Hyagriv N. Simhan

Maternal Serum 25-Hydroxyvitamin D Concentrations Are Associated with Small-for-Gestational Age Births in White Women

Maternal vitamin D deficiency has been associated with numerous adverse health outcomes, but its association with fetal growth restriction remains uncertain. We sought to elucidate the association between maternal serum 25-hydroxyvitamin D [25(OH)D] concentrations in early pregnancy and the risk of small-for-gestational age birth (SGA) and explore the association between maternal single nucleotide polymorphisms (SNP) in the vitamin D receptor (VDR) gene and the risk of SGA. We conducted a nested case-control study of nulliparous pregnant women with singleton pregnancies who delivered SGA infants (n = 77 white and n = 34 black) or non-SGA infants (n = 196 white and n = 105 black). Women were followed from <16 wk gestation to delivery. Womens banked sera at <22 wk were newly measured for 25(OH)D and DNA extracted for VDR genotyping. SGA was defined as live-born infants that were <10th percentile of birth weight according to nomograms based on gender and gestational age. After confounder adjustment, there was a U-shaped relation between serum 25(OH)D and risk of SGA among white mothers, with the lowest risk from 60 to 80 nmol/L. Compared with serum 25(OH)D 37.5-75 nmol/L, SGA odds ratios (95% CI) for levels <37.5 and >75 nmol/L were 7.5 (1.8, 31.9) and 2.1 (1.2, 3.8), respectively. There was no relation between 25(OH)D and SGA risk among black mothers. One SNP in the VDR gene among white women and 3 SNP in black women were significantly associated with SGA. Our results suggest that vitamin D has a complex relation with fetal growth that may vary by race.

Severe obesity, gestational weight gain, and adverse birth outcomes

BACKGROUND The 2009 Institute of Medicine (IOM) Committee to Reevaluate Gestational Weight Gain Guidelines concluded that there were too few data to inform weight-gain guidelines by obesity severity. Therefore, the committee recommended a single range, 5-9 kg at term, for all obese women. OBJECTIVE We explored associations between gestational weight gain and small-for-gestational-age (SGA) births, large-for-gestational-age (LGA) births, spontaneous preterm births (sPTBs), and medically indicated preterm births (iPTBs) among obese women who were stratified by severity of obesity. DESIGN We studied a cohort of singleton, live-born infants without congenital anomalies born to obesity class 1 (prepregnancy body mass index [BMI (in kg/m(2))]: 30-34.9; n = 3254), class 2 (BMI: 35-39.9; n = 1451), and class 3 (BMI: > or =40; n = 845) mothers. We defined the adequacy of gestational weight gain as the ratio of observed weight gain to IOM-recommended gestational weight gain. RESULTS The prevalence of excessive gestational weight gain declined, and weight loss increased, as obesity became more severe. Generally, weight loss was associated with an elevated risk of SGA, iPTB, and sPTB, and a high weight gain tended to increase the risk of LGA and iPTB. Weight gains associated with probabilities of SGA and LGA of < or =10% and a minimal risk of iPTB and sPTB were as follows: 9.1-13.5 kg (obesity class 1), 5.0-9 kg (obesity class 2), 2.2 to <5.0 kg (obesity class 3 white women), and <2.2 kg (obesity class 3 black women). CONCLUSION These data suggest that the range of gestational weight gain to balance risks of SGA, LGA, sPTB, and iPTB may vary by severity of obesity.

Maternal Vitamin D Deficiency Is Associated with Bacterial Vaginosis in the First Trimester of Pregnancy

Bacterial vaginosis (BV) is a highly prevalent vaginal infection that is associated with adverse pregnancy outcomes. Vitamin D exerts an influence on the immune system and may play a role in BV. The objective of this study was to examine the association between maternal vitamin D status and the prevalence of BV in early pregnancy. Women (n = 469) enrolled in a pregnancy cohort study at <16 wk underwent a pelvic examination and provided a blood sample for determination of serum 25-hydroxyvitamin D [25(OH)D]. BV was diagnosed using Gram-stained vaginal smears interpreted using the method of Nugent. Approximately 41% of women had BV (Nugent score 7-10) and 52% had a serum 25(OH)D concentration <37.5 nmol/L. The mean unadjusted serum 25(OH)D concentration was lower among BV cases (29.5 nmol/L; 95% CI: 27.1, 32.0) compared with women with normal vaginal flora (40.1 nmol/L; 95% CI: 37.0, 43.5; P < 0.001). BV prevalence decreased as vitamin D status improved (P < 0.001). Approximately 57% of the women with a serum 25(OH)D concentration <20 nmol/L had BV compared with 23% of women with a serum 25(OH)D concentration >80 nmol/L. There was a dose-response association between 25(OH)D and the prevalence of BV. The prevalence declined as 25(OH)D increased to 80 nmol/L, then reached a plateau. Compared with a serum 25(OH)D concentration of 75 nmol/L, there were 1.65-fold (95% CI: 1.01, 2.69) and 1.26-fold (1.01, 1.57) increases in the prevalence of BV associated with a serum 25(OH)D concentration of 20 and 50 nmol/L, respectively, after adjustment for race and sexually transmitted diseases. Vitamin D deficiency is associated with BV and may contribute to the strong racial disparity in the prevalence of BV.

Amniotic fluid infection, inflammation, and colonization in preterm labor with intact membranes

OBJECTIVE The purpose of this study was to compare intraamniotic inflammation vs microbial invasion of the amniotic cavity (MIAC) as predictors of adverse outcome in preterm labor with intact membranes. STUDY DESIGN Interleukin-6 (IL-6) was measured in prospectively collected amniotic fluid from 305 women with preterm labor. MIAC was defined by amniotic fluid culture and/or detection of microbial 16S ribosomal DNA. Cases were categorized into 5 groups: infection (MIAC; IL-6, ≥11.3 ng/mL); severe inflammation (no MIAC; IL-6, ≥11.3 ng/mL); mild inflammation (no MIAC; IL-6, 2.6-11.2 ng/mL); colonization (MIAC; IL-6, <2.6 ng/mL); negative (no MIAC; IL-6, <2.6 ng/mL). RESULTS The infection (n = 27) and severe inflammation (n = 36) groups had similar latency (median, <1 day and 2 days, respectively) and similar rates of composite perinatal morbidity and mortality (81% and 72%, respectively). The colonization (n = 4) and negative (n = 195) groups had similar outcomes (median latency, 23.5 and 25 days; composite morbidity and mortality rates, 21% and 25%, respectively). The mild inflammation (n = 47) groups had outcomes that were intermediate to the severe inflammation and negative groups (median latency, 7 days; composite morbidity and mortality rates, 53%). In logistic regression adjusting for gestational age at enrollment, IL-6 ≥11.3 and 2.6-11.2 ng/mL, but not MIAC, were associated significantly with composite morbidity and mortality rates (odds ratio [OR], 4.9; 95% confidence interval [CI], 2.2-11.2, OR, 3.1; 95% CI, 1.5-6.4, and OR, 1.8; 95% CI, 0.6-5.5, respectively). CONCLUSION We confirmed previous reports that intraamniotic inflammation is associated with adverse perinatal outcomes whether or not intraamniotic microbes are detected. Colonization without inflammation appears relatively benign. Intraamniotic inflammation is not simply present or absent but also has degrees of severity that correlate with adverse outcomes. We propose the designation amniotic inflammatory response syndrome to denote the adverse outcomes that are associated with intraamniotic inflammation.

Preterm premature rupture of membranes: diagnosis, evaluation and management strategies

Preterm premature rupture of the membranes (PPROM) is responsible for one‐third of all preterm births and affects 120,000 pregnancies in the United States each year. Effective treatment relies on accurate diagnosis and is gestational age dependent. The diagnosis of PPROM is made by a combination of clinical suspicion, patient history and some simple tests. PPROM is associated with significant maternal and neonatal morbidity and mortality from infection, umbilical cord compression, placental abruption and preterm birth. Subclinical intrauterine infection has been implicated as a major aetiological factor in the pathogenesis and subsequent maternal and neonatal morbidity associated with PPROM. The frequency of positive cultures obtained by transabdominal amniocentesis at the time of presentation with PPROM in the absence of labour is 25–40%. The majority of amniotic fluid infection in the setting of PPROM does not produce the signs and symptoms traditionally used as diagnostic criteria for clinical chorioamnionitis. Any evidence of infection by amniocentesis should be considered carefully as an indication for delivery. Documentation of amniotic fluid infection in women who present with PPROM enables us to triage our therapeutic decision making rationally. In PPROM, the optimal interval for delivery occurs when the risks of immaturity are outweighed by the risks of pregnancy prolongation (infection, abruption and cord accident). Lung maturity assessment may be a useful guide when planning delivery in the 32‐ to 34‐week interval. A gestational age approach to therapy is important and should be adjusted for each hospitals neonatal intensive care unit. Antenatal antibiotics and corticosteroid therapies have clear benefits and should be offered to all women without contraindications. During conservative management, women should be monitored closely for placental abruption, infection, labour and a non‐reassuring fetal status. Women with PPROM after 32 weeks of gestation should be considered for delivery, and after 34 weeks the benefits of delivery clearly outweigh the risks.

Risk of uterine rupture and adverse perinatal outcome at term after cesarean delivery.

OBJECTIVE: Current information on the risk of uterine rupture after cesarean delivery has generally compared the risk after trial of labor to that occurring with an elective cesarean delivery without labor. Because antepartum counseling cannot account for whether a woman will develop an indication requiring a repeat cesarean delivery or whether labor will occur before scheduled cesarean delivery, the purpose of this analysis was to provide clinically useful information regarding the risks of uterine rupture and adverse perinatal outcome for women at term with a history of prior cesarean delivery. METHODS: Women with a term singleton gestation and prior cesarean delivery were studied over 4 years at 19 centers. For this analysis, outcomes from five groups were studied: trial of labor, elective repeat with no labor, elective repeat with labor (women presenting in early labor who subsequently underwent cesarean delivery), indicated repeat with labor, and indicated repeat without labor. All cases of uterine rupture were reviewed centrally to assure accuracy of diagnosis. RESULTS: A total of 39,117 women were studied. In term pregnant women with a prior cesarean delivery, the overall risk for uterine rupture was 0.32% (125 of 39,117), and the overall risk for serious adverse perinatal outcome (stillbirth, hypoxic ischemic encephalopathy, neonatal death) was 106 of 39,049 (0.27%). The uterine rupture risk for indicated repeat cesarean delivery (labor or without labor) was 7 of 6,080 (0.12%); the risk for elective (no indication) repeat cesarean delivery (labor or without labor) was 4 of 17,714 (0.02%). Indicated repeat cesarean delivery increased the risk of uterine rupture by a factor of 5 (odds ratio 5.1, 95% confidence interval 1.49–17.44). In the absence of an indication, the presence of labor also increased the risk of uterine rupture (4 of 2,721 [0.15%] compared with 0 of 14,993, P<.01). The highest rate of uterine rupture occurred in women undergoing trial of labor (0.74%, 114 of 15,323). CONCLUSION: At term, the risk of uterine rupture and adverse perinatal outcome for women with a singleton and prior cesarean delivery is low regardless of mode of delivery, occurring in 3 per 1,000 women. Maternal complications occurred in 3–8% of women within the five delivery groups. LEVEL OF EVIDENCE: II

Interleukin-6 promoter −174 polymorphism and spontaneous preterm birth☆

OBJECTIVE We assessed the relationship between interleukin-6 (IL-6) promoter -174 polymorphism and spontaneous preterm birth (sPTB) less than 34 weeks and the relationship of polymorphism status with race. STUDY DESIGN Polymerase chain reaction was used to evaluate DNA from 156 controls who delivered after spontaneous labor at term and 51 subjects who had sPTB less than 34 weeks. RESULTS Among the 156 controls, the C/C variant was present in 30 (19.2%). Among the 51 subjects, the C/C variant was present in 2 (6.3%) (odds ratio 0.17, 95% CI 0.04-0.74). Among white women, the C/C variant was present in 30 (27.2%) controls but only 2 (5.2%) cases. No African American women carried the C/C variant. The racial disparity was statistically significant. (P<.001) CONCLUSION The IL-6 promoter -174 allelic variant C/C is significantly less frequent among women with sPTB less than 34 weeks. There is a dramatic racial disparity in the distribution of allelic variants of this polymorphism.

Vitamin D may be a link to black-white disparities in adverse birth outcomes.

In the United States, significant, intractable disparities exist in rates of major pregnancy outcomes between non-Hispanic black and non-Hispanic white women. A previously unexplored candidate influence on the black-white disparity in adverse birth outcomes is maternal vitamin D status. This review summarizes the evidence relating maternal vitamin D to preeclampsia, spontaneous preterm birth, gestational diabetes, and fetal growth restriction, and addresses gaps in our understanding of the contribution of vitamin D to the intractable black-white disparity in these conditions. The literature reviewed highlights strong biologic plausibility of role for vitamin D in the pathophysiology of these poor pregnancy outcomes. Data also suggest that maternal vitamin D deficiency may increase the risk of preeclampsia and fetal growth restriction. Less research has been done in support of relations with spontaneous preterm birth and gestational diabetes, and fetal and infant survival have rarely been studied. Few trials of vitamin D supplementation have been conducted in pregnant women with adequate power to test effects on birth outcomes. Importantly, black pregnant women have rarely been studied in vitamin D—birth outcomes research. Although vitamin D is a promising candidate influence on black-white disparities in preeclampsia, spontaneous preterm birth, fetal growth restriction, and gestational diabetes, these associations require further study in large samples of black US women. Because vitamin D deficiency is widespread and black-white disparities in pregnancy outcomes and infant survival have been resistant to previous interventions, research to test vitamin D as a causal factor is of major public health significance. Target Audience: Obstetricians & Gynecologist, Family Physicians. Learning Objectives: After completion of this educational activity, the reader will be able to appreciate risk factors for inadequate vitamin D status. Understand the basic aspects of vitamin D metabolism. Become aware of recent literature linking inadequate vitamin D status and adverse pregnancy outcomes such as preeclampsia and preterm birth.

Center of excellence for placenta accreta

Placenta accreta spectrum is one of the most morbid conditions obstetricians will encounter. The incidence has dramatically increased in the last 20 years. The major contributing factor to this is believed to be the increase in the rate of cesarean delivery. Despite the increased incidence of placenta accreta, most obstetricians have personally managed only a small number of women with placenta accreta. The condition poses dramatic risk for massive hemorrhage and associated complication such as consumption coagulopathy, multisystem organ failure, and death. In addition, there is an increased risk for surgical complications such as injury to bladder, ureters, and bowel and the need for reoperation. Most women require blood transfusion, often in large quantities, and many require admission to an intensive care unit. As a result of indicated, often emergent preterm delivery, many babies require admission to a neonatal care intensive care unit. Outcomes are improved when delivery is accomplished in centers with multidisciplinary expertise and experience in the care of placenta accreta. Such expertise may include maternal-fetal medicine, gynecologic surgery, gynecologic oncology, vascular, trauma and urologic surgery, transfusion medicine, intensivists, neonatologists, interventional radiologists, anesthesiologists, specialized nursing staff, and ancillary personnel. This article highlights the desired features for a center of excellence in placenta accreta, and which patients should be referred for evaluation and/or delivery in such centers.

Maternal Serum 25-Hydroxyvitamin D and Measures of Newborn and Placental Weight in a U.S. Multicenter Cohort Study

CONTEXT Inconsistent associations between maternal vitamin D status and fetal size have been published in small studies. OBJECTIVE Our objective was to examine the association between maternal 25-hydroxyvitamin D [25(OH)D] levels and measures of newborn and placental weight. DESIGN AND SETTING We measured maternal 25(OH)D in mothers from the Collaborative Perinatal Project, an observational cohort conducted in 12 U.S. medical centers from 1959 to 1965. PARTICIPANTS Women delivering singleton, term, live births with 25(OH)D measured at a gestation of 26 wk or less (n = 2146). MAIN OUTCOME MEASURES Birth weight, ponderal index, placental weight, the placental to fetal weight ratio, and small for gestational age were measured. Hypotheses were formulated after data collection. RESULTS After confounder adjustment, mothers with 25(OH)D of 37.5 nmol/liter or greater gave birth to newborns with 46 g [95% confidence interval (CI), 9-82 g] higher birth weights and 0.13 cm (0.01-0.25 cm) larger head circumferences compared with mothers with less than 37.5 nmol/liter. Birth weight and head circumference rose with increasing 25(OH)D up to 37.5 nmol/liter and then leveled off (P < 0.05). No association was observed between 25(OH)D and ponderal index, placental weight, or the placental to fetal weight ratio. Maternal 25(OH)D of 37.5 nmol/liter or greater vs. less than 37.5 nmol/liter in the first trimester was associated with half the risk of small for gestational age (adjusted odds ratio 0.5; 95% CI 0.3-0.9), but no second-trimester association was observed. CONCLUSIONS Maternal vitamin D status is independently associated with markers of physiological and pathological growth in term infants. Adequately powered randomized controlled trials are needed to test whether maternal vitamin D supplementation may improve fetal growth.