p-values.
Results
Women aged 45 years and older had higher odds of gestational diabetes (OR 2.05; 95% CI 1.3–3.3); antepartum haemorrhage (OR 1.89; 95% CI 1.01–3.5), and placenta praevia (OR 4.88; 95% CI 2.4–9.5). The older age-group also had higher odds of preterm birth between 32–36 weeks (OR 2.61; 95% CI 1.8–3.8); low birth-weight (<2,500 gr) (OR 2.22; 95% CI 1.5–3.3) and small for gestational age (OR 1.53; 95% CI 1.0–2.3). Stratified analysis revealed that VAMA was most strongly associated with caesarean section in primiparous women (OR 8.24; 95% CI 4.5, 15.4) and those using ART (OR 5.75; 95% CI 2.5, 13.3), but the relationship persisted regardless of parity, ART use and plurality. Low birthweight was associated with VAMA only in first births (OR 3.90; 95% CI 2.3, 6.6), while preterm birth was more common in older women for both first (OR 3.13; 95% CI 1.8, 5.3) and subsequent (OR 2.08; 95% CI 1.2, 3.5) births, and for those having singleton births (OR 2.11; 95% CI 1.3, 3.4), and those who did not use ART (OR 2.10; 95% CI 1.3, 3.4). Preterm birth was very common in multiple births and following ART use, regardless of maternal age.
Conclusions
This study demonstrates that women aged 45 years and older, in Victoria, Australia, have higher rates of pregnancy and perinatal complications, compared to women aged 30–34 years.
doi:10.1186/1471-2393-13-80
PMCID: PMC3637179  PMID: 23537152
Perinatal death; Very advanced maternal age; Low birth weight; Preterm birth; Haemorrhage
25.  A Risk Prediction Model for the Assessment and Triage of Women with Hypertensive Disorders of Pregnancy in Low-Resourced Settings: The miniPIERS (Pre-eclampsia Integrated Estimate of RiSk) Multi-country Prospective Cohort Study 
PLoS Medicine  2014;11(1):e1001589.
Beth Payne and colleagues use a risk prediction model, the Pre-eclampsia Integrated Estimate of RiSk (miniPIERS) to help inform the clinical assessment and triage of women with hypertensive disorders of pregnancy in low-resourced settings.
Please see later in the article for the Editors' Summary
Background
Pre-eclampsia/eclampsia are leading causes of maternal mortality and morbidity, particularly in low- and middle- income countries (LMICs). We developed the miniPIERS risk prediction model to provide a simple, evidence-based tool to identify pregnant women in LMICs at increased risk of death or major hypertensive-related complications.
Methods and Findings
From 1 July 2008 to 31 March 2012, in five LMICs, data were collected prospectively on 2,081 women with any hypertensive disorder of pregnancy admitted to a participating centre. Candidate predictors collected within 24 hours of admission were entered into a step-wise backward elimination logistic regression model to predict a composite adverse maternal outcome within 48 hours of admission. Model internal validation was accomplished by bootstrapping and external validation was completed using data from 1,300 women in the Pre-eclampsia Integrated Estimate of RiSk (fullPIERS) dataset. Predictive performance was assessed for calibration, discrimination, and stratification capacity. The final miniPIERS model included: parity (nulliparous versus multiparous); gestational age on admission; headache/visual disturbances; chest pain/dyspnoea; vaginal bleeding with abdominal pain; systolic blood pressure; and dipstick proteinuria. The miniPIERS model was well-calibrated and had an area under the receiver operating characteristic curve (AUC ROC) of 0.768 (95% CI 0.735–0.801) with an average optimism of 0.037. External validation AUC ROC was 0.713 (95% CI 0.658–0.768). A predicted probability ≥25% to define a positive test classified women with 85.5% accuracy. Limitations of this study include the composite outcome and the broad inclusion criteria of any hypertensive disorder of pregnancy. This broad approach was used to optimize model generalizability.
Conclusions
The miniPIERS model shows reasonable ability to identify women at increased risk of adverse maternal outcomes associated with the hypertensive disorders of pregnancy. It could be used in LMICs to identify women who would benefit most from interventions such as magnesium sulphate, antihypertensives, or transportation to a higher level of care.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Each year, ten million women develop pre-eclampsia or a related hypertensive (high blood pressure) disorder of pregnancy and 76,000 women die as a result. Globally, hypertensive disorders of pregnancy cause around 12% of maternal deaths—deaths of women during or shortly after pregnancy. The mildest of these disorders is gestational hypertension, high blood pressure that develops after 20 weeks of pregnancy. Gestational hypertension does not usually harm the mother or her unborn child and resolves after delivery but up to a quarter of women with this condition develop pre-eclampsia, a combination of hypertension and protein in the urine (proteinuria). Women with mild pre-eclampsia may not have any symptoms—the condition is detected during antenatal checks—but more severe pre-eclampsia can cause headaches, blurred vision, and other symptoms, and can lead to eclampsia (fits), multiple organ failure, and death of the mother and/or her baby. The only “cure” for pre-eclampsia is to deliver the baby as soon as possible but women are sometimes given antihypertensive drugs to lower their blood pressure or magnesium sulfate to prevent seizures.
Why Was This Study Done?
Women in low- and middle-income countries (LMICs) are more likely to develop complications of pre-eclampsia than women in high-income countries and most of the deaths associated with hypertensive disorders of pregnancy occur in LMICs. The high burden of illness and death in LMICs is thought to be primarily due to delays in triage (the identification of women who are or may become severely ill and who need specialist care) and delays in transporting these women to facilities where they can receive appropriate care. Because there is a shortage of health care workers who are adequately trained in the triage of suspected cases of hypertensive disorders of pregnancy in many LMICs, one way to improve the situation might be to design a simple tool to identify women at increased risk of complications or death from hypertensive disorders of pregnancy. Here, the researchers develop miniPIERS (Pre-eclampsia Integrated Estimate of RiSk), a clinical risk prediction model for adverse outcomes among women with hypertensive disorders of pregnancy suitable for use in community and primary health care facilities in LMICs.
What Did the Researchers Do and Find?
The researchers used data on candidate predictors of outcome that are easy to collect and/or measure in all health care settings and that are associated with pre-eclampsia from women admitted with any hypertensive disorder of pregnancy to participating centers in five LMICs to build a model to predict death or a serious complication such as organ damage within 48 hours of admission. The miniPIERS model included parity (whether the woman had been pregnant before), gestational age (length of pregnancy), headache/visual disturbances, chest pain/shortness of breath, vaginal bleeding with abdominal pain, systolic blood pressure, and proteinuria detected using a dipstick. The model was well-calibrated (the predicted risk of adverse outcomes agreed with the observed risk of adverse outcomes among the study participants), it had a good discriminatory ability (it could separate women who had a an adverse outcome from those who did not), and it designated women as being at high risk (25% or greater probability of an adverse outcome) with an accuracy of 85.5%. Importantly, external validation using data collected in fullPIERS, a study that developed a more complex clinical prediction model based on data from women attending tertiary hospitals in high-income countries, confirmed the predictive performance of miniPIERS.
What Do These Findings Mean?
These findings indicate that the miniPIERS model performs reasonably well as a tool to identify women at increased risk of adverse maternal outcomes associated with hypertensive disorders of pregnancy. Because miniPIERS only includes simple-to-measure personal characteristics, symptoms, and signs, it could potentially be used in resource-constrained settings to identify the women who would benefit most from interventions such as transportation to a higher level of care. However, further external validation of miniPIERS is needed using data collected from women living in LMICs before the model can be used during routine antenatal care. Moreover, the value of miniPIERS needs to be confirmed in implementation projects that examine whether its potential translates into clinical improvements. For now, though, the model could provide the basis for an education program to increase the knowledge of women, families, and community health care workers in LMICs about the signs and symptoms of hypertensive disorders of pregnancy.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001589.
The World Health Organization provides guidelines for the management of hypertensive disorders of pregnancy in low-resourced settings
The Maternal and Child Health Integrated Program provides information on pre-eclampsia and eclampsia targeted to low-resourced settings along with a tool-kit for LMIC providers
The US National Heart, Lung, and Blood Institute provides information about high blood pressure in pregnancy and a guide to lowering blood pressure in pregnancy
The UK National Health Service Choices website provides information about pre-eclampsia
The US not-for profit organization Preeclampsia Foundation provides information about all aspects of pre-eclampsia; its website includes some personal stories
The UK charity Healthtalkonline also provides personal stories about hypertensive disorders of pregnancy
MedlinePlus provides links to further information about high blood pressure and pregnancy (in English and Spanish); the MedlinePlus Encyclopedia has a video about pre-eclampsia (also in English and Spanish)
More information about miniPIERS and about fullPIERS is available
doi:10.1371/journal.pmed.1001589
PMCID: PMC3897359  PMID: 24465185

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