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In a large, systematic study of genetic diagnosis in stillborn infants, microarray analysis provided a higher likelihood of obtaining an interpretable result and revealed pathogenic variants in more stillborn infants than did karyotype analysis. Stillbirth, which is defined as fetal death at or after 20 weeks of gestation, occurs in 1 of every 160 births in the United States. 1 Despite extensive evaluation, 25 to 60% of stillbirths remain unexplained. 2 Karyotypic abnormalities are detected in 6 to 13% of stillbirths with a successful karyotype analysis. 3 , 4 Some stillbirths may have chromosomal imbalances below the resolution of conventional cytogenetic analysis, which is typically 5 to 10 Mb. Single-nucleotide polymorphism (SNP) oligonucleotide microarray analysis detects almost all genomic imbalances recognized by karyotyping, as well as smaller deletions and duplications in the kilobase range, termed copy-number variants. Microarray . . .

Stillbirth is strongly related to impaired fetal growth. However, the relationship between fetal growth and stillbirth is difficult to determine because of uncertainty in the timing of death and confounding characteristics affecting normal fetal growth. We conducted a population-based case-control study of all stillbirths and a representative sample of live births in 59 hospitals in five geographic areas in the US. Fetal growth abnormalities were categorized as small for gestational age (SGA) (<10th percentile) or large for gestational age (LGA) (>90th percentile) at death (stillbirth) or delivery (live birth) using population, ultrasound, and individualized norms. Gestational age at death was determined using an algorithm that considered the time-of-death interval, postmortem examination, and reliability of the gestational age estimate. Data were weighted to account for the sampling design and differential participation rates in various subgroups. Among 527 singleton stillbirths and 1,821 singleton live births studied, stillbirth was associated with SGA based on population, ultrasound, and individualized norms (odds ratio [OR] [95% CI]: 3.0 [2.2 to 4.0]; 4.7 [3.7 to 5.9]; 4.6 [3.6 to 5.9], respectively). LGA was also associated with increased risk of stillbirth using ultrasound and individualized norms (OR [95% CI]: 3.5 [2.4 to 5.0]; 2.3 [1.7 to 3.1], respectively), but not population norms (OR [95% CI]: 0.6 [0.4 to 1.0]). The associations were stronger with more severe SGA and LGA (<5th and >95th percentile). Analyses adjusted for stillbirth risk factors, subset analyses excluding potential confounders, and analyses in preterm and term pregnancies showed similar patterns of association. In this study 70% of cases and 63% of controls agreed to participate. Analysis weights accounted for differences between consenting and non-consenting women. Some of the characteristics used for individualized fetal growth estimates were missing and were replaced with reference values. However, a sensitivity analysis using individualized norms based on the subset of stillbirths and live births with non-missing variables showed similar findings. Stillbirth is associated with both growth restriction and excessive fetal growth. These findings suggest that, contrary to current practices and recommendations, stillbirth prevention strategies should focus on both severe SGA and severe LGA pregnancies. Please see later in the article for the Editors' Summary.

Worldwide, stillbirth is one of the leading causes of death. Altered fetal growth and placental abnormalities are the strongest and most prevalent known risk factors for stillbirth. The aim of this study was to identify patterns of association between placental abnormalities, fetal growth, and stillbirth. Population-based case-control study of all stillbirths and a representative sample of live births in 59 hospitals in 5 geographic areas in the U.S. Fetal growth abnormalities were categorized as small (<10th percentile) and large (>90th percentile) for gestational age at death (stillbirth) or delivery (live birth) using a published algorithm. Placental examination by perinatal pathologists was performed using a standardized protocol. Data were weighted to account for the sampling design. Among 319 singleton stillbirths and 1119 singleton live births at ≥24 weeks at death or delivery respectively, 25 placental findings were investigated. Fifteen findings were significantly associated with stillbirth. Ten of the 15 were also associated with fetal growth abnormalities (single umbilical artery; velamentous insertion; terminal villous immaturity; retroplacental hematoma; parenchymal infarction; intraparenchymal thrombus; avascular villi; placental edema; placental weight; ratio birth weight/placental weight) while 5 of the 15 associated with stillbirth were not associated with fetal growth abnormalities (acute chorioamnionitis of placental membranes; acute chorioamionitis of chorionic plate; chorionic plate vascular degenerative changes; perivillous, intervillous fibrin, fibrinoid deposition; fetal vascular thrombi in the chorionic plate). Five patterns were observed: placental findings associated with (1) stillbirth but not fetal growth abnormalities; (2) fetal growth abnormalities in stillbirths only; (3) fetal growth abnormalities in live births only; (4) fetal growth abnormalities in stillbirths and live births in a similar manner; (5) a different pattern of fetal growth abnormalities in stillbirths and live births. The patterns of association between placental abnormalities, fetal growth, and stillbirth provide insights into the mechanism of impaired placental function and stillbirth. They also suggest implications for clinical care, especially for placental findings amenable to prenatal diagnosis using ultrasound that may be associated with term stillbirths.

In a large study comparing different strategies for screening for Down's syndrome, first-trimester combined screening (measurement of nuchal translucency, pregnancy-associated plasma protein A [PAPP-A], and the free beta subunit of human chorionic gonadotropin [fβhCG]) at 11 weeks was better than second-trimester quadruple screening (measurement of alpha-fetoprotein, hCG, unconjugated estriol, and inhibin A). Strategies combining first-trimester and second-trimester screening provide high detection rates at acceptable false positive rates. These findings will help guide the choice of screening strategies for Down's syndrome. In a large study comparing different strategies for screening for Down's syndrome, first-trimester combined screening at 11 weeks was better than second-trimester quadruple screening. Strategies combining first-trimester and second-trimester screening provide high detection rates at acceptable false positive rates. First-trimester screening for Down's syndrome that includes the use of ultrasonography to assess nuchal translucency has become widespread since its introduction by Nicolaides and colleagues in the early 1990s. 1 – 4 The largest U.S. study of first-trimester screening to date, involving 8514 pregnancies, reported a 79 percent detection rate at a 5 percent false positive rate. 5 Second-trimester screening remains the most common approach to assessing the risk of Down's syndrome in the United States. 6 When inhibin A is included in second-trimester quadruple screening, the estimated detection rate for Down's syndrome is 81 percent with a 5 percent false positive rate. 7 However, . . .

Child birth via Cesarean section accounts for approximately 32% of all births each year in the United States. A variety of risk factors and complications can lead caregivers and patients to plan for a Cesarean delivery in advance before onset of labor. However, a non-trivial subset of Cesarean sections (∼25%) are unplanned and occur after an initial trial of labor is attempted. Unfortunately, patients who deliver via unplanned Cesarean sections have increased maternal morbidity and mortality rates and higher rates of neonatal intensive care admissions. In an effort to develop models aimed at improving health outcomes in labor and delivery, this work seeks to explore the use of national vital statistics data to quantify the likelihood of an unplanned Cesarean section based on 22 maternal characteristics. Machine learning techniques are used to ascertain influential features, train and evaluate models, and assess accuracy against available test data. Based on cross-validation results from a large training cohort ( n = 6,530,467 births), the gradient-boosted tree algorithm was identified as the best performer and was evaluated on a large test cohort ( n = 10,613,877 births) for two prediction scenarios. Area under the receiver operating characteristic curves of 0.77 or higher and recall scores of 0.78 or higher were obtained and the resulting models are well calibrated. Combined with feature importance analysis to explain why certain maternal characteristics lead to a specific prediction in individual patients, the developed analysis pipeline provides additional quantitative information to aid in the decision process on whether to plan for a Cesarean section in advance, a substantially safer option among women at a high risk of unplanned Cesarean delivery during labor.

Background Preeclampsia is characterized by decreased trophoblastic angiogenesis leading to abnormal invasion of spiral arteries, shallow implantation and resulting in compromised placentation with poor uteroplacental perfusion. Vitamin D plays an important role in pregnancy influencing implantation, angiogenesis and placental development. The objective of this study was to determine whether there is an association between serum vitamin D levels, and anti-angiogenic factors at the time of delivery and the occurrence of preeclampsia. Methods This nested case control study analyzed frozen serum samples at the time of delivery and related clinical data from women with singleton liveborn pregnancies who had participated in studies of the NICHD Stillbirth Collaborative Research Network. Women with a recorded finding of preeclampsia and who had received magnesium sulfate treatment prior to delivery were considered index cases ( N  = 56). Women without a finding of preeclampsia were controls ( N  = 341). Results Women with preeclampsia had 14.5% lower serum vitamin D levels than women in the control group (16.5 ng/ml vs. 19 ng/ml, p  = 0.014) with 64.5% higher sFlt-1 levels (11,600 pg/ml vs. 7050 pg/ml, p  < 0.001) and greater than 2 times higher endoglin levels (18.6 ng/ml vs. 8.7 ng/ml, < 0.001). After controlling for gestational age at delivery and maternal BMI, vitamin D levels were 0.88 times lower ( P  = 0.051), while endoglin levels were 2.5 times higher and sFlt-1 levels were 2.1 times higher than in control pregnancies ( P  < 0.001). Conclusions Women with preeclampsia at time of delivery have higher maternal antiangiogenetic factors and may have lower maternal serum vitamin D levels. These findings may lead to a better understanding of the underlying etiology of preeclampsia as well as possible modifiable treatment options which could include assuring adequate levels of maternal serum vitamin D prior to pregnancy.

Delivery of a small for gestational age (SGA) infant has been associated with increased maternal risk of ischemic heart disease (IHD). It is uncertain whether giving birth to SGA infant is a specific determinant of later IHD, independent of other risk factors, or a marker of general poor health. The purpose of this study was to investigate the association between delivery of a SGA infant and maternal risk for IHD in relation to traditional IHD risk factors. Risk of maternal IHD was evaluated in a population based cross-sectional study of 6,608 women with a prior live term birth who participated in the National Health and Nutrition Examination Survey (1999-2006), a probability sample of the U.S. population. Sequence of events was determined from age at last live birth and at diagnosis of IHD. Delivery of a SGA infant is strongly associated with greater maternal risk for IHD (age adjusted OR; 95% CI: 1.8; 1.2, 2.9; p = 0.012). The association was independent of the family history of IHD, stroke, hypertension and diabetes (family history-adjusted OR; 95% CI: 1.9; 1.2, 3.0; p = 0.011) as well as other risk factors for IHD (risk factor-adjusted OR; 95% CI: 1.7; 1.1, 2.7; p = 0.025). Delivery of a SGA infant was associated with earlier onset of IHD and preceded it by a median of 30 (interquartile range: 20, 36) years. Giving birth to a SGA infant is strongly and independently associated with IHD and a potential risk factor that precedes IHD by decades. A pregnancy that produces a SGA infant may induce long-term cardiovascular changes that increase risk for IHD.

Low plasma folate concentrations in pregnancy are associated with preterm birth. Here we show an association between preconceptional folate supplementation and the risk of spontaneous preterm birth. In a cohort of 34,480 low-risk singleton pregnancies enrolled in a study of aneuploidy risk, preconceptional folate supplementation was prospectively recorded in the first trimester of pregnancy. Duration of pregnancy was estimated based on first trimester ultrasound examination. Natural length of pregnancy was defined as gestational age at delivery in pregnancies with no medical or obstetrical complications that may have constituted an indication for delivery. Spontaneous preterm birth was defined as duration of pregnancy between 20 and 37 wk without those complications. The association between preconceptional folate supplementation and the risk of spontaneous preterm birth was evaluated using survival analysis. Comparing to no supplementation, preconceptional folate supplementation for 1 y or longer was associated with a 70% decrease in the risk of spontaneous preterm delivery between 20 and 28 wk (41 [0.27%] versus 4 [0.04%] spontaneous preterm births, respectively; HR 0.22, 95% confidence interval [CI] 0.08-0.61, p = 0.004) and a 50% decrease in the risk of spontaneous preterm delivery between 28 and 32 wk (58 [0.38%] versus 12 [0.18%] preterm birth, respectively; HR 0.45, 95% CI 0.24-0.83, p = 0.010). Adjustment for maternal characteristics age, race, body mass index, education, marital status, smoking, parity, and history of prior preterm birth did not have a material effect on the association between folate supplementation for 1 y or longer and spontaneous preterm birth between 20 and 28, and 28 to 32 wk (adjusted HR 0.31, 95% CI 0.11-0.90, p = 0.031 and 0.53, 0.28-0.99, p = 0.046, respectively). Preconceptional folate supplementation was not significantly associated with the risk of spontaneous preterm birth beyond 32 wk. The association between shorter duration (<1 y) of preconceptional folate supplementation and the risk of spontaneous preterm birth was not significant after adjustment for maternal characteristics. However, the risk of spontaneous preterm birth decreased with the duration of preconceptional folate supplementation (test for trend of survivor functions, p = 0.01) and was the lowest in women who used folate supplementation for 1 y or longer. There was also no significant association with other complications of pregnancy studied after adjustment for maternal characteristics. Preconceptional folate supplementation is associated with a 50%-70% reduction in the incidence of early spontaneous preterm birth. The risk of early spontaneous preterm birth is inversely proportional to the duration of preconceptional folate supplementation. Preconceptional folate supplementation was specifically related to early spontaneous preterm birth and not associated with other complications of pregnancy.

Previous studies have shown that woman's risk of breast cancer in later life is associated with her infants birth weights. The objective of this study was to determine if this association is independent of breast cancer risk factors, mother's own birth weight and to evaluate association between infants birth weight and hormonal environment during pregnancy. Independent association would have implications for understanding the mechanism, but also for prediction and prevention of breast cancer. Risk of breast cancer in relation to a first infant's birth weight, mother's own birth weight and breast cancer risk factors were evaluated in a prospective cohort of 410 women in the Framingham Study. Serum concentrations of estriol (E3), anti-estrogen alpha-fetoprotein (AFP), and pregnancy-associated plasma protein-A (PAPP-A) were measured in 23,824 pregnant women from a separate prospective cohort, the FASTER trial. During follow-up (median, 14 years) 31 women (7.6%) were diagnosed with breast cancer. Women with large birth weight infants (in the top quintile) had a higher breast cancer risk compared to other women (hazard ratio (HR), 2.5; 95% confidence interval (CI), 1.2-5.2; P = 0.012). The finding was not affected by adjustment for birth weight of the mother and traditional breast cancer risk factors (adjusted HR, 2.5; 95% CI, 1.2-5.6; P = 0.021). An infant's birth weight had a strong positive relationship with the mother's serum E3/AFP ratio and PAPP-A concentration during pregnancy. Adjustment for breast cancer risk factors did not have a material effect on these relationships. Giving birth to an infant with high birth weight was associated with increased breast cancer risk in later life, independently of mother's own birth weight and breast cancer risk factors and was also associated with a hormonal environment during pregnancy favoring future breast cancer development and progression.

Preterm labor, failure to progress, and postpartum hemorrhage are the common causes of maternal and neonatal mortality or morbidity. All result from defects in the complex mechanisms controlling labor, which coordinate changes in the uterine fundus, lower segment, and cervix. We aimed to assess labor-associated gene expression profiles in these functionally distinct areas of the human uterus by using microarrays. Samples of uterine fundus, lower segment, and cervix were obtained from patients at term (mean +/- SD = 39.1 +/- 0.5 wk) prior to the onset of labor (n = 6), or in active phase of labor with spontaneous onset (n = 7). Expression of 12,626 genes was evaluated using microarrays (Human Genome U95A; Affymetrix) and compared between labor and non-labor samples. Genes with the largest labor-associated change and the lowest variability in expression are likely to be fundamental for parturition, so gene expression was ranked accordingly. From 500 genes with the highest rank we identified genes with similar expression profiles using two independent clustering techniques. Sets of genes with a probability of chance grouping by both techniques less than 0.01 represented 71.2%, 81.8%, and 79.8% of the 500 genes in the fundus, lower segment, and cervix, respectively. We identified 14, 14, and 12 those sets of genes in the fundus, lower segment, and cervix, respectively. This enabled networks of co-regulated and co-expressed genes to be discovered. Many genes within the same cluster shared similar functions or had functions pertinent to the process of labor. Our results provide support for many of the established processes of parturition and also describe novel-to-labor genes not previously associated with this process. The elucidation of these mechanisms likely to be fundamental for controlling labor is an important prerequisite to the development of effective treatments for major obstetric problems--including prematurity, with its long-term consequences to the health of mother and offspring.