Gordon Smith argues for more and better research in screening for pregnancy outcomes, using the example of previous trials in pre-eclampsia.

Objective

To assess time trends in socioeconomic inequalities in overall and cause-specific stillbirth rates in England.

Design

Population-based retrospective study.

Setting

England.

Participants

Stillbirths occurring among singleton infants born between 1 January 2000 and 31 December 2007.

Main outcome measure

Cause-specific stillbirth rate per 10 000 births by deprivation tenth and year of birth. Deprivation measured using the UK index of multiple deprivation at Super Output Area level.

Methods

Poisson regression models were used to estimate the relative deprivation gap (comparing the most and least deprived tenths) in rates of stillbirths (overall and cause-specific). Excess mortality was calculated by applying the rates seen in the least deprived tenth to the entire population at risk. Discussions with our local NHS multicentre ethics committee deemed that this analysis of national non-identifiable data did not require separate ethics approval.

Results

There were 44 stillbirths per 10 000 births, with no evidence of a change in rates over time. Rates were twice as high in the most deprived tenth compared with the least (rate ratio (RR) 2.1, 95% CI 2.0 to 2.2) with no evidence of a change over time. There was a significant deprivation gap for all specific causes except mechanical events (RR 1.2, 95% CI 0.9 to 1.5). The widest gap was seen for stillbirths due to antepartum haemorrhages (RR 3.1, 95% CI 2.8 to 3.5). No evidence of a change in the rate of stillbirth or deprivation gap over time was seen for any specific cause.

Conclusion

A wide deprivation gap exists in stillbirth rates for most causes and is not diminishing. Unexplained antepartum stillbirths accounted for 50% of the deprivation gap, and a better understanding of these stillbirths is necessary to reduce socioeconomic inequalities.

Article summary

Article focus

To explore time trends in socioeconomic inequalities in cause-specific stillbirths in England over an 8-year period.

To aid understanding of the deprivation gap in overall and cause-specific stillbirth rates.

Key messages

A wide deprivation gap exists in the rates of stillbirth, and this has remained constant over time.

Significant deprivation differences were seen between the most and least deprived groups in all causes except mechanical events that occurred during labour.

Future collection of more detailed information is necessary in order to better identify modifiable risk factors and thus permit the introduction of appropriate targets and interventions.

Strengths and limitations of this study

Individual-level information was not available, and therefore, we could not explore issues such as smoking status.

However, these analyses based on routine data are straightforward to undertake and allow health service planners to monitor trends in stillbirths.

Background

To estimate the effectiveness of routine antenatal anti-D prophylaxis for preventing sensitisation in pregnant Rhesus negative women, and to explore whether this depends on the treatment regimen adopted.

Methods

Ten studies identified in a previous systematic literature search were included. Potential sources of bias were systematically identified using bias checklists, and their impact and uncertainty were quantified using expert opinion. Study results were adjusted for biases and combined, first in a random-effects meta-analysis and then in a random-effects meta-regression analysis.

Results

In a conventional meta-analysis, the pooled odds ratio for sensitisation was estimated as 0.25 (95% CI 0.18, 0.36), comparing routine antenatal anti-D prophylaxis to control, with some heterogeneity (I2 = 19%). However, this naïve analysis ignores substantial differences in study quality and design. After adjusting for these, the pooled odds ratio for sensitisation was estimated as 0.31 (95% CI 0.17, 0.56), with no evidence of heterogeneity (I2 = 0%). A meta-regression analysis was performed, which used the data available from the ten anti-D prophylaxis studies to inform us about the relative effectiveness of three licensed treatments. This gave an 83% probability that a dose of 1250 IU at 28 and 34 weeks is most effective and a 76% probability that a single dose of 1500 IU at 28–30 weeks is least effective.

Conclusion

There is strong evidence for the effectiveness of routine antenatal anti-D prophylaxis for prevention of sensitisation, in support of the policy of offering routine prophylaxis to all non-sensitised pregnant Rhesus negative women. All three licensed dose regimens are expected to be effective.

Objective To determine the effect of time and day of birth on the risk of neonatal death at term.

Design Population based retrospective cohort study.

Setting Data from the linked Scottish morbidity records, Stillbirth and Infant Death Survey, and birth certificate database of live births in Scotland, 1985-2004.

Subjects Liveborn term singletons with cephalic presentation. Perinatal deaths from congenital anomalies excluded. Final sample comprised 1 039 560 live births.

Main outcome measure All neonatal deaths (in the first four weeks of life) unrelated to congenital abnormality, plus a subgroup of deaths ascribed to intrapartum anoxia.

Results The risk of neonatal death was 4.2 per 10 000 during the normal working week (Monday to Friday, 0900-1700) and 5.6 per 10 000 at all other times (out of hours) (unadjusted odds ratio 1.3, 95% confidence interval 1.1 to 1.6). Adjustment for maternal characteristics had no material effect. The higher rate of death out of hours was because of an increased risk of death ascribed to intrapartum anoxia (adjusted odds ratio 1.7, 1.2 to 2.3). Though exclusion of elective caesarean deliveries attenuated the association between death ascribed to anoxia and delivery out of hours, a significant association persisted (adjusted odds ratio 1.5, 1.1 to 2.0). The attributable fraction of neonatal deaths ascribed to intrapartum anoxia associated with delivery out of hours was 26% (95% confidence interval 5% to 42%).

Conclusions Delivering an infant outside the normal working week was associated with an increased risk of neonatal death at term ascribed to intrapartum anoxia.

A retrospective cohort study of 407,503 schoolchildren by Jill Pell and colleagues finds that gestational age at delivery has a dose-dependent relationship with the risk of special educational needs that extends across the full gestational range.

Background

Previous studies have demonstrated an association between preterm delivery and increased risk of special educational need (SEN). The aim of our study was to examine the risk of SEN across the full range of gestation.

Methods and Findings

We conducted a population-based, retrospective study by linking school census data on the 407,503 eligible school-aged children resident in 19 Scottish Local Authority areas (total population 3.8 million) to their routine birth data. SEN was recorded in 17,784 (4.9%) children; 1,565 (8.4%) of those born preterm and 16,219 (4.7%) of those born at term. The risk of SEN increased across the whole range of gestation from 40 to 24 wk: 37–39 wk adjusted odds ratio (OR) 1.16, 95% confidence interval (CI) 1.12–1.20; 33–36 wk adjusted OR 1.53, 95% CI 1.43–1.63; 28–32 wk adjusted OR 2.66, 95% CI 2.38–2.97; 24–27 wk adjusted OR 6.92, 95% CI 5.58–8.58. There was no interaction between elective versus spontaneous delivery. Overall, gestation at delivery accounted for 10% of the adjusted population attributable fraction of SEN. Because of their high frequency, early term deliveries (37–39 wk) accounted for 5.5% of cases of SEN compared with preterm deliveries (<37 wk), which accounted for only 3.6% of cases.

Conclusions

Gestation at delivery had a strong, dose-dependent relationship with SEN that was apparent across the whole range of gestation. Because early term delivery is more common than preterm delivery, the former accounts for a higher percentage of SEN cases. Our findings have important implications for clinical practice in relation to the timing of elective delivery.

Please see later in the article for the Editors' Summary

Editors' Summary

Background

Most pregnancies last around 40 weeks, but the number of babies who are born early is increasing. In the US, for example, more than half a million babies a year are now born before 37 weeks of gestation (gestation is the period during which a baby develops in its mother). Sadly, babies born this early (premature babies) are more likely to die than babies delivered between 37 and 42 weeks of gestation (term babies) and many have short- and/or long-term health problems. They are also more likely to have a “special educational need” (SEN) as children, a learning difficulty (for example, dyslexia or autism), or a physical difficulty such as deafness or poor vision that requires special educational help, than term babies. The severity of all the problems associated with being born early depends on the degree of prematurity. Thus, the risk of SEN associated with prematurity declines steadily with advancing gestational age up to 36 weeks. That is, a baby born at 24 weeks of gestation is more likely to have an SEN later in life than one born at 36 weeks of gestation.

Why Was This Study Done?

Early term births (between 37 and 39 weeks of gestation) are also becoming more common, because more mothers are electing to be delivered early for nonmedical reasons (so-called birth scheduling). Unfortunately, it is not known whether early term babies have an increased risk of SEN compared with babies born at 40 weeks, because few studies have looked at SEN in children born between 37 and 39 weeks of gestation. In this retrospective cohort study, the researchers investigate the risk of SEN across the whole spectrum of gestational age at delivery and use their results to calculate the fraction of SEN associated with delivery at different gestational ages—the “population attributable risk.” In a retrospective cohort study, researchers examine the medical records of groups of people who differ in a specific characteristic (in this case, having an SEN) for a particular outcome (in this case, gestational age at birth).

What Did the Researchers Do and Find?

The researchers linked 2005 School Census data (which includes a record of all children with an SEN) for more than 400,000 school-aged children in 19 Scottish Local Authority areas (covering three-quarters of the Scottish population) with routine birth data held in the Scottish Morbidity Record. SEN was recorded for nearly 18,000 children (4.9% of the children). 8.4% of the children who were born preterm and 4.7% of those born at term were recorded as having an SEN. The risk of SEN increased across the gestation range from 40 to 24 weeks. Thus, compared to children born at 40 weeks, children born at 37–39 weeks of gestation were 1.16 times as likely to have an SEN—an odds ratio of 1.16. Children born at 33–36, 28–32, and 24–27 weeks were 1.53, 2.66, and 6.92 times as likely to have an SEN, respectively, as children born at 40 weeks. Although the risk of SEN was much higher in preterm than in early term babies, because many more children were born between 37 and 39 weeks (about a third of babies) than before 37 weeks (one in 20 babies), early term births accounted for 5.5% of cases of SEN, whereas preterm deliveries accounted for only 3.6% of cases.

What Do These Findings Mean?

These findings show that gestational age at delivery strongly affects a child's subsequent risk of having an SEN in a dose-dependent manner across the whole range of gestational age. Furthermore, because early term delivery is much more common than preterm delivery, these findings show that early term delivery is responsible for more cases of SEN than preterm delivery. These findings, which are likely to be accurate because of the large size of the study and its design, have important implications for the timing of elective delivery. They suggest that deliveries should ideally wait until 40 weeks of gestation because even a baby born at 39 weeks—the normal timing for elective deliveries these days—has an increased risk of SEN compared with a baby born a week later.

Additional Information

Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000289.

The March of Dimes, a nonprofit organization for pregnancy and baby health, provides information on preterm birth and an article on why the last weeks of pregnancy count (in English and Spanish)

The US National Institute of Child Health and Human Development has information on preterm labor and birth and on learning disabilities

The UK Government provides information for parents on special educational needs

Medline Plus has links to further information on both premature birth and learning disabilities (in English and Spanish)

Stillbirth is a major obstetric complication, with 3.2 million stillbirths worldwide and 26,000 stillbirths in the United States every year. The Eunice Kennedy Shriver National Institute of Child Health and Human Development held a workshop from October 22–24, 2007, to review the pathophysiology of conditions underlying stillbirth to define causes of death. The optimal classification system would identify the pathophysiologic entity initiating the chain of events that irreversibly led to death. Because the integrity of the classification is based on available pathologic, clinical, and diagnostic data, experts emphasized that a complete stillbirth workup should be performed. Experts developed evidence-based characteristics of maternal, fetal, and placental conditions to attribute a condition as a cause of stillbirth. These conditions include infection, maternal medical conditions, antiphospholipid syndrome, heritable thrombophilias, red cell alloimmunization, platelet alloimmunization, congenital malformations, chromosomal abnormalities including confined placental mosaicism, fetomaternal hemorrhage, placental and umbilical cord abnormalities including vasa previa and placental abruption, complications of multifetal gestation, and uterine complications. In all cases, owing to lack of sufficient knowledge about disease states and normal development, there will be a degree of uncertainty regarding whether a specific condition was indeed the cause of death.

Policy decisions often require synthesis of evidence from multiple sources, and the source studies typically vary in rigour and in relevance to the target question. We present simple methods of allowing for differences in rigour (or lack of internal bias) and relevance (or lack of external bias) in evidence synthesis. The methods are developed in the context of reanalysing a UK National Institute for Clinical Excellence technology appraisal in antenatal care, which includes eight comparative studies. Many were historically controlled, only one was a randomized trial and doses, populations and outcomes varied between studies and differed from the target UK setting. Using elicited opinion, we construct prior distributions to represent the biases in each study and perform a bias-adjusted meta-analysis. Adjustment had the effect of shifting the combined estimate away from the null by approximately 10%, and the variance of the combined estimate was almost tripled. Our generic bias modelling approach allows decisions to be based on all available evidence, with less rigorous or less relevant studies downweighted by using computationally simple methods.

Background

The relationship between population trends in delaying childbirth and rising rates of primary cesarean delivery is unclear. The aims of the present study were (1) to characterize the association between maternal age and the outcome of labor, (2) to determine the proportion of the increase in primary cesarean rates that could be attributed to changes in maternal age distribution, and (3) to determine whether the contractility of uterine smooth muscle (myometrium) varied with maternal age.

Methods and Findings

We utilized nationally collected data from Scotland, from 1980 to 2005, and modeled the risk of emergency cesarean section among women delivering a liveborn infant in a cephalic presentation at term. We also studied isolated myometrial strips obtained from 62 women attending for planned cesarean delivery in Cambridge, England, from 2005 to 2007. Among 583,843 eligible nulliparous women, there was a linear increase in the log odds of cesarean delivery with advancing maternal age from 16 y upwards, and this increase was unaffected by adjustment for a range of maternal characteristics (adjusted odds ratio for a 5-y increase 1.49, 95% confidence interval [CI] 1.48–1.51). Increasing maternal age was also associated with a longer duration of labor (0.49 h longer for a 5-y increase in age, 95% CI 0.46–0.51) and an increased risk of operative vaginal birth (adjusted odds ratio for a 5-y increase 1.49, 95% CI 1.48–1.50). Over the period from 1980 to 2005, the cesarean delivery rate among nulliparous women more than doubled and the proportion of women aged 30–34 y increased 3-fold, the proportion aged 35–39 y increased 7-fold, and the proportion aged ≥40 y increased 10-fold. Modeling indicated that if the age distribution had stayed the same over the period of study, 38% of the additional cesarean deliveries would have been avoided. Similar associations were observed in multiparous women. When studied in vitro, increasing maternal age was associated with reduced spontaneous activity and increased likelihood of multiphasic spontaneous myometrial contractions.

Conclusions

Delaying childbirth has significantly contributed to rising rates of intrapartum primary cesarean delivery. The association between increasing maternal age and the risk of intrapartum cesarean delivery is likely to have a biological basis.

Gordon Smith and colleagues find a linear increase in the log odds of cesarean delivery with advancing maternal age from 16 years upwards, and that increasing maternal age is associated with reduced spontaneous uterine activity but increased multiphasic spontaneous myometrial contractions.

Editors' Summary

Background.

The rising rates of cesarean sections have been a concern for over two decades. An acceptable rate of cesarean sections is between 10% and 15% for countries in the developed world, according to the World Health Organization (WHO). However, the estimated rate in the United Kingdom was 20% in 2004. In Canada, it was estimated at 22.5% in 2001–2002. And in the United States, the rate was 30.2% in 2005 (rising 46% since 1996).

This increase may have implications for the mother, baby, healthcare providers, and policy makers. Though it is difficult to directly compare risks between vaginal and cesarean deliveries, higher mortality and morbidity rates are associated with the latter. Risks encountered during the operation may include anesthetic complications and difficulty in stopping bleeding. Later risks include infections, wound healing problems, and increased risk of problems in subsequent pregnancies including malpresentation, placenta previa, and uterine rupture.

Why Was This Study Done?

The trend of increased rates of cesarean sections with maternal age appears to be consistent in different countries and has previously been reported by several epidemiological studies. However, it remains unclear why the risk of having cesarean section is associated with advancing maternal age. Could the association reflect a biological effect of advanced age, or is it a consequence of physician and maternal preference?

The researchers aimed to (1) characterize the association between maternal age and the outcome of labor, (2) determine the proportion of the increase in primary cesarean rates that could be attributed to changes in maternal age distribution, and (3) determine whether the contractility of uterine smooth muscle (myometrium) varied with maternal age.

What Did the Researchers Do and Find?

To address aims (1) and (2), the researchers analyzed data collected over the period 1980 to 2005 by the Scottish Morbidity Record (SMR2), which has been demonstrated to be 99% complete since the late 1970s and free from substantial errors in more than 98% of the records in most of the specific fields used for their analysis.

Their analysis showed a linear association between the risk of having a cesarean section and advancing maternal age in first pregnancies. The cesarean rate also more than doubled over the study period. They estimated that 38% of the additional procedures would have been avoided if maternal age distribution had remained the same as in 1980. Therefore they conclude that a substantial part of the increase may be associated with the trend of delaying of first childbirth.

They then hypothesized that this trend is a result of a biological effect of aging on the contractility of the uterus. This hypothesis was further evaluated with aim (3) of the study, where they biopsied the uteri of 62 women (of mixed parity) undergoing routine elective cesarean delivery to test their contractility. They found that advancing age was associated with impaired uterine function as evidenced by a reduced degree of spontaneous contraction and the type of spontaneous contraction.

What Do These Findings Mean?

This study adds to the evidence that advancing maternal age is associated with higher rates of cesarean sections. It also suggests a possible mechanism for this association, i.e., impaired uterine function. Though it was not studied here, the researchers hypothesize that impaired uterine contractility may be a consequence of prolonged stimulation of the uterus by estrogen and progesterone, resulting from a prolonged interval between menarche and first birth. Further research is needed to understand the determinants and management of dysfunctional labor in older women to help design strategies for reducing population cesarean delivery rates without adversely affecting maternal and infant outcomes.

Additional Information.

Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0050144.

NHS Choices is a patient information Web site developed to help patients take control of their health care

Wikipedia has a section on cesarean section (Note that Wikipedia is an internet encyclopedia that anyone can edit)

MedlinePlus also has information on cesarean section

Objective To determine if first trimester fetal growth is associated with birth weight, duration of pregnancy, and the risk of delivering a small for gestational age infant.

Design Prospective cohort study of 38 033 pregnancies between 1999 and 2003.

Setting 15 centres representing major regions of the United States.

Participants 976 women from the original cohort who conceived as the result of assisted reproductive technology, had a first trimester ultrasound measurement of fetal crown-rump length, and delivered live singleton infants without evidence of chromosomal or congenital abnormalities. First trimester growth was expressed as the difference between the observed and expected size of the fetus, expressed as equivalence to days of gestational age.

Main outcome measures Birth weight, duration of pregnancy, and risk of delivering a small for gestational age infant.

Results For each one day increase in the observed size of the fetus, birth weight increased by 28.2 (95% confidence interval 14.6 to 41.2) g. The association was substantially attenuated by adjustment for duration of pregnancy (adjusted coefficient 17.1 (6.6 to 27.5) g). Further adjustments for maternal characteristics and complications of pregnancy did not have a significant effect. The risk of delivering a small for gestational age infant decreased with increasing size in the first trimester (odds ratio for a one day increase 0.87, 0.81 to 0.94). The association was not materially affected by adjustment for maternal characteristics or complications of pregnancy.

Conclusion Variation in birth weight may be determined, at least in part, by fetal growth in the first 12 weeks after conception through effects on timing of delivery and fetal growth velocity.

Objective To determine the effect of birth order on the risk of perinatal death in twin pregnancies.

Design Retrospective cohort study.

Setting England, Northern Ireland, and Wales, 1994-2003.

Participants 1377 twin pregnancies with one intrapartum stillbirth or neonatal death from causes other than congenital abnormality and one surviving infant.

Main outcome measures The risk of perinatal death in the first and second twin estimated with conditional logistic regression.

Results There was no association between birth order and the risk of death overall (odds ratio 1.0, 95% confidence interval 0.9 to 1.1). However, there was a highly significant interaction with gestational age (P<0.001). There was no association between birth order and the risk of death among infants born before 36 weeks' gestation but there was an increased risk of death among second twins born at term (2.3, 1.7 to 3.2, P<0.001), which was stronger for deaths caused by intrapartum anoxia or trauma (3.4, 2.2 to 5.3). Among term births, there was a trend (P=0.1) towards a greater risk of the second twin dying from anoxia among those delivered vaginally (4.1, 1.8 to 9.5) compared with those delivered by caesarean section (1.8, 0.9 to 3.6).

Conclusions In this cohort, compared with first twins, second twins born at term were at increased risk of perinatal death related to delivery. Vaginally delivered second twins had a fourfold risk of death caused by intrapartum anoxia.

Background

There is currently no validated method for antepartum prediction of the risk of failed vaginal birth after cesarean section and no information on the relationship between the risk of emergency cesarean delivery and the risk of uterine rupture.

Methods and Findings

We linked a national maternity hospital discharge database and a national registry of perinatal deaths. We studied 23,286 women with one prior cesarean delivery who attempted vaginal birth at or after 40-wk gestation. The population was randomly split into model development and validation groups. The factors associated with emergency cesarean section were maternal age (adjusted odds ratio [OR] = 1.22 per 5-y increase, 95% confidence interval [CI]: 1.16 to 1.28), maternal height (adjusted OR = 0.75 per 5-cm increase, 95% CI: 0.73 to 0.78), male fetus (adjusted OR = 1.18, 95% CI: 1.08 to 1.29), no previous vaginal birth (adjusted OR = 5.08, 95% CI: 4.52 to 5.72), prostaglandin induction of labor (adjusted OR = 1.42, 95% CI: 1.26 to 1.60), and birth at 41-wk (adjusted OR = 1.30, 95% CI: 1.18 to 1.42) or 42-wk (adjusted OR = 1.38, 95% CI: 1.17 to 1.62) gestation compared with 40-wk. In the validation group, 36% of the women had a low predicted risk of caesarean section (<20%) and 16.5% of women had a high predicted risk (>40%); 10.9% and 47.7% of these women, respectively, actually had deliveries by caesarean section. The predicted risk of caesarean section was also associated with the risk of all uterine rupture (OR for a 5% increase in predicted risk = 1.22, 95% CI: 1.14 to 1.31) and uterine rupture associated with perinatal death (OR for a 5% increase in predicted risk = 1.32, 95% CI: 1.02 to 1.73). The observed incidence of uterine rupture was 2.0 per 1,000 among women at low risk of cesarean section and 9.1 per 1,000 among those at high risk (relative risk = 4.5, 95% CI: 2.6 to 8.1). We present the model in a simple-to-use format.

Conclusions

We present, to our knowledge, the first validated model for antepartum prediction of the risk of failed vaginal birth after prior cesarean section. Women at increased risk of emergency caesarean section are also at increased risk of uterine rupture, including catastrophic rupture leading to perinatal death.

By studying a large group of Scottish women giving birth, Gordon Smith and colleagues developed and validated a tool to assess the risk of failed vaginal birth after prior caesarean section.

Objective To determine the factors associated with an increased risk of perinatal death related to uterine rupture during attempted vaginal birth after caesarean section.

Design Population based retrospective cohort study.

Setting Data from the linked Scottish Morbidity Record and Stillbirth and Infant Death Survey of births in Scotland, 1985-98.

Participants All women with one previous caesarean delivery who gave birth to a singleton infant at term by a means other than planned repeat caesarean section (n = 35 854).

Main outcome measures All intrapartum uterine rupture and uterine rupture resulting in perinatal death (that is, death of the fetus or neonate).

Results The overall proportion of vaginal births was 74.2% and of uterine rupture was 0.35%. The risk of intrapartum uterine rupture was higher among women who had not previously given birth vaginally (adjusted odds ratio 2.5, 95% confidence interval 1.6 to 3.9, P < 0.001) and those whose labour was induced with prostaglandin (2.9, 2.0 to 4.3, P < 0.001). Both factors were also associated with an increased risk of perinatal death due to uterine rupture. Delivery in a hospital with < 3000 births a year did not increase the overall risk of uterine rupture (1.1, 0.8 to 1.5, P = 0.67). However, the risk of perinatal death due to uterine rupture was significantly higher in hospitals with < 3000 births a year (one per 1300 births) than in hospitals with ≥ 3000 births a year (one per 4700; 3.4, 1.0 to 14.3, P = 0.04).

Conclusion Women who have not previously given birth vaginally and those whose labour is induced with prostaglandin are at increased risk of uterine rupture when attempting vaginal birth after caesarean section. The risk of consequent death of the infant is higher in units with lower annual numbers of births.

Objectives To determine whether parachutes are effective in preventing major trauma related to gravitational challenge.

Design Systematic review of randomised controlled trials.

Data sources: Medline, Web of Science, Embase, and the Cochrane Library databases; appropriate internet sites and citation lists.

Study selection: Studies showing the effects of using a parachute during free fall.

Main outcome measure Death or major trauma, defined as an injury severity score > 15.

Results We were unable to identify any randomised controlled trials of parachute intervention.

Conclusions As with many interventions intended to prevent ill health, the effectiveness of parachutes has not been subjected to rigorous evaluation by using randomised controlled trials. Advocates of evidence based medicine have criticised the adoption of interventions evaluated by using only observational data. We think that everyone might benefit if the most radical protagonists of evidence based medicine organised and participated in a double blind, randomised, placebo controlled, crossover trial of the parachute.

Objective To determine whether a short interval between pregnancies is an independent risk factor for adverse obstetric outcome.

Design Retrospective cohort study.

Setting Scotland.

Subjects 89 143 women having second births in 1992-8 who conceived within five years of their first birth.

Main outcome measures Intrauterine growth restriction (birth weight less than the 5th centile for gestational age), extremely preterm birth (24-32 weeks), moderately preterm birth (33-36 weeks), and perinatal death.

Results Women whose subsequent interpregnancy interval was less than six months were more likely than other women to have had a first birth complicated by intrauterine growth restriction (odds ratio 1.3, 95% confidence interval 1.1 to 1.5), extremely preterm birth (4.1, 3.2 to 5.3), moderately preterm birth (1.5, 1.3 to 1.7), or perinatal death (24.4, 18.9 to 31.5). They were also shorter, less likely to be married, and more likely to be aged less than 20 years at the time of the second birth, to smoke, and to live in an area of high socioeconomic deprivation. When the outcome of the second birth was analysed in relation to the preceding interpregnancy interval and the analysis confined to women whose first birth was a term live birth (n = 69 055), no significant association occurred (adjusted for age, marital status, height, socioeconomic deprivation, smoking, previous birth weight vigesimal, and previous caesarean delivery) between interpregnancy interval and intrauterine growth restriction or stillbirth. However, a short interpregnancy interval (< 6 months) was an independent risk factor for extremely preterm birth (adjusted odds ratio 2.2, 1.3 to 3.6), moderately preterm birth (1.6, 1.3 to 2.0), and neonatal death unrelated to congenital abnormality (3.6, 1.2 to 10.7). The adjusted attributable fractions for these associations were 6.1%, 3.9%, and 13.8%. The associations were very similar when the analysis was confined to married non-smokers aged 25 and above.

Conclusions A short interpregnancy interval is an independent risk factor for preterm delivery and neonatal death in the second birth.

Objective

To determine whether twins born second are at increased risk of perinatal death because of complications during labour and delivery.

Design

Retrospective cohort study.

Setting

Scotland, 1992 and 1997.

Participants

All twin births at or after 24 weeks' gestation, excluding twin pairs in which either twin died before labour or delivery or died during or after labour and delivery because of congenital abnormality, non-immune hydrops, or twin to twin transfusion syndrome.

Main outcome measure

Delivery related perinatal deaths (deaths during labour or the neonatal period).

Results

Overall, delivery related perinatal deaths were recorded for 23 first twins only and 23 second twins only of 1438 twin pairs born before 36 weeks (preterm) by means other than planned caesarean section (P>0.99). No deaths of first twins and nine deaths of second twins (P=0.004) were recorded among the 2436 twin pairs born at or after 36 weeks (term). Discordance between first and second twins differed significantly in preterm and term births (P=0.007). Seven of nine deaths of second twins at term were due to anoxia during the birth (2.9 (95% confidence interval 1.2 to 5.9) per 1000); five of these deaths were associated with mechanical problems with the second delivery following vaginal delivery of the first twin. No deaths were recorded among 454 second twins delivered at term by planned caesarean section.

Conclusions

Second twins born at term are at higher risk than first twins of death due to complications of delivery. Previous studies may not have shown an increased risk because of inadequate categorisation of deaths, lack of statistical power, inappropriate analyses, and pooling of data about preterm births and term births.

What is already known on this topicIt is difficult to assess the wellbeing of second twins during labourDeliveries of second twins are at increased risk of mechanical problems, such as cord prolapse and malpresentation, after vaginal delivery of first twinsIncreased risks of perinatal death in second twins have not been shown, but the methods of these studies were flawedWhat this study addsSecond twins delivered at term are at increased risk of delivery related perinatal deathsIntrapartum anoxia caused 75% of these deaths in second twins, and most of these resulted from mechanical problems after vaginal delivery of first twinsPlanned caesarean section of twins at term may prevent perinatal deaths

Objective

To determine whether first and second births among teenagers are associated with increased risk of adverse perinatal outcomes after confounding variables have been taken into account.

Design

Population based retrospective cohort study using routine discharge data for 1992-8.

Setting

Scotland.

Main outcome measures

Stillbirth, preterm delivery, emergency caesarean section, and small for gestational age baby among non-smoking mothers aged 15-19 and 20-29.

Results

The 110 233 eligible deliveries were stratified into first and second births. Among first births, the only significant difference in adverse outcomes by age group was for emergency caesarean section, which was less likely among younger mothers (odds ratio 0.5, 95% confidence interval 0.5 to 0.6). Second births in women aged 15-19 were associated with an increased risk of moderate (1.6, 1.2 to 2.1) and extreme prematurity (2.5, 1.5 to 4.3) and stillbirth (2.6, 1.3 to 5.3) but a reduced risk of emergency caesarean section (0.7, 0.5 to 1.0).

Conclusions

First teenage births are not independently associated with an increased risk of adverse pregnancy outcome and are at decreased risk of delivery by emergency caesarean section. However, second teenage births are associated with an almost threefold risk of preterm delivery and stillbirth.

What is already known on this topicTeenage mothers are more likely to deliver prematurely and to have a perinatal death than older womenTeenage mothers are also more likely to smoke, be having a first baby, and live in adverse social circumstancesWhat this study addsNon-smoking women aged 15-19 having a first birth were not at increased risk of adverse obstetric outcomes compared with women aged 20-29 after potential confounding variables were adjusted forNon-smoking women aged 15-19 having a second birth were at significantly increased risk of both premature delivery and stillbirth compared with women aged 20-29

Objectives To compare changes in inequalities in sudden infant death syndrome with other causes of infant mortality and stillbirth in Scotland, 1985-2008.

Design Retrospective cohort study.

Setting Scotland 1985-2008, analysed by four epochs of six years.

Participants Singleton births of infants with birth weight >500 g born at 28-43 weeks’ gestation.

Main outcome measures Sudden infant death syndrome, other causes of postneonatal infant death, neonatal death, and stillbirth. Odds ratios expressed as the association across the range of seven categories of Carstairs deprivation score.

Results The association between deprivation and the risk of all cause stillbirth and infant death varied between the four epochs (P=0.04). This was wholly explained by variation in the risk of sudden infant death syndrome (P<0.001 for interaction). Among women living in areas of low deprivation, there was a sharp decline in the rate of sudden infant death syndrome from 1990 to 1993. Among women living in areas of high deprivation, there was a slower decline in sudden infant death syndrome rates between 1992 and 2004. Consequently, the odds ratio for the association between socioeconomic deprivation and sudden infant death syndrome increased from 2.04 (95% confidence interval 1.53 to 2.72) in 1985-90, to 7.52 (4.62 to 12.25) in 1991-6, and 9.50 (5.46 to 16.53) in 1997-2002 but fell to 1.78 (0.87 to 3.65) in 2002-8. The interaction remained significant after adjustment for maternal characteristics.

Conclusion The rate of sudden infant death syndrome declined throughout Scotland in the early 1990s. The decline had a later onset and was slower among women living in areas of high deprivation, probably because of slower uptake of recommended changes in infant sleeping position. The effect was to create a strong independent association between deprivation and sudden infant death syndrome where one did not exist before.

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)

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

Using data collected as a follow-up to a randomized trial, Melissa Gladstone and colleagues show that during the first two years of life, infants born preterm in southern Malawi are disadvantaged in terms of mortality, growth, and development.

Background

Preterm birth is considered to be associated with an estimated 27% of neonatal deaths, the majority in resource-poor countries where rates of prematurity are high. There is no information on medium term outcomes after accurately determined preterm birth in such settings.

Methods and Findings

This community-based stratified cohort study conducted between May–December 2006 in Southern Malawi followed up 840 post-neonatal infants born to mothers who had received antenatal antibiotic prophylaxis/placebo in an attempt to reduce rates of preterm birth (APPLe trial ISRCTN84023116). Gestational age at delivery was based on ultrasound measurement of fetal bi-parietal diameter in early-mid pregnancy. 247 infants born before 37 wk gestation and 593 term infants were assessed at 12, 18, or 24 months. We assessed survival (death), morbidity (reported by carer, admissions, out-patient attendance), growth (weight and height), and development (Ten Question Questionnaire [TQQ] and Malawi Developmental Assessment Tool [MDAT]). Preterm infants were at significantly greater risk of death (hazard ratio 1.79, 95% CI 1.09–2.95). Surviving preterm infants were more likely to be underweight (weight-for-age z score; p<0.001) or wasted (weight-for-length z score; p<0.01) with no effect of gestational age at delivery. Preterm infants more often screened positively for disability on the Ten Question Questionnaire (p = 0.002). They also had higher rates of developmental delay on the MDAT at 18 months (p = 0.009), with gestational age at delivery (p = 0.01) increasing this likelihood. Morbidity—visits to a health centre (93%) and admissions to hospital (22%)—was similar for both groups.

Conclusions

During the first 2 years of life, infants who are born preterm in resource poor countries, continue to be at a disadvantage in terms of mortality, growth, and development. In addition to interventions in the immediate neonatal period, a refocus on early childhood is needed to improve outcomes for infants born preterm in low-income settings.

Please see later in the article for the Editors' Summary

Editors' Summary

Background

Being born at term in Africa is not necessarily straightforward. In Malawi, 33 of every 1,000 infants born die in the first 28 days after birth; the lifetime risk for a mother dying during or shortly after pregnancy is one in 36. The comparable figures for the United Kingdom are three infants dying per 1,000 births and a lifetime risk of maternal death of one in 4,700. But for a baby, being born preterm is even more risky and the gap between low- and high-income countries widens still further. According to a World Health Organization report in 2010, a baby born at 32 weeks of gestation (weighing around 2,000 g) in Africa has little chance of survival, while the chances of survival for a baby born at 32 weeks in North America or Europe are similar to one born at term. There are very few data on the longer term outcomes of babies born preterm in Africa and there are multiple challenges involved in gathering such information. As prenatal ultrasound is not routinely available, gestational age is often uncertain. There may be little routine follow-up of preterm babies as is commonplace in high-income countries. Data are needed from recent years that take into account both improvements in perinatal care and adverse factors such as a rising number of infants becoming HIV positive around the time of birth.

Why Was This Study Done?

We could improve outcomes for babies born preterm in sub-Saharan Africa if we understood more about what happens to them after birth. We cannot assume that the progress of these babies will be the same as those born preterm in a high-income country, as the latter group will have received different care, both before and after birth. If we can document the problems that these preterm babies face in a low-income setting, we can consider why they happen and what treatments can be realistically tested in this setting. It is also helpful to establish baseline data so that changes over time can be recorded.

The aim of this study was to document four specific outcomes up to the age of two years, on which there were few data previously from rural sub-Saharan Africa: how many babies survived, visits to a health center and admissions to the hospital, growth, and developmental delay.

What Did the Researchers Do and Find?

The researchers examined a group of babies that had been born to mothers who had taken part in a randomized controlled trial of an antibiotic to prevent preterm birth. The trial had previously shown that the antibiotic (azithromycin) had no effect on how many babies were born preterm or on other measures of the infants' wellbeing, and so the researchers followed up babies from both arms of the trial to look at longer term outcomes. From the original group of 2,297 women who took part in the trial, they compared 247 infants born preterm against 593 term infants randomly chosen as controls, assessed at 12, 18, or 24 months. The majority of the preterm babies who survived past a month of age (all but ten) were born after 32 weeks of gestation. Compared to the babies born at term, the infants born preterm were nearly twice as likely to die subsequently in the next two years, were more likely to be underweight (a third were moderately underweight), and to have higher rates of developmental delay. The commonest causes of death were gastroenteritis, respiratory problems, and malaria. Visits to a health center and admissions to hospital were similar in both groups.

What Do these Findings Mean?

This study documents longer term outcomes of babies born preterm in sub-Saharan Africa in detail for the first time. The strengths of the study include prenatal ultrasound dating and correct adjustment of follow-up age (which takes into account being born before term). Because the researchers defined morbidity using routine health center attendances and self-report of illnesses by parents, this outcome does not seem to have been as useful as the others in differentiating between the preterm and term babies. Better means of measuring morbidity are needed in this setting.

In the developed world, there is considerable investment being made to improve care during pregnancy and in the neonatal period. This investment in care may help by predicting which mothers are more likely to give birth early and preventing preterm birth through drug or other treatments. It is to be hoped that some of the benefit will be transferable to low-income countries. A baby born at 26 weeks' gestation and admitted to a neonatal unit in the United Kingdom has a 67% chance of survival; preterm babies born in sub-Saharan Africa face a starkly contrasting future.

Additional Information

Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001121.

UNICEF presents useful statistics on mother and child outcomes

The World Health Organization has attempted to analyse preterm birth rates worldwide, including mapping the regional distribution and has also produced practical guides on strategies such as Kangaroo Mother Care, which can be used for the care of preterm infants in low resource settings

Healthy Newborn Network has good information on initiatives taking place to improve neonatal outcomes in low income settings

The March of Dimes, a nonprofit organization for pregnancy and baby health, provides information on research being conducted into preterm birth

Tommy's is a nonprofit organization that funds research and provides information on the risks and causes of premature birth

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)