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1.  The Effect of Changing Patterns of Obstetric Care in Scotland (1980–2004) on Rates of Preterm Birth and Its Neonatal Consequences: Perinatal Database Study 
PLoS Medicine  2009;6(9):e1000153.
Jane Norman and colleagues analyzed linked perinatal surveillance data in Scotland and find that between 1980 and 2004 increases in spontaneous and medically induced preterm births contributed equally to the rising rate of preterm births.
Background
Rates of preterm birth are rising worldwide. Studies from the United States and Latin America suggest that much of this rise relates to increased rates of medically indicated preterm birth. In contrast, European and Australian data suggest that increases in spontaneous preterm labour also play a role. We aimed, in a population-based database of 5 million people, to determine the temporal trends and obstetric antecedents of singleton preterm birth and its associated neonatal mortality and morbidity for the period 1980–2004.
Methods and Findings
There were 1.49 million births in Scotland over the study period, of which 5.8% were preterm. We found a percentage increase in crude rates of both spontaneous preterm birth per 1,000 singleton births (10.7%, p<0.01) and medically indicated preterm births (41.2%, p<0.01), which persisted when adjusted for maternal age at delivery. The greater proportion of spontaneous preterm births meant that the absolute increase in rates of preterm birth in each category were similar. Of specific maternal complications, essential and pregnancy-induced hypertension, pre-eclampsia, and placenta praevia played a decreasing role in preterm birth over the study period, with gestational and pre-existing diabetes playing an increasing role. There was a decline in stillbirth, neonatal, and extended perinatal mortality associated with preterm birth at all gestation over the study period but an increase in the rate of prolonged hospital stay for the neonate. Neonatal mortality improved in all subgroups, regardless of obstetric antecedent of preterm birth or gestational age. In the 28 wk and greater gestational groups we found a reduction in stillbirths and extended perinatal mortality for medically induced but not spontaneous preterm births (in the absence of maternal complications) although at the expense of a longer stay in neonatal intensive care. This improvement in stillbirth and neonatal mortality supports the decision making behind the 34% increase in elective/induced preterm birth in these women. Although improvements in neonatal outcomes overall are welcome, preterm birth still accounts for over 66% of singleton stillbirths, 65% of singleton neonatal deaths, and 67% of infants whose stay in the neonatal unit is “prolonged,” suggesting this condition remains a significant contributor to perinatal mortality and morbidity.
Conclusions
In our population, increases in spontaneous and medically induced preterm births have made equal contributions to the rising rate of preterm birth. Despite improvements in related perinatal mortality, preterm birth remains a major obstetric and neonatal problem, and its frequency is increasing.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Most pregnancies last about 40 weeks but increasing numbers of babies are being born preterm, before they reach 37 weeks of gestation (gestation is the period during which a baby develops in its mother). Nowadays in the US, for example, more than half a million babies arrive earlier than expected every year (1 in 8 babies). Although improvements in the care of newborn babies (neonatal care) mean that preterm babies are more likely to survive than in the past, preterm birth remains the single biggest cause of infant death in many developed countries, and many preterm babies who survive have long-term health problems and disabilities, particularly those born before 32 weeks of gestation. Preterm births can be spontaneous or medically induced. At present, it impossible to predict which mothers will spontaneously deliver early and there is no effective way to prevent these preterm births; medically induced early labor is undertaken when either the unborn baby or mother would be at risk if the pregnancy continued to full term.
Why Was This Study Done?
Preterm birth rates need to be reduced, but before this can be done it is important to know how the causes of preterm birth, the numbers of preterm stillbirths, and the numbers of preterm babies who die at birth (neonatal deaths) or soon after (perinatal deaths) are changing with time. If, for example, the rise in preterm births is mainly due to an increase in medically induced labor and if this change in practice has reduced neonatal deaths, it would be unwise to try to reduce the preterm birth rate by discouraging medically induced preterm births. So far, data from the US and Latin America suggest that the increase in preterm births in these countries is solely due to increased rates of medically induced preterm births. However, in Europe and Australia, the rate of spontaneous preterm births also seems to be increasing. In this study, the researchers examine the trends over time and causes of preterm birth and of neonatal death and illness in Scotland over a 25-year period.
What Did the Researchers Do and Find?
By searching a Scottish database of linked maternity records and infant health and death records, the researchers identified 1.49 million singleton births that occurred between 1980 and 2004 of which nearly 90,000 were preterm births. Over the study period, the rates of spontaneous and of medically induced preterm births per 1,000 births increased by 10.7% and 41.2%, respectively, but because there were more spontaneous preterm births than medically induced preterm births, the absolute increase in the rates of each type of birth was similar. Several maternal complications including preeclampsia (a condition that causes high blood pressure) and placenta previa (covering of the opening of the cervix by the placenta) played a decreasing role in preterm births over the study period, whereas gestational and preexisting diabetes played an increasing role. Finally, there was a decline in stillbirths and in neonatal and perinatal deaths among preterm babies, although more babies remained in the hospital longer than 7 days after birth. More specifically, after 28 weeks of gestation, stillbirths and perinatal deaths decreased among medically induced preterm births but not among spontaneous preterm births.
What Do These Findings Mean?
These findings indicate that in Scotland between 1980 and 2004, increases in spontaneous and medically induced preterm births contributed equally to the rising rate of preterm births. Importantly, they also show that the increase in induced preterm births helped to reduce stillbirths and neonatal and perinatal deaths, a finding that supports the criteria that clinicians currently use to decide whether to induce an early birth. Nevertheless, preterm births still account for two-thirds of all stillbirths, neonatal deaths, and extended neonatal stays in hospital and thus cause considerable suffering and greatly increase the workload in neonatal units. The rates of such births consequently need to be reduced and, for Scotland at least, ways will have to be found to reduce the rates of both spontaneous and induced preterm births to achieve this goal while continuing to identify those sick babies who need to be delivered early to give them the best chance of survival.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000153
Tommys is a nonprofit organization that funds research and provides information on the causes and prevention of miscarriage, premature birth, and stillbirth
The March of Dimes, a nonprofit organization for pregnancy and baby health, provides information on preterm birth (in English and Spanish)
The Nemours Foundation, another nonprofit organization for child health, also provides information on premature babies (in English and Spanish)
The US Centers for Disease Control and Prevention provides information on maternal and infant health (in English and Spanish)
The US National Women's Health Information Center has detailed information about pregnancy, including a section on pregnancy complications
MedlinePlus provides links to other information on premature babies and to information on pregnancy (in English and Spanish)
doi:10.1371/journal.pmed.1000153
PMCID: PMC2740823  PMID: 19771156
2.  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
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.  Uterine Rupture by Intended Mode of Delivery in the UK: A National Case-Control Study 
PLoS Medicine  2012;9(3):e1001184.
A case-control study using UK data estimates the risk of uterine rupture in subsequent deliveries amongst women who have had a previous caesarean section.
Background
Recent reports of the risk of morbidity due to uterine rupture are thought to have contributed in some countries to a decrease in the number of women attempting a vaginal birth after caesarean section. The aims of this study were to estimate the incidence of true uterine rupture in the UK and to investigate and quantify the associated risk factors and outcomes, on the basis of intended mode of delivery.
Methods and Findings
A UK national case-control study was undertaken between April 2009 and April 2010. The participants comprised 159 women with uterine rupture and 448 control women with a previous caesarean delivery. The estimated incidence of uterine rupture was 0.2 per 1,000 maternities overall; 2.1 and 0.3 per 1,000 maternities in women with a previous caesarean delivery planning vaginal or elective caesarean delivery, respectively. Amongst women with a previous caesarean delivery, odds of rupture were also increased in women who had ≥ two previous caesarean deliveries (adjusted odds ratio [aOR] 3.02, 95% CI 1.16–7.85) and <12 months since their last caesarean delivery (aOR 3.12, 95% CI 1.62–6.02). A higher risk of rupture with labour induction and oxytocin use was apparent (aOR 3.92, 95% CI 1.00–15.33). Two women with uterine rupture died (case fatality 1.3%, 95% CI 0.2–4.5%). There were 18 perinatal deaths associated with uterine rupture among 145 infants (perinatal mortality 124 per 1,000 total births, 95% CI 75–189).
Conclusions
Although uterine rupture is associated with significant mortality and morbidity, even amongst women with a previous caesarean section planning a vaginal delivery, it is a rare occurrence. For women with a previous caesarean section, risk of uterine rupture increases with number of previous caesarean deliveries, a short interval since the last caesarean section, and labour induction and/or augmentation. These factors should be considered when counselling and managing the labour of women with a previous caesarean section.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Uterine rupture is a serious complication of pregnancy in which the wall of the uterus (womb) tears during pregnancy or early labor. Signs and symptoms of uterine rupture include fetal heart rate abnormalities, abdominal pain, and vaginal bleeding. If uterine rupture happens during labor, the woman must have an immediate caesarean section (surgical delivery of her baby) to save both her life and that of her baby. The woman's womb and nearby organs can be damaged at rupture or removed during surgery and she may need a blood transfusion because of severe bleeding. Moreover, her baby may develop respiratory distress syndrome and other life-threatening complications. In high income countries, uterine rupture most commonly occurs in women who have delivered a previous pregnancy by caesarean section. In a caesarean section, the baby is delivered through a cut made through the abdominal wall and the uterine wall. The stretching that occurs during pregnancy or the strong contractions of labor can tear the scar left by this cut, resulting in uterine rupture.
Why Was This Study Done?
Women who have had a caesarean delivery are generally encouraged to try to deliver subsequent babies vaginally. However, recent reports of an increased risk of complications (morbidity) and death (mortality) due to uterine rupture are thought to reduce women's willingness to attempt vaginal birth after caesarean (VBAC) in some countries. In the UK, for example, where one in four babies is delivered by caesarean section, a previous caesarean delivery is one of commonest reasons for a repeat section. Obstetricians (doctors who care for women during child birth) need to know as much as possible about the incidence of uterine rupture and about the risk factors for it so that they can advise women who have had a previous caesarean section about their delivery options. In this national case-control study (a study that compares the characteristics of people with and without a specific condition), the researchers estimate the incidence of uterine rupture in the UK by intended mode of delivery and investigate and quantify the risk factors for and outcomes of uterine rupture.
What Did the Researchers Do and Find?
The researchers used the UK Obstetric Surveillance System (UKOSS) to identify all the women in the UK who had a uterine rupture over a 13-month period (159 women, 139 of whom had had a previous caesarean delivery). Controls for the study were women who had not had a uterine rupture but who had previously delivered by caesarean section. Overall, the incidence of uterine rupture was 0.2 per 1,000 maternities. In women with a previous caesarean delivery, 2.1 and 0.3 per 1,000 maternities ended in uterine rupture in women planning vaginal delivery and caesarean delivery, respectively. Amongst women who had had a previous caesarean delivery, the risk of uterine rupture was greater among those who had had two or more previous caesarean deliveries or a caesarean delivery less than 12 months previously, or whose labor was induced. Two women died following uterine rupture (a case fatality of 1.3%) and 18 babies died around the time of birth (a perinatal mortality rate of 124 per 1,000 live births; the UK perinatal mortality rate is 7.5 per 1,000 live births). 15 of the women who had a uterine rupture had their womb removed, 10 had other organs damaged, and nearly half had other complications; 19 of the surviving babies had health problems.
What Do These Findings Mean?
These findings indicate that, in the UK, although uterine rupture is associated with significant mortality and morbidity, it is a rare occurrence even among women who have had a previous caesarean delivery and are planning a vaginal delivery. They also indicate that, for women who have previously had a caesarean section, the risk of rupture increases with the number of previous caesarean deliveries, with a short interval since the last caesarean section, and with labor induction. Although the researchers may not have identified all the women who had a uterine rupture during the study period or may have identified only the worst cases, these findings provide valuable information about the factors that obstetricians need to consider when advising women who have previously had a caesarean section and when managing their labor.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001184.
This study is linked to a PLoS Medicine Research Article by Caroline Crowther and a PLoS Medicine Perspective by Catherine Spong
Wikipedia has a page on uterine rupture (note: Wikipedia is a free online encyclopedia that anyone can edit; available in several languages)
The American Congress of Obstetricians and Gynecologists has information sheets for patients on caesarean sections and on vaginal birth after caesarean delivery
The Royal College of Obstetricians and Gynaecologists in the UK has information for women on birth after previous caesarean
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
A personal story of uterine rupture during an attempted VBAC is available
The UK Obstetric Surveillance System studies rare disorders of pregnancy in the UK
doi:10.1371/journal.pmed.1001184
PMCID: PMC3302846  PMID: 22427745
5.  Timing of birth for women with a twin pregnancy at term: a randomised controlled trial 
Background
There is a well recognized risk of complications for both women and infants of a twin pregnancy, increasing beyond 37 weeks gestation. Preterm birth prior to 37 weeks gestation is a recognized complication of a twin pregnancy, however, up to 50% of twins will be born after this time.
The aims of this randomised trial are to assess whether elective birth at 37 weeks gestation compared with standard care in women with a twin pregnancy affects the risk of perinatal death, and serious infant complications.
Methods/Design
Design: Multicentred randomised trial.
Inclusion Criteria: women with a twin pregnancy at 366 weeks or more without contraindication to continuation of pregnancy.
Trial Entry & Randomisation: Following written informed consent, eligible women will be randomised from 36+6 weeks gestation. The randomisation schedule uses balanced variable blocks, with stratification for centre of birth and planned mode of birth. Women will be randomised to either elective birth or standard care.
Treatment Schedules: Women allocated to the elective birth group will be planned for elective birth from 37 weeks gestation. Where the plan is for vaginal birth, this will involve induction of labour. Where the plan is for caesarean birth, this will involve elective caesarean section. For women allocated to standard care, birth will be planned for 38 weeks gestation or later. Where the plan is for vaginal birth, this will involve either awaiting the spontaneous onset of labour, or induction of labour if required. Where the plan is for caesarean birth, this will involve elective caesarean section (after 38 and as close to 39 weeks as possible).
Primary Study Outcome: A composite of perinatal mortality or serious neonatal morbidity.
Sample Size: 460 women with a twin pregnancy to show a reduction in the composite outcome from 16.3% to 6.7% with adjustment for the clustering of twin infants within mothers (p = 0.05, 80% power).
Discussion
This is a protocol for a randomised trial, the findings of which will contribute information about the optimal time of birth for women with an uncomplicated multiple pregnancy at and beyond 37 weeks gestation.
Clinical Trial Registration
Current Controlled Trials ISRCTN15761056
doi:10.1186/1471-2393-10-68
PMCID: PMC2978123  PMID: 20973989
6.  Induction of labour for improving birth outcomes for women at or beyond term 
Background
As a pregnancy continues beyond term the risks of babies dying inside the womb or in the immediate newborn period increase. Whether a policy of labour induction at a predetermined gestational age can reduce this increased risk is the subject of this review.
Objectives
To evaluate the benefits and harms of a policy of labour induction at term or post-term compared with awaiting spontaneous labour or later induction of labour.
Search methods
We searched the Cochrane Pregnancy and Childbirth Group’s Trials Register (31 March 2012).
Selection criteria
Randomised controlled trials conducted in women at or beyond term. The eligible trials were those comparing a policy of labour induction with a policy of awaiting spontaneous onset of labour. Cluster-randomised trials and cross-over trials are not included. Quasi-random allocation schemes such as alternation, case record numbers or open random-number lists were not eligible.
Data collection and analysis
Two review authors independently assessed trials for inclusion. Two review authors independently assessed trial quality and extracted data. Data were checked for accuracy. Outcomes are analysed in two main categories: gestational age and cervix status.
Main results
We included 22 trials reporting on 9383 women. The trials were generally at moderate risk of bias.
Compared with a policy of expectant management, a policy of labour induction was associated with fewer (all-cause) perinatal deaths: risk ratio (RR) 0.31, 95% confidence interval (CI) 0.12 to 0.88; 17 trials, 7407 women. There was one perinatal death in the labour induction policy group compared with 13 perinatal deaths in the expectant management group. The number needed to treat to benefit (NNTB) with induction of labour in order to prevent one perinatal death was 410 (95% CI 322 to 1492).
For the primary outcome of perinatal death and most other outcomes, no differences between timing of induction subgroups were seen; the majority of trials adopted a policy of induction at 41 completed weeks (287 days) or more.
Fewer babies in the labour induction group had meconium aspiration syndrome (RR 0.50, 95% CI 0.34 to 0.73; eight trials, 2371 infants) compared with a policy of expectant management. There was no statistically significant difference between the rates of neonatal intensive care unit (NICU) admission for induction compared with expectant management (RR 0.90, 95% CI 0.78 to 1.04; 10 trials, 6161 infants). For women in the policy of induction arms of trials, there were significantly fewer caesarean sections compared with expectant management in 21 trials of 8749 women (RR 0.89, 95% CI 0.81 to 0.97).
Authors’ conclusions
A policy of labour induction compared with expectant management is associated with fewer perinatal deaths and fewer caesarean sections. Some infant morbidities such as meconium aspiration syndrome were also reduced with a policy of post-term labour induction although no significant differences in the rate of NICU admission were seen.
However, the absolute risk of perinatal death is small. Women should be appropriately counselled in order to make an informed choice between scheduled induction for a post-term pregnancy or monitoring without induction (or delayed induction).
doi:10.1002/14651858.CD004945.pub3
PMCID: PMC4065650  PMID: 22696345
* Pregnancy, Prolonged; *Watchful Waiting; Cesarean Section [utilization]; Infant Mortality; Infant, Newborn; Labor, Induced [*adverse effects]; Randomized Controlled Trials as Topic; Risk; Female; Humans; Pregnancy
7.  Theory of obstetrics: An epidemiologic framework for justifying medically indicated early delivery 
Background
Modern obstetrics is faced with a serious paradox. Obstetric practice is becoming increasingly interventionist based on empirical evidence but without a theoretical basis for such intervention. Whereas obstetric models of perinatal death show that mortality declines exponentially with increasing gestational duration, temporal increases in medically indicated labour induction and cesarean delivery have resulted in rising rates of preterm birth and declining rates of postterm birth. Other problems include a disconnection between patterns of gestational age-specific growth restriction (constant across gestation) and gestational age-specific perinatal mortality (exponential decline with increasing duration) and the paradox of intersecting perinatal mortality curves (low birth weight infants of smokers have lower neonatal mortality rates than the low birth weight infants of non-smokers).
Discussion
The fetuses at risk approach is a causal model that brings coherence to the various perinatal phenomena. Under this formulation, pregnancy complications (such as preeclampsia), labour induction/cesarean delivery, birth, revealed small-for-gestational age and death show coherent patterns of incidence. The fetuses at risk formulation also provides a theoretical justification for medically indicated early delivery, the cornerstone of modern obstetrics. It permits a conceptualization of the number needed to treat (e.g., as low as 2 for emergency cesarean delivery in preventing perinatal death given placental abruption and fetal bradycardia) and a calculation of the marginal number needed to treat (i.e., the number of additional medically indicated labour inductions/cesarean deliveries required to prevent one perinatal death). Data from the United States showed that between 1995–96 and 1999–2000 rates of labour induction/cesarean delivery increased by 45.1 per 1,000 and perinatal mortality decreased by 0.31 per 1,000 total births among singleton pregnancies at > = 28 weeks of gestation. The marginal number needed to treat was 145 (45.1/0.31), showing that 145 excess labour inductions/cesarean deliveries in 1999–2000 (relative to 1995–96) were responsible for preventing 1 perinatal death among singleton pregnancies at > = 28 weeks gestation.
Summary
The fetuses at risk approach, with its focus on incidence measures, provides a coherent view of perinatal phenomena. It also provides a theoretical justification for medically indicated early delivery and reconciles the contemporary divide between obstetric theory and obstetric practice.
doi:10.1186/1471-2393-7-4
PMCID: PMC1851971  PMID: 17391525
8.  Screening and subsequent management for gestational diabetes for improving maternal and infant health 
Background
Gestational diabetes mellitus (GDM) is a form of diabetes that occurs in pregnancy. Although GDM usually resolves following birth, it is associated with significant morbidities for mother and baby both perinatally and in the long term. There is strong evidence to support treatment for GDM. However, there is little consensus on whether or not screening for GDM will improve maternal and infant health and if so, the most appropriate protocol to follow.
Objectives
To assess the effects of different methods of screening for gestational diabetes mellitus and maternal and infant outcomes.
Search methods
We searched the Cochrane Pregnancy and Childbirth Group’s Trials Register (April 2010).
Selection criteria
Randomised and quasi-randomised trials evaluating the effects of different methods of screening for gestational diabetes mellitus.
Data collection and analysis
Two review authors independently conducted data extraction and quality assessment. We resolved disagreements through discussion or through a third author.
Main results
We included four trials involving 3972 women were included in the review. One quasi-randomised trial compared risk factor screening with universal or routine screening by 50 g oral glucose challenge testing. Women in the universal screening group were more likely to be diagnosed with GDM (one trial, 3152 women, risk ratio (RR) 0.44 95% confidence interval (CI) 0.26 to 0.75). Infants of mothers in the risk factor screening group were born marginally earlier than infants of mothers in the routine screening group (one trial, 3152 women, mean difference −0.15 weeks, 95% CI −0.27 to −0.53).
The remaining three trials evaluated different methods of administering a 50 g glucose load. Two small trials compared glucose monomer with glucose polymer testing, with one of these trials including a candy bar group. One trial compared a glucose solution with food. No differences in diagnosis of GDM were found between each comparison. Overall, women drinking the glucose monomer experienced fewer side effects from testing than women drinking the glucose polymer (two trials, 151 women, RR 2.80, 95% CI 1.10 to 7.13). However, we observed high heterogeneity between the trials for this result (I2 = 61%).
Authors’ conclusions
There was insufficient evidence to determine if screening for gestational diabetes, or what types of screening, can improve maternal and infant health outcomes.
doi:10.1002/14651858.CD007222.pub2
PMCID: PMC4161118  PMID: 20614455
Diabetes, Gestational [*diagnosis; therapy]; Glucose Tolerance Test [adverse effects; *methods]; Infant Welfare; Infant, Newborn; Mass Screening [*methods]; Maternal Welfare; Pregnancy Outcome; Randomized Controlled Trials as Topic; Female; Humans; Pregnancy
9.  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
10.  Mild gestational diabetes in pregnancy and the adipoinsular axis in babies born to mothers in the ACHOIS randomised controlled trial 
BMC Pediatrics  2007;7:18.
Background
Mild gestational diabetes is a common complication of pregnancy, affecting up to 9% of pregnant women. Treatment of mild GDM is known to reduce adverse perinatal outcomes such as macrosomia and associated birth injuries, such as shoulder dystocia, bone fractures and nerve palsies. This study aimed to compare the plasma glucose concentrations and serum insulin, leptin and adiponectin in cord blood of babies of women (a) without gestational diabetes mellitus (GDM), (b) with mild GDM under routine care, or (c) mild GDM with treatment.
Methods
95 women with mild GDM on oral glucose tolerance testing (OGTT) at one tertiary level maternity hospital who had been recruited to the ACHOIS trial at one of the collaborating hospitals and randomised to either Treatment (n = 46) or Routine Care (n = 49) and Control women with a normal OGTT (n = 133) were included in the study. Women with mild GDM (treatment or routine care group) and OGTT normal women received routine pregnancy care. In addition, women with treated mild GDM received dietary advice, blood glucose monitoring and insulin if necessary.
The primary outcome measures were cord blood concentrations of glucose, insulin, adiponectin and leptin.
Results
Cord plasma glucose was higher in women receiving routine care compared with control, but was normalized by treatment for mild GDM (p = 0.01). Cord serum insulin and insulin to glucose ratio were similar between the three groups. Leptin concentration in cord serum was lower in GDM treated women compared with routine care (p = 0.02) and not different to control (p = 0.11). Adiponectin was lower in both mild GDM groups compared with control (Treatment p = 0.02 and Routine Care p = 0.07), while the adiponectin to leptin ratio was lower for women receiving routine care compared with treatment (p = 0.08) and control (p = 0.05).
Conclusion
Treatment of women with mild GDM using diet, blood glucose monitoring and insulin if necessary, influences the altered fetal adipoinsular axis characteristic of mild GDM in pregnancy.
doi:10.1186/1471-2431-7-18
PMCID: PMC1865537  PMID: 17430602
11.  Impact of Scotland's Smoke-Free Legislation on Pregnancy Complications: Retrospective Cohort Study 
PLoS Medicine  2012;9(3):e1001175.
An analysis of pregnancy data for the whole of Scotland demonstrates a reduction in small-for-gestational-age births and preterm delivery since the introduction of legislation banning smoking in enclosed public spaces.
Background
Both active smoking and environmental tobacco smoke exposure are associated with pregnancy complications. In March 2006, Scotland implemented legislation prohibiting smoking in all wholly or partially enclosed public spaces. The aim of this study was to determine the impact of this legislation on preterm delivery and small for gestational age.
Methods and Findings
We conducted logistic regression analyses using national administrative pregnancy data covering the whole of Scotland. Of the two breakpoints tested, 1 January 2006 produced a better fit than the date when the legislation came into force (26 March 2006), suggesting an anticipatory effect. Among the 716,941 eligible women who conceived between August 1995 and February 2009 and subsequently delivered a live-born, singleton infant between 24 and 44 wk gestation, the prevalence of current smoking fell from 25.4% before legislation to 18.8% after legislation (p<0.001). Three months prior to the legislation, there were significant decreases in small for gestational age (−4.52%, 95% CI −8.28, −0.60, p = 0.024), overall preterm delivery (−11.72%, 95% CI −15.87, −7.35, p<0.001), and spontaneous preterm labour (−11.35%, 95% CI −17.20, −5.09, p = 0.001). In sub-group analyses, significant reductions were observed among both current and never smokers.
Conclusions
Reductions were observed in the risk of preterm delivery and small for gestational age 3 mo prior to the introduction of legislation, although the former reversed partially following the legislation. There is growing evidence of the potential for tobacco control legislation to have a positive impact on health.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
The risks of smoking during pregnancy, both on mother and fetus, are well established: women who smoke during pregnancy are more likely to have a miscarriage. Smoking can cause placental problems, such as placental abruption, which can result in heavy bleeding during pregnancy, which is dangerous for both mother and baby. Other dangers of smoking during pregnancy include the baby being born too early (premature birth), the baby being below average weight (small for gestational age), birth defects, and infant death. Because of the serious damage to health caused by smoking, in 2005, under the auspices of the World Health Organization, countries adopted the Framework Convention on Tobacco Control to protect present and future generations from the devastating health, social, environmental, and economic consequences of tobacco consumption and exposure to tobacco smoke. Article 8 of the treaty obliges member states who have ratified the treaty—168 so far—to protect all people from exposure to tobacco smoke in indoor workplaces, public transport, and indoor public places. As a result, many countries around the world have banned smoking in public places.
Why Was This Study Done?
Scotland was the first country in the United Kingdom to ban smoking in public places, which was implemented as part of the Smoking, Health and Social Care (Scotland) Bill on 26 March 2006. Previous studies have shown that the introduction of the legislation led directly to a reduction in smoking and also a reduction in environmental tobacco smoke exposure in adults and children. Furthermore, the Scottish legislation has been accompanied by significant reductions in both cardiovascular and respiratory disease. Because of the known risks of smoking during pregnancy, the researchers wanted to investigate whether the change in policy on smoking in public places had positive benefits on the health of mothers and babies. They evaluated this by measuring the rates of preterm delivery and small for gestational age before and after the Scottish legislation went into effect.
What Did the Researchers Do and Find?
The researchers collected information on preterm delivery and small for gestational age in all single babies born live at 22–44 weeks gestation between 1 January 1996 and 31 December 2009 by using the Scottish Morbidity Record (SMR2), which collects relevant information on all women discharged from Scottish maternity hospitals, including maternal and infant characteristics and pregnancy complications. The researchers categorized preterm delivery into mild, moderate, and extreme depending on how much before 37 weeks the baby was born. They defined small for gestational age as the smallest 10% (below the 10th centile) for sex-specific birth weight at delivery, and very small for gestational age as the smallest 3% (below the 3rd centile), for all deliveries in Scotland over the study period. As some people may have stopped smoking in anticipation of the smoking ban, in their statistical model, the researchers included two possible breakpoints for the effect of the legislation—the actual date of implementation and 1 January 2006.
The researchers found that of the 716,968 pregnancies (the number eligible for inclusion in the study), 99.9% of women had their smoking status recorded, and among these 23.9% were current smokers, 57.6% never smokers, and 8.7% former smokers. However, following implementation of the legislation the researchers noted that there was a significant reduction in current smokers to 18.8%. In their statistical model, the researchers found that following 1 January 2006, there was a significant drop in overall preterm deliveries, which remained after adjustment for potential confounding factors. Likewise, there was a significant decrease in the number of infants born small, and very small, for gestational age after 1 January 2006. Furthermore, the researchers found that these significant reductions occurred in both mothers who smoked and those who had never smoked.
What Do These Findings Mean?
These findings suggest that the introduction of national, comprehensive smoke-free legislation in Scotland was associated with significant reductions in preterm delivery and babies being born small for gestational age. These findings are plausible and add to the growing evidence of the wide-ranging health benefits of smoke-free legislation, and support the adoption of such legislation in other countries that have yet to implement smoking bans.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001175.
More information is available on the World Health Organization's Framework Convention for Tobacco Control
More information on the Smoking, Health and Social Care (Scotland) Bill is available
The US Centers for Disease Control and Prevention has more information about the risks of smoking in pregnancy, as does the UK National Health Service's smokefree web page
NHS Health Scotland has a website that summarises all the studies to date evaluating the Scottish smoke-free legislation
doi:10.1371/journal.pmed.1001175
PMCID: PMC3295815  PMID: 22412353
12.  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
13.  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
14.  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
15.  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
16.  The IDEAL study: investigation of dietary advice and lifestyle for women with borderline gestational diabetes: a randomised controlled trial - study protocol 
Background
The Australian Carbohydrate Intolerance Study in Pregnant Women (ACHOIS) showed that treatment of pregnant women with mild gestational diabetes mellitus is beneficial for both women and their infants. It is still uncertain whether there are benefits of similar treatment for women with borderline gestational diabetes.
This trial aims to assess whether dietary and lifestyle advice and treatment given to pregnant women who screen for borderline gestational diabetes reduces neonatal complications and maternal morbidities.
Methods/design
Design: Multicentre, randomised controlled trial.
Inclusion criteria: Women between 240 and 346 weeks gestation with a singleton pregnancy, a positive oral glucose challenge test (venous plasma glucose ≥7.8 mmol/L) and a normal oral 75 gram glucose tolerance test (fasting venous plasma glucose <5.5 mmol/L and a 2 hour glucose <7.8 mmol/L) with written, informed consent.
Trial entry and randomisation: Women with an abnormal oral glucose tolerance test (fasting venous plasma glucose ≥5.5 mmol/L or 2 hour glucose ≥7.8 mmol/L) will not be eligible and will be offered treatment for gestational diabetes, consistent with recommendations based on results of the ACHOIS trial. Eligible women will be randomised into either the ‘Routine Care Group’ or the ‘Intervention Group’.
Study groups: Women in the ‘Routine Care Group’ will receive routine obstetric care reflecting current clinical practice in Australian hospitals. Women in the ‘Intervention Group’ will receive obstetric care, which will include dietary and lifestyle advice, monitoring of blood glucose and further medical treatment for hyperglycaemia as appropriate.
Primary study outcome: Incidence of large for gestational age infants.
Sample size: A sample size of 682 women will be sufficient to show a 50% reduction in the risk of large for gestational age infants (alpha 0.05 two-tailed, 80% power, 4% loss to follow up) from 14% to 7% with dietary and lifestyle advice and treatment.
Discussion
A conclusive trial outcome will provide reliable evidence of relevance for the care of women with borderline glucose intolerance in pregnancy and their infants.
Trial registration
Australian New Zealand Clinical Trials Registry - ACTRN12607000174482
doi:10.1186/1471-2393-12-106
PMCID: PMC3506505  PMID: 23046499
Borderline gestational diabetes; Gestational diabetes mellitus; Randomised controlled trial; Diet; Lifestyle; Large for gestational age
17.  Caesarean section versus vaginal delivery for preterm birth in singletons 
Background
Planned caesarean delivery for women thought be in preterm labour may be protective for baby, but could also be quite traumatic for both mother and baby. The optimal mode of delivery of preterm babies for both cephalic and breech presentation remains, therefore, controversial.
Objectives
To assess the effects of a policy of planned immediate caesarean delivery versus planned vaginal birth for women in preterm labour.
Search methods
We searched the Cochrane Pregnancy and Childbirth Group’s Trials Register (24 April 2012).
Selection criteria
Randomised trials comparing a policy of planned immediate caesarean delivery versus planned vaginal delivery for preterm birth.
Data collection and analysis
Two review authors independently assessed trials for inclusion. Two review authors independently extracted data and assessed risk of bias. Data were checked for accuracy.
Main results
We included six studies (involving 122 women) but only four studies (involving only 116 women) contributed data to the analyses.
Infant
There were very little data of relevance to the three main (primary) outcomes considered in this review: There was no significant difference between planned immediate caesarean section and planned vaginal delivery with respect to birth injury to infant (risk ratio (RR) 0.56, 95%, confidence interval (CI) 0.05 to 5.62; one trial, 38 women) or birth asphyxia (RR 1.63, 95% CI 0.84 to 3.14; onetrial, 12 women). The only cases of birth trauma were a laceration of the buttock in a baby who was delivered by caesarean section and mild bruising in another allocated to the group delivered vaginally.
The difference between the two groups with regard to perinatal deaths was not significant (0.29, 95% CI 0.07 to 1.14; three trials, 89 women) and there were no data specifically relating to neonatal admission to special care and/or intensive care unit.
There was also no difference between the caesarean or vaginal delivery groups in terms of markers of possible birth asphyxia (RR 1.63, 95% CI 0.84 to 3.14; one trial, 12 women) or Apgar score less than seven at five minutes (RR 0.83, 95% CI 0.43 to 1.60; four trials, 115 women) and no difference in attempts at breastfeeding (RR 1.40, 95% 0.11 to 17.45; one trial, 12 women). There was also no difference in neonatal fitting/seizures (RR 0.22, 95% CI 0.01 to 4.32; three trials, 77 women), hypoxic ischaemic encephalopathy (RR 4.00, 95% CI 0.20 to 82.01;one trial, 12 women) or respiratory distress syndrome (RR 0.55, 95% CI 0.27 to 1.10; three trials, 103 women). There were no data reported in the trials specifically relating to meconium aspiration. There was also no significant difference between the two groups for abnormal follow-up in childhood (RR 0.65, 95% CI 0.19 to 2.22; one trial, 38 women) or delivery less than seven days after entry (RR 0.95, 95% CI 0.73 to 1.24; two trials, 51 women).
Mother
There were no data reported on maternal admissions to intensive care. However, there were seven cases of major maternal postpartum complications in the group allocated to planned immediate caesarean section and none in the group randomised to vaginal delivery (RR 7.21, 95% CI 1.37 to 38.08; four trials, 116 women).
There were no data reported in the trials specifically relating to maternal satisfaction (postnatal). There was no significant difference between the two groups with regard to postpartum haemorrhage. A number of non-prespecified secondary outcomes were also considered in the analyses. There was a significant advantage for women in the vaginal delivery group with respect to maternal puerperal pyrexia (RR 2.98, 95% CI 1.18 to 7.53; three trials, 89 women) and other maternal infection (RR 2.63, 95% CI 1.02 to 6.78; three trials, 103 women), but no significant differences in wound infection (RR 1.16, 95% CI 0.18 to 7.70; three trials, 103 women), maternal stay more than 10 days (RR 1.27, 95% CI 0.35 to 4.65; three trials, 78 women) or the need for blood transfusion (results not estimable).
Authors’ conclusions
There is not enough evidence to evaluate the use of a policy of planned immediate caesarean delivery for preterm babies. Further studies are needed in this area, but recruitment is proving difficult.
doi:10.1002/14651858.CD000078.pub2
PMCID: PMC4164504  PMID: 22696314
*Delivery, Obstetric; *Obstetric Labor, Premature; Birth Injuries [etiology]; Cesarean Section [adverse effects]; Infant, Newborn; Infant, Premature; Infant, Small for Gestational Age; Perinatal Mortality; Randomized Controlled Trials as Topic; Surgical Procedures, Elective; Female; Humans; Pregnancy
18.  Post-neonatal Mortality, Morbidity, and Developmental Outcome after Ultrasound-Dated Preterm Birth in Rural Malawi: A Community-Based Cohort Study 
PLoS Medicine  2011;8(11):e1001121.
Using data collected as a follow-up to a randomized trial, Melissa Gladstone and colleagues show that during the first two years of life, infants born preterm in southern Malawi are disadvantaged in terms of mortality, growth, and development.
Background
Preterm birth is considered to be associated with an estimated 27% of neonatal deaths, the majority in resource-poor countries where rates of prematurity are high. There is no information on medium term outcomes after accurately determined preterm birth in such settings.
Methods and Findings
This community-based stratified cohort study conducted between May–December 2006 in Southern Malawi followed up 840 post-neonatal infants born to mothers who had received antenatal antibiotic prophylaxis/placebo in an attempt to reduce rates of preterm birth (APPLe trial ISRCTN84023116). Gestational age at delivery was based on ultrasound measurement of fetal bi-parietal diameter in early-mid pregnancy. 247 infants born before 37 wk gestation and 593 term infants were assessed at 12, 18, or 24 months. We assessed survival (death), morbidity (reported by carer, admissions, out-patient attendance), growth (weight and height), and development (Ten Question Questionnaire [TQQ] and Malawi Developmental Assessment Tool [MDAT]). Preterm infants were at significantly greater risk of death (hazard ratio 1.79, 95% CI 1.09–2.95). Surviving preterm infants were more likely to be underweight (weight-for-age z score; p<0.001) or wasted (weight-for-length z score; p<0.01) with no effect of gestational age at delivery. Preterm infants more often screened positively for disability on the Ten Question Questionnaire (p = 0.002). They also had higher rates of developmental delay on the MDAT at 18 months (p = 0.009), with gestational age at delivery (p = 0.01) increasing this likelihood. Morbidity—visits to a health centre (93%) and admissions to hospital (22%)—was similar for both groups.
Conclusions
During the first 2 years of life, infants who are born preterm in resource poor countries, continue to be at a disadvantage in terms of mortality, growth, and development. In addition to interventions in the immediate neonatal period, a refocus on early childhood is needed to improve outcomes for infants born preterm in low-income settings.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Being born at term in Africa is not necessarily straightforward. In Malawi, 33 of every 1,000 infants born die in the first 28 days after birth; the lifetime risk for a mother dying during or shortly after pregnancy is one in 36. The comparable figures for the United Kingdom are three infants dying per 1,000 births and a lifetime risk of maternal death of one in 4,700. But for a baby, being born preterm is even more risky and the gap between low- and high-income countries widens still further. According to a World Health Organization report in 2010, a baby born at 32 weeks of gestation (weighing around 2,000 g) in Africa has little chance of survival, while the chances of survival for a baby born at 32 weeks in North America or Europe are similar to one born at term. There are very few data on the longer term outcomes of babies born preterm in Africa and there are multiple challenges involved in gathering such information. As prenatal ultrasound is not routinely available, gestational age is often uncertain. There may be little routine follow-up of preterm babies as is commonplace in high-income countries. Data are needed from recent years that take into account both improvements in perinatal care and adverse factors such as a rising number of infants becoming HIV positive around the time of birth.
Why Was This Study Done?
We could improve outcomes for babies born preterm in sub-Saharan Africa if we understood more about what happens to them after birth. We cannot assume that the progress of these babies will be the same as those born preterm in a high-income country, as the latter group will have received different care, both before and after birth. If we can document the problems that these preterm babies face in a low-income setting, we can consider why they happen and what treatments can be realistically tested in this setting. It is also helpful to establish baseline data so that changes over time can be recorded.
The aim of this study was to document four specific outcomes up to the age of two years, on which there were few data previously from rural sub-Saharan Africa: how many babies survived, visits to a health center and admissions to the hospital, growth, and developmental delay.
What Did the Researchers Do and Find?
The researchers examined a group of babies that had been born to mothers who had taken part in a randomized controlled trial of an antibiotic to prevent preterm birth. The trial had previously shown that the antibiotic (azithromycin) had no effect on how many babies were born preterm or on other measures of the infants' wellbeing, and so the researchers followed up babies from both arms of the trial to look at longer term outcomes. From the original group of 2,297 women who took part in the trial, they compared 247 infants born preterm against 593 term infants randomly chosen as controls, assessed at 12, 18, or 24 months. The majority of the preterm babies who survived past a month of age (all but ten) were born after 32 weeks of gestation. Compared to the babies born at term, the infants born preterm were nearly twice as likely to die subsequently in the next two years, were more likely to be underweight (a third were moderately underweight), and to have higher rates of developmental delay. The commonest causes of death were gastroenteritis, respiratory problems, and malaria. Visits to a health center and admissions to hospital were similar in both groups.
What Do these Findings Mean?
This study documents longer term outcomes of babies born preterm in sub-Saharan Africa in detail for the first time. The strengths of the study include prenatal ultrasound dating and correct adjustment of follow-up age (which takes into account being born before term). Because the researchers defined morbidity using routine health center attendances and self-report of illnesses by parents, this outcome does not seem to have been as useful as the others in differentiating between the preterm and term babies. Better means of measuring morbidity are needed in this setting.
In the developed world, there is considerable investment being made to improve care during pregnancy and in the neonatal period. This investment in care may help by predicting which mothers are more likely to give birth early and preventing preterm birth through drug or other treatments. It is to be hoped that some of the benefit will be transferable to low-income countries. A baby born at 26 weeks' gestation and admitted to a neonatal unit in the United Kingdom has a 67% chance of survival; preterm babies born in sub-Saharan Africa face a starkly contrasting future.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001121.
UNICEF presents useful statistics on mother and child outcomes
The World Health Organization has attempted to analyse preterm birth rates worldwide, including mapping the regional distribution and has also produced practical guides on strategies such as Kangaroo Mother Care, which can be used for the care of preterm infants in low resource settings
Healthy Newborn Network has good information on initiatives taking place to improve neonatal outcomes in low income settings
The March of Dimes, a nonprofit organization for pregnancy and baby health, provides information on research being conducted into preterm birth
Tommy's is a nonprofit organization that funds research and provides information on the risks and causes of premature birth
doi:10.1371/journal.pmed.1001121
PMCID: PMC3210771  PMID: 22087079
19.  A Multicenter, Randomized Trial of Treatment for Mild Gestational Diabetes 
The New England journal of medicine  2009;361(14):1339-1348.
BACKGROUND
It is uncertain whether treatment of mild gestational diabetes mellitus improves pregnancy outcomes.
METHODS
Women who were in the 24th to 31st week of gestation and who met the criteria for mild gestational diabetes mellitus (i.e., an abnormal result on an oral glucose-tolerance test but a fasting glucose level below 95 mg per deciliter [5.3 mmol per liter]) were randomly assigned to usual prenatal care (control group) or dietary intervention, self-monitoring of blood glucose, and insulin therapy, if necessary (treatment group). The primary outcome was a composite of stillbirth or perinatal death and neonatal complications, including hyperbilirubinemia, hypoglycemia, hyperinsulinemia, and birth trauma.
RESULTS
A total of 958 women were randomly assigned to a study group — 485 to the treatment group and 473 to the control group. We observed no significant difference between groups in the frequency of the composite outcome (32.4% and 37.0% in the treatment and control groups, respectively; P = 0.14). There were no perinatal deaths. However, there were significant reductions with treatment as compared with usual care in several prespecified secondary outcomes, including mean birth weight (3302 vs. 3408 g), neonatal fat mass (427 vs. 464 g), the frequency of large-for-gestational-age infants (7.1% vs. 14.5%), birth weight greater than 4000 g (5.9% vs. 14.3%), shoulder dystocia (1.5% vs. 4.0%), and cesarean delivery (26.9% vs. 33.8%). Treatment of gestational diabetes mellitus, as compared with usual care, was also associated with reduced rates of preeclampsia and gestational hypertension (combined rates for the two conditions, 8.6% vs. 13.6%; P = 0.01).
CONCLUSIONS
Although treatment of mild gestational diabetes mellitus did not significantly reduce the frequency of a composite outcome that included stillbirth or perinatal death and several neonatal complications, it did reduce the risks of fetal overgrowth, shoulder dystocia, cesarean delivery, and hypertensive disorders.
doi:10.1056/NEJMoa0902430
PMCID: PMC2804874  PMID: 19797280
20.  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
21.  In Vitro Fertilization and Multiple Pregnancies 
Executive Summary
Objective
The objective of this health technology policy assessment was to determine the clinical effectiveness and cost-effectiveness of IVF for infertility treatment, as well as the role of IVF in reducing the rate of multiple pregnancies.
Clinical Need: Target Population and Condition
Typically defined as a failure to conceive after a year of regular unprotected intercourse, infertility affects 8% to 16% of reproductive age couples. The condition can be caused by disruptions at various steps of the reproductive process. Major causes of infertility include abnormalities of sperm, tubal obstruction, endometriosis, ovulatory disorder, and idiopathic infertility. Depending on the cause and patient characteristics, management options range from pharmacologic treatment to more advanced techniques referred to as assisted reproductive technologies (ART). ART include IVF and IVF-related procedures such as intra-cytoplasmic sperm injection (ICSI) and, according to some definitions, intra-uterine insemination (IUI), also known as artificial insemination. Almost invariably, an initial step in ART is controlled ovarian stimulation (COS), which leads to a significantly higher rate of multiple pregnancies after ART compared with that following natural conception. Multiple pregnancies are associated with a broad range of negative consequences for both mother and fetuses. Maternal complications include increased risk of pregnancy-induced hypertension, pre-eclampsia, polyhydramnios, gestational diabetes, fetal malpresentation requiring Caesarean section, postpartum haemorrhage, and postpartum depression. Babies from multiple pregnancies are at a significantly higher risk of early death, prematurity, and low birth weight, as well as mental and physical disabilities related to prematurity. Increased maternal and fetal morbidity leads to higher perinatal and neonatal costs of multiple pregnancies, as well as subsequent lifelong costs due to disabilities and an increased need for medical and social support.
The Technology Being Reviewed
IVF was first developed as a method to overcome bilateral Fallopian tube obstruction. The procedure includes several steps: (1) the woman’s egg is retrieved from the ovaries; (2) exposed to sperm outside the body and fertilized; (3) the embryo(s) is cultured for 3 to 5 days; and (4) is transferred back to the uterus. IFV is considered to be one of the most effective treatments for infertility today. According to data from the Canadian Assisted Reproductive Technology Registry, the average live birth rate after IVF in Canada is around 30%, but there is considerable variation in the age of the mother and primary cause of infertility.
An important advantage of IVF is that it allows for the control of the number of embryos transferred. An elective single embryo transfer in IVF cycles adopted in many European countries was shown to significantly reduce the risk of multiple pregnancies while maintaining acceptable birth rates. However, when number of embryos transferred is not limited, the rate of IVF-associated multiple pregnancies is similar to that of other treatments involving ovarian stimulation. The practice of multiple embryo transfer in IVF is often the result of pressures to increase success rates due to the high costs of the procedure. The average rate of multiple pregnancies resulting from IVF in Canada is currently around 30%.
An alternative to IVF is IUI. In spite of reported lower success rates of IUI (pregnancy rates per cycle range from 8.7% to 17.1%) it is generally attempted before IVF due to its lower invasiveness and cost.
Two major drawbacks of IUI are that it cannot be used in cases of bilateral tubal obstruction and it does not allow much control over the risk of multiple pregnancies compared with IVF. The rate of multiple pregnancies after IUI with COS is estimated to be about 21% to 29%.
Ontario Health Insurance Plan Coverage
Currently, the Ontario Health Insurance Plan covers the cost of IVF for women with bilaterally blocked Fallopian tubes only, in which case it is funded for 3 cycles, excluding the cost of drugs. The cost of IUI is covered except for preparation of the sperm and drugs used for COS.
Diffusion of Technology
According to Canadian Assisted Reproductive Technology Registry data, in 2004 there were 25 infertility clinics across Canada offering IVF and 7,619 IVF cycles performed. In Ontario, there are 13 infertility clinics with about 4,300 IVF cycles performed annually.
Literature Review
Royal Commission Report on Reproductive Technologies
The 1993 release of the Royal Commission report on reproductive technologies, Proceed With Care, resulted in the withdrawal of most IVF funding in Ontario, where prior to 1994 IVF was fully funded. Recommendations of the Commission to withdraw IVF funding were largely based on findings of the systematic review of randomized controlled trials (RCTs) published before 1990. The review showed IVF effectiveness only in cases of bilateral tubal obstruction. As for nontubal causes of infertility, there was not enough evidence to establish whether IVF was effective or not.
Since the field of reproductive technology is constantly evolving, there have been several changes since the publication of the Royal Commission report. These changes include: increased success rates of IVF; introduction of ICSI in the early 1990’s as a treatment for male factor infertility; and improved embryo implantation rates allowing for the transfer of a single embryo to avoid multiple pregnancies after IVF.
Studies After the Royal Commission Report: Review Strategy
Three separate literature reviews were conducted in the following areas: clinical effectiveness of IVF, cost-effectiveness of IVF, and outcomes of single embryo transfer (SET) in IVF cycles.
Clinical effectiveness of IVF: RCTs or meta-analyses of RCTs that compared live birth rates after IVF versus alternative treatments, where the cause of infertility was clearly stated or it was possible to stratify the outcome by the cause of infertility.
Cost effectiveness of IVF: All relevant economic studies comparing IVF to alternative methods of treatment were reviewed
Outcomes of IVF with SET: RCTs or meta-analyses of RCTs that compared live birth rates and multiple birth rates associated with transfer of single versus double embryos.
OVID MEDLINE, MEDLINE In-Process & Other Non-Indexed Citations, EMBASE, Cochrane Library, the International Agency for Health Technology Assessment database, and websites of other health technology assessment agencies were searched using specific subject headings and keywords to identify relevant studies.
Summary of Findings
Comparative Clinical Effectiveness of IVF
Overall, there is a lack of well composed RCTs in this area and considerable diversity in both definition and measurement of outcomes exists between trials. Many studies used fertility or pregnancy rates instead of live birth rates. Moreover, the denominator for rate calculation varied from study to study (e.g. rates were calculated per cycle started, per cycle completed, per couple, etc...).
Nevertheless, few studies of sufficient quality were identified and categorized by the cause of infertility and existing alternatives to IVF. The following are the key findings:
A 2005 meta-analysis demonstrated that, in patients with idiopathic infertility, IVF was clearly superior to expectant management, but there were no statistically significant differences in live birth rates between IVF and IUI, nor between IVF and gamete-intra-Fallopian transfer.
A subset of data from a 2000 study showed no significant differences in pregnancy rates between IVF and IUI for moderate male factor infertility.
In patients with moderate male factor infertility, standard IVF was also compared with ICSI in a 2002 meta-analysis. All studies included in the meta-analysis showed superior fertilization rates with ICSI, and the pooled risk ratio for oocyte fertilization was 1.9 (95% Confidence Interval 1.4-2.5) in favour of ICSI. Two other RCTs in this area published after the 2002 meta-analysis had similar results and further confirmed these findings. There were no RCTs comparing IVF with ICSI in patients with severe male factor infertility, mainly because based on the expert opinion, ICSI might only be an effective treatment for severe male factor infertility.
Cost-Effectiveness of IVF
Five economic evaluations of IVF were found, including one comprehensive systematic review of 57 health economic studies. The studies compared cost-effectiveness of IVF with a number of alternatives such as observation, ovarian stimulation, IUI, tubal surgery, varicocelectomy, etc... The cost-effectiveness of IVF was analyzed separately for different types of infertility. Most of the reviewed studies concluded that due to the high cost, IVF has a less favourable cost-effectiveness profile compared with alternative treatment options. Therefore, IVF was not recommended as the first line of treatment in the majority of cases. The only two exceptions were bilateral tubal obstruction and severe male factor infertility, where an immediate offer of IVF/ICSI might the most cost-effective option.
Clinical Outcomes After Single Versus Double Embryo Transfer Strategies of IVF
Since the SET strategy has been more widely adopted in Europe, all RCT outcomes of SET were conducted in European countries. The major study in this area was a large 2005 meta-analysis, followed by two other published RCTs.
All of these studies reached similar conclusions:
Although a single SET cycle results in lower birth rates than a single double embryo transfer (DET) cycle, the cumulative birth rate after 2 cycles of SET (fresh + frozen-thawed embryos) was comparable to the birth rate after a single DET cycle (~40%).
SET was associated with a significant reduction in multiple births compared with DET (0.8% vs. 33.1% respectively in the largest RCT).
Most trials on SET included women younger than 36 years old with a sufficient number of embryos available for transfer that allowed for selection of the top quality embryo(s). A 2006 RCT, however, compared SET and DET strategies in an unselected group of patients without restrictions on the woman’s age or embryo quality. This study demonstrated that SET could be applied to older women.
Estimate of the Target Population
Based on results of the literature review and consultations with experts, four categories of infertile patients who may benefit from increased access to IVF/ICSI were identified:
Patients with severe male factor infertility, where IVF should be offered in conjunction with ICSI;
Infertile women with serious medical contraindications to multiple pregnancy, who should be offered IVF-SET;
Infertile patients who want to avoid the risk of multiple pregnancy and thus opt for IVF-SET; and
Patients who failed treatment with IUI and wish to try IVF.
Since, however, the latter indication does not reflect any new advances in IVF technology that would alter existing policy, it was not considered in this analysis.
Economic Analysis
Economic Review: Cost–Effectiveness of SET Versus DET
Conclusions of published studies on cost-effectiveness of SET versus DET were not consistent. While some studies found that SET strategy is more cost-effective due to avoidance of multiple pregnancies, other studies either did not find any significant differences in cost per birth between SET and DET, or favoured DET as a more cost-effective option.
Ontario-Based Economic Analysis
An Ontario-based economic analysis compared cost per birth using three treatment strategies: IUI, IVF-SET, and IVF-DET. A decision-tree model assumed three cycles for each treatment option. Two separate models were considered; the first included only fresh cycles of IVF, while the second had a combination of fresh and frozen cycles. Even after accounting for cost-savings due to avoidance of multiple pregnancies (only short-term complications), IVF-SET was still associated with a highest cost per birth. The approximate budget impact to cover the first three indications for IVF listed above (severe male factor infertility, women with medical contraindications to multiple pregnancy, and couples who wish to avoid the risk of multiple pregnancy) is estimated at $9.8 to $12.8 million (Cdn). Coverage of only first two indications, namely, ICSI in patients with severe male factor infertility and infertile women with serious medical contraindications to multiple pregnancy, is estimated at $3.8 to $5.5 million Cdn.
Other Considerations
International data shows that both IVF utilization and the average number of embryos transferred in IVF cycles are influenced by IVF funding policy. The success of the SET strategy in European countries is largely due to the fact that IVF treatment is subsidized by governments.
Surveys of patients with infertility demonstrated that a significant proportion (~40%) of patients not only do not mind having multiple babies, but consider twins being an ideal outcome of infertility treatment.
A women’s age may impose some restrictions on the implementation of a SET strategy.
Conclusions and Recommendations
A review of published studies has demonstrated that IVF-SET is an effective treatment for infertility that avoids multiple pregnancies.
However, results of an Ontario-based economic analysis shows that cost savings associated with a reduction in multiple pregnancies after IVF-SET does not justify the cost of universal IVF-SET coverage by the province. Moreover, the province currently funds IUI, which has been shown to be as effective as IVF for certain types of infertility and is significantly less expensive.
In patients with severe male factor infertility, IVF in conjunction with ICSI may be the only effective treatment.
Thus, 2 indications where additional IVF access should be considered include:
IVF/ICSI for patients with severe male factor infertility
IVF-SET in infertile women with serious medical contraindications to multiple pregnancy
PMCID: PMC3379537  PMID: 23074488
22.  Fetal growth restriction and the risk of perinatal mortality–case studies from the multicentre PORTO study 
Background
Intrauterine growth restriction (IUGR) is the single largest contributing factor to perinatal mortality in non-anomalous fetuses. Advances in antenatal and neonatal critical care have resulted in a reduction in neonatal deaths over the past decades, while stillbirth rates have remained unchanged. Antenatal detection rates of fetal growth failure are low, and these pregnancies carry a high risk of perinatal death.
Methods
The Prospective Observational Trial to Optimize Paediatric Health in IUGR (PORTO) Study recruited 1,200 ultrasound-dated singleton IUGR pregnancies, defined as EFW <10th centile, between 24+0 and 36+6 weeks gestation. All recruited fetuses underwent serial sonographic assessment of fetal weight and multi-vessel Doppler studies until birth. Perinatal outcomes were recorded for all pregnancies. Case records of the perinatal deaths from this prospectively recruited IUGR cohort were reviewed, their pregnancy details and outcome were analysed descriptively and compared to the entire cohort.
Results
Of 1,116 non-anomalous singleton infants with EFW <10th centile, 6 resulted in perinatal deaths including 3 stillbirths and 3 early neonatal deaths. Perinatal deaths occurred between 24+6 and 35+0 weeks gestation corresponding to birthweights ranging from 460 to 2260 grams. Perinatal deaths occurred more commonly in pregnancies with severe growth restriction (EFW <3rd centile) and associated abnormal Doppler findings resulting in earlier gestational ages at delivery and lower birthweights. All of the described pregnancies were complicated by either significant maternal comorbidities, e.g. hypertension, systemic lupus erythematosus (SLE) or diabetes, or poor obstetric histories, e.g. prior perinatal death, mid-trimester or recurrent pregnancy loss. Five of the 6 mortalities occurred in women of non-Irish ethnic backgrounds. All perinatal deaths showed abnormalities on placental histopathological evaluation.
Conclusions
The PNMR in this cohort of prenatally identified IUGR cases was 5.4/1,000 and compares favourably to the overall national rate of 4.1/1,000 births, which can be attributed to increased surveillance and timely delivery. Despite antenatal recognition of IUGR and associated maternal risk factors, not all perinatal deaths can be prevented.
doi:10.1186/1471-2393-14-63
PMCID: PMC3923738  PMID: 24517273
Perinatal mortality; Antepartum stillbirth; Neonatal death; Intrauterine growth restriction; PORTO Study
23.  Triple-Antiretroviral Prophylaxis to Prevent Mother-To-Child HIV Transmission through Breastfeeding—The Kisumu Breastfeeding Study, Kenya: A Clinical Trial 
PLoS Medicine  2011;8(3):e1001015.
Timothy Thomas and colleagues report the results of the Kisumu breastfeeding study (Kenya), a single-arm trial that assessed the feasibility and safety of a triple-antiretroviral regimen to suppress maternal HIV load in late pregnancy.
Background
Effective strategies are needed for the prevention of mother-to-child HIV transmission (PMTCT) in resource-limited settings. The Kisumu Breastfeeding Study was a single-arm open label trial conducted between July 2003 and February 2009. The overall aim was to investigate whether a maternal triple-antiretroviral regimen that was designed to maximally suppress viral load in late pregnancy and the first 6 mo of lactation was a safe, well-tolerated, and effective PMTCT intervention.
Methods and Findings
HIV-infected pregnant women took zidovudine, lamivudine, and either nevirapine or nelfinavir from 34–36 weeks' gestation to 6 mo post partum. Infants received single-dose nevirapine at birth. Women were advised to breastfeed exclusively and wean rapidly just before 6 mo. Using Kaplan-Meier methods we estimated HIV-transmission and death rates from delivery to 24 mo. We compared HIV-transmission rates among subgroups defined by maternal risk factors, including baseline CD4 cell count and viral load.
Among 487 live-born, singleton, or first-born infants, cumulative HIV-transmission rates at birth, 6 weeks, and 6, 12, and 24 mo were 2.5%, 4.2%, 5.0%, 5.7%, and 7.0%, respectively. The 24-mo HIV-transmission rates stratified by baseline maternal CD4 cell count <500 and ≥500 cells/mm3 were 8.4% (95% confidence interval [CI] 5.8%–12.0%) and 4.1% (1.8%–8.8%), respectively (p = 0.06); the corresponding rates stratified by baseline maternal viral load <10,000 and ≥10,000 copies/ml were 3.0% (1.1%–7.8%) and 8.7% (6.1%–12.3%), respectively (p = 0.01). None of the 12 maternal and 51 infant deaths (including two second-born infants) were attributed to antiretrovirals. The cumulative HIV-transmission or death rate at 24 mo was 15.7% (95% CI 12.7%–19.4%).
Conclusions
This trial shows that a maternal triple-antiretroviral regimen from late pregnancy through 6 months of breastfeeding for PMTCT is safe and feasible in a resource-limited setting. These findings are consistent with those from other trials using maternal triple-antiretroviral regimens during breastfeeding in comparable settings.
Trial registration
ClinicalTrials.gov NCT00146380
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Every year, about half a million children become infected with human immunodeficiency virus (HIV), which causes acquired immunodeficiency syndrome (AIDS). Nearly all these newly infected children live in resource-limited countries and most acquire HIV from their mother, so-called mother-to-child transmission (MTCT). Without intervention, 25%–50% of babies born to HIV-positive mothers become infected with HIV during pregnancy, delivery, or breastfeeding. This infection rate can be reduced by treating mother and child with antiretroviral (ARV) drugs. A single dose of nevirapine (a “non-nucleoside reverse transcriptase inhibitor” or NNRTI) given to the mother at the start of labor and to her baby soon after birth nearly halves the risk of MTCT. Further reductions in risk can be achieved by giving mother and baby three ARVs—an NNRTI and two nucleoside reverse transcriptase inhibitors (NRTIs such as zidovudine and lamivudine)—during pregnancy and perinatally (around the time of birth).
Why Was This Study Done?
Breastfeeding is crucial for child survival in poor countries but it is also responsible for up to half of MTCT. Consequently, many researchers are investigating how various ARV regimens given to mothers and/or their infants during the first few months of life as well as during pregnancy and perinatally affect MTCT. In this single-arm trial, the researchers assess the feasibility and safety of using a triple-ARV regimen to suppress the maternal HIV load (amount of virus in the blood) from late pregnancy though 6 months of breastfeeding among HIV-positive women in Kisumu, Kenya, and ask whether this approach achieves a lower HIV transmission rate than other ARV regimens that have been tested in resource-limited settings. In a single-arm trial, all the participants are given the same treatment. By contrast, in a “randomized controlled” trial, half the participants chosen at random are given the treatment under investigation and the rest are given a control treatment. A randomized controlled trial provides a better comparison of treatments than a single-arm trial but is more costly.
What Did the Researchers Do and Find?
In the Kisumu Breastfeeding Study (KiBS), HIV-infected pregnant women took a triple-ARV regimen containing zidovudine and lamivudine and either nevirapine or the protease inhibitor nelfinavir from 34–36 weeks of pregnancy to 6 months after delivery. They were advised to breastfeed their babies (who received single-dose nevirapine at birth), and to wean them rapidly just before 6 months. The researchers then used Kaplan-Meier statistical methods to estimate HIV transmission and death rates among 487 live-born infants from delivery to 24 months. The cumulative HIV transmission rate rose from 2.5% at birth to 7.0% at 24 months. The cumulative HIV transmission or death rate at 24 months was 15.7%; no infant deaths were attributed to ARVs. At 24 months, 3.0% of babies born to mothers with a low viral load were HIV positive compared to 8.7% of babies born to mothers with a high viral load, a statistically significant difference. Similarly, at 24 months, 8.4% of babies born to mothers with low baseline CD4 cell counts (CD4 cells are immune system cells that are killed by HIV; CD4 cell counts indicate the level of HIV-inflicted immune system damage) were HIV positive compared to 4.1% of babies born to mothers with high baseline CD4 cell counts, although this difference did not achieve statistical significance.
What Do These Findings Mean?
Although these findings are limited by the single-arm design, they support the idea that giving breastfeeding women a triple-ARV regimen from late pregnancy to 6 months is a safe, feasible way to reduce MTCT in resource-limited settings. The HIV transmission rates in this study are comparable to those recorded in similar trials in other resource-limited settings and are lower than MTCT rates observed previously in Kisumu in a study in which no ARVs were used. Importantly, the KiBS mothers took most of the ARVs they were prescribed and most stopped breastfeeding by 6 months as advised. The intense follow-up employed in KiBS may be partly responsible for this good adherence to the trial protocol and thus this study's findings may not be generalizable to all resource-limited settings. Nevertheless, they suggest that a simple triple-ARV regimen given to HIV-positive pregnant women regardless of their baseline CD4 cell count can reduce MTCT during pregnancy and breastfeeding in resource-limited setting.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001015.
The accompanying PLoS Medicine Research article by Zeh and colleagues describes the emergence of resistance to ARVs in KiBS
Information on HIV and AIDS is available from the US National Institute of Allergy and Infectious Diseases
HIV InSite has comprehensive information on all aspects of HIV/AIDS
Information is available from Avert, an international AIDS charity, on many aspects of HIV/AIDS, including information on children, HIV, and AIDS and on preventing mother-to-child transmission of HIV (in English and Spanish)
UNICEF also has information about children and HIV and AIDS (in several languages)
The World Health organization has information on mother-to-child transmission of HIV http://www.who.int/hiv/topics/mtct/en/index.html (in several languages)
doi:10.1371/journal.pmed.1001015
PMCID: PMC3066129  PMID: 21468300
24.  The INeS study: prevention of multiple pregnancies: a randomised controlled trial comparing IUI COH versus IVF e SET versus MNC IVF in couples with unexplained or mild male subfertility 
BMC Women's Health  2009;9:35.
Background
Multiple pregnancies are high risk pregnancies with higher chances of maternal and neonatal mortality and morbidity. In the past decades the number of multiple pregnancies has increased. This trend is partly due to the fact that women start family planning at an increased age, but also due to the increased use of ART.
Couples with unexplained or mild male subfertility generally receive intrauterine insemination IUI with controlled hormonal stimulation (IUI COH). The cumulative pregnancy rate is 40%, with a 10% multiple pregnancy rate.
This study aims to reveal whether alternative treatments such as IVF elective Single Embryo Transfer (IVF e SET) or Modified Natural Cycle IVF (MNC IVF) can reduce the number of multiple pregnancy rates, but uphold similar pregnancy rates as IUI COH in couples with mild male or unexplained subfertility. Secondly, the aim is to perform a cost effective analyses and assess treatment preference of these couples.
Methods/Design
We plan a multicentre randomised controlled clinical trial in the Netherlands comparing six cycles of intra-uterine insemination with controlled ovarian hyperstimulation or six cycles of Modified Natural Cycle (MNC) IVF or three cycles with IVF-elective Single Embryo Transfer (eSET) plus cryo-cycles within a time frame of 12 months.
Couples with unexplained subfertility or mild male subfertility and a poor prognosis for treatment independent pregnancy will be included. Women with anovulatory cycles, severe endometriosis, double sided tubal pathology or serious endocrine illness will be excluded.
Our primary outcome is the birth of a healthy singleton. Secondary outcomes are multiple pregnancy, treatment costs, and patient experiences in each treatment arm. The analysis will be performed according tot the intention to treat principle. We will test for non-inferiority of the three arms with respect to live birth. As we accept a 12.5% loss in pregnancy rate in one of the two IVF arms to prevent multiple pregnancies, we need 200 couples per arm (600 couples in total).
Discussion
Determining the safest and most cost-effective treatment will ensure optimal chances of pregnancy for subfertile couples with substantially diminished perinatal and maternal complications. Should patients find the most cost-effective treatment acceptable or even preferable, this could imply the need for a world wide shift in the primary treatment.
Trial registration
Current Controlled Trials ISRCTN 52843371
doi:10.1186/1472-6874-9-35
PMCID: PMC2804565  PMID: 20021654
25.  Pre-pregnancy body mass index and the risk of adverse outcome in type 1 diabetic pregnancies: a population-based cohort study 
BMJ Open  2012;2(1):e000601.
Objective
To assess the risk of perinatal complications in overweight and obese women with and without type 1 diabetes (T1DM).
Design
Prospective population-based cohort study.
Setting
This study was based on data from the Swedish Medical Birth Registry from 1998 to 2007.
Participants
3457 T1DM and 764 498 non-diabetic pregnancies were included. T1DM was identified based on ICD code O24.0. Mothers were categorised according to pre-pregnancy body mass index (BMI: weight in kilograms per height in square metres) as normal weight (BMI 18.5–24.9), overweight (BMI 25–29.9) or obese (BMI ≥30). Only women with singleton pregnancies and with data on BMI were included.
Primary/secondary outcomes
The primary outcome was large for gestational age (LGA: birth weight >90th percentile) infants. Secondary outcomes were major malformations, pre-eclampsia (PE), preterm delivery, perinatal mortality, delivery by Caesarean section and neonatal overweight. Logistic regression analysis was performed with normal weight non-diabetic women as the reference category and also within the diabetic cohort with normal weight type 1 diabetic women as the reference. The ORs were adjusted for ethnicity, maternal age, height, parity, smoking and chronic hypertension.
Results
35% of women with T1DM were overweight and 18% were obese, as compared with 26% and 11%, respectively, in non-diabetic pregnancies. The incidences of adverse outcome increased with greater BMI category. As compared with non-diabetic normal weight women, the adjusted OR for obese T1DM for LGA was 13.26 (95% CI 11.27 to 15.59), major malformations 4.11 (95% CI 2.99 to 5.65) and PE 14.19 (95% CI 11.50 to 17.50). T1DM was a significant effect modifier of the association between BMI and LGA, major malformations and PE (p<0.001).
Conclusion
High pre-pregnancy BMI is an important risk factor for adverse outcome in type 1 diabetic pregnancies. The combined effect of both T1DM and overweight or obesity constitutes the greatest risk. It seems prudent to strive towards normal pre-pregnancy BMI in women with T1DM.
Article summary
Article focus
To assess the risk of obstetric and perinatal complications in overweight and obese women with and without type 1 diabetes (T1DM).
Key messages
High pre-pregnancy body mass index (BMI) is an important risk factor for adverse outcome in type 1 diabetic pregnancies.
The combined effect of both T1DM and overweight or obesity constitutes the greatest risk.
T1DM is a significant effect modifier of the association between BMI and large for gestational age, major malformations and pre-eclampsia (p<0.001).
Strengths and limitations of this study
The present study is to our knowledge, the first to present risk estimates of several obstetric and perinatal complications in women with T1DM, stratified by BMI category and compared with a non-diabetic reference population. The population-based study design, including a very large cohort of T1DM pregnancies, offers a unique possibility to provide solid data on risks associated with high BMI, including comparatively rare outcomes such as perinatal mortality. A potential limitation is that the study design did not allow assessment of the impact of maternal glycaemic control on the association between exposure and outcome.
doi:10.1136/bmjopen-2011-000601
PMCID: PMC3282288  PMID: 22334581

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