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Background: Makena (17-hydroxyprogesterone caproate) was approved by the United States Food and Drug Administration for the prevention of recurrent spontaneous preterm birth in 2011 under the accelerated approval pathway, but fundamental pharmacokinetic or pharmacodynamic (Phase 1 and Phase 2) studies were not performed. At the time, there were no dose-response or concentration-response data. The therapeutic concentration was not known. The lack of such data brings into question the dosing regimen for 17-hydroxyprogesterone caproate and if it was optimized., Objective: The purpose of this study was to evaluate the dosing regimen for 17-hydroxyprogesterone by analyzing 3 data sets in which the 17-hydroxyprogesterone caproate pharmacology was evaluated, namely the Maternal-Fetal Medicine Omega 3 study, the Obstetric-Fetal Pharmacology Research Units study, and the Obstetrical-Fetal Pharmacology Research Centers study. If an inappropriate dosing regimen could be identified, such information could inform future studies of pharmacotherapy in pregnancy., Study Design: Data from the Omega 3 study were used to determine if plasma concentration was related to spontaneous preterm birth risk and if a threshold concentration could be identified. Data from the Obstetric-Fetal Pharmacology Research Units study were used to determine the half-life of 17-hydroxyprogesterone caproate and to develop a model to simulate drug concentrations with various dosing regimens. Data from the Obstetrical-Fetal Pharmacology Research Centers study were used to determine the relationship between dose and safety outcomes., Results: Analysis of the Omega 3 data set indicated that the risk for spontaneous preterm birth decreased as the log concentration of 17-hydroxyprogesterone caproate increased (odds ratio, 0.04; 95% confidence interval, 0.00-0.90). A steady state concentration of >9 ng/mL (equivalent to >8 ng/mL at 25-28 weeks) was associated with the lowest risk for spontaneous preterm birth (hazard ratio, 0.52; 95% confidence interval, 0.27-0.98; P=.04); this concentration was not achieved in 25% of subjects who received the 250 mg weekly dose. In the Obstetrical-Fetal Pharmacology Research Units study, the adjusted half-life (median and interquartile range) of 17-hydroxyprogesterone caproate was 14.0 (11.5-17.2) days. Simulations indicated that with the 250 mg weekly dose, >5 weekly injections were required to reach the 9 ng/mL target; however, those with the shortest half-life (corresponding to higher clearance), never reached the targeted 9 ng/mL concentration. In 75% of subjects, a loading dose of 500 mg weekly for 2 weeks followed by 250 mg weekly achieved and maintained the 9 ng/mL concentration within 2 weeks but in those 25% with the shortest half-life, concentrations exceeded the 9 ng/mL target for only 3 weeks. In the Obstetrical-Fetal Pharmacology Research Centers study, all 65 subjects who received a weekly dose of 500 mg exceeded the 9 ng/mL steady state., Conclusion: The dosing regimen for 17-hydroxyprogesterone caproate was inadequate. There is a significant inverse relationship between drug concentration and spontaneous preterm birth. The risk was lowest when the concentration exceeded 9 ng/mL, but 25% of women who received the 250 mg weekly dose never reached or maintained this concentration. The drug's long half-life necessitates a loading dose to achieve therapeutic concentrations rapidly. The omission of basic pharmacologic studies to determine the proper dosing may have compromised the effectiveness of 17-hydroxyprogesterone caproate. Future pharmacotherapy trials in pregnancy must first complete fundamental pharmacology studies., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Preeclampsia, especially before term, increases the risk of child neurodevelopmental adverse outcomes. Biological plausibility, preclinical studies, and pilot clinical trials conducted by the Eunice Kennedy Shriver National Institute of Child Health and Human Development and the Obstetric-Fetal Pharmacology Research Centers Network support the safety and use of pravastatin to prevent preeclampsia., Objective: This study aimed to determine the effect of antenatal pravastatin treatment in high-risk pregnant individuals on their child's health, growth, and neurodevelopment., Study Design: This was an ancillary follow-up cohort study of children born to mothers who participated in the Obstetric-Fetal Pharmacology Research Centers Network pilot trials of pravastatin vs placebo in individuals at high risk of preeclampsia (ClinicalTrials.gov; identifier NCT01717586). After obtaining written informed consent (and assent as appropriate), the parent was instructed to complete the Child Behavior Checklist. To assess the child's motor, cognitive, and developmental outcomes, a certified and blinded study psychologist completed child motor, cognitive, emotional, and behavioral assessments using validated tools. Given the small number of individuals in the studies, the 10- and 20-mg pravastatin groups were combined into 1 group, and the results of the pravastatin group were compared with that of the placebo group., Results: Of 40 children born to mothers in the original trial, 30 (15 exposed in utero to pravastatin and 15 to placebo) were enrolled in this follow-up study. The time of follow-up, which was 4.7 years (interquartile range, 2.5-6.9), was not different between children in the pravastatin group and children in the placebo group. There was no difference in the child's body mass index percentiles per sex and corrected age, the rates of extremes of body mass index percentiles, or the report of any other medical or developmental complications between the 2 groups. No child born in the pravastatin group had any limitation in motor assessment compared with 2 children (13.3%) who walked with difficulty and 4 children (26.7%) who had reduced manual abilities in the placebo group. Moreover, children born to mothers who received pravastatin had a higher general mean conceptual ability score (98.2±16.7 vs 89.7±11.0; P=.13) and a lower frequency (15.4% vs 35.7%; P=.38) of having a score of <85 (ie, 1 standard deviation lower than the mean) compared with those in the placebo group. Finally, there was no difference in the parents' report on the Child Behavior Checklist between the 2 groups., Conclusion: This study reported on the long-term neuromotor, cognitive, and behavioral outcomes among children exposed to pravastatin in utero during the second and third trimesters of pregnancy. Although the data were limited by the original trial's sample size, no identifiable long-term neurodevelopmental safety signal was evident with the use of pravastatin during pregnancy. This favorable neonatal risk-benefit analysis justifies continued research using pravastatin in clinical trials., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: Understanding and improving obstetrical quality and safety is an important goal of professional societies, and many interventions such as checklists, safety bundles, educational interventions, or other culture changes have been implemented to improve the quality of care provided to obstetrical patients. Although many factors contribute to delivery decisions, a reduced workload has addressed how provider issues such as fatigue or behaviors surrounding impending shift changes may influence the delivery mode and outcomes., Objective: The objective was to assess whether intrapartum obstetrical interventions and adverse outcomes differ based on the temporal proximity of the delivery to the attending's shift change., Study Design: This was a secondary analysis from a multicenter obstetrical cohort in which all patients with cephalic, singleton gestations who attempted vaginal birth were eligible for inclusion. The primary exposure used to quantify the relationship between the proximity of the provider to their shift change and a delivery intervention was the ratio of time from the most recent attending shift change to vaginal delivery or decision for cesarean delivery to the total length of the shift. Ratios were used to represent the proportion of time completed in the shift by normalizing for varying shift lengths. A sensitivity analysis restricted to patients who were delivered by physicians working 12-hour shifts was performed. Outcomes chosen included cesarean delivery, episiotomy, third- or fourth-degree perineal laceration, 5-minute Apgar score of <4, and neonatal intensive care unit admission. Chi-squared tests were used to evaluate outcomes based on the proportion of the attending's shift completed. Adjusted and unadjusted logistic models fitting a cubic spline (when indicated) were used to determine whether the frequency of outcomes throughout the shift occurred in a statistically significant, nonlinear pattern RESULTS: Of the 82,851 patients eligible for inclusion, 47,262 (57%) had ratio data available and constituted the analyzable sample. Deliveries were evenly distributed throughout shifts, with 50.6% taking place in the first half of shifts. There were no statistically significant differences in the frequency of cesarean delivery, episiotomy, third- or fourth-degree perineal lacerations, or 5-minute Apgar scores of <4 based on the proportion of the shift completed. The findings were unchanged when evaluated with a cubic spline in unadjusted and adjusted logistic models. Sensitivity analyses performed on the 22.2% of patients who were delivered by a physician completing a 12-hour shift showed similar findings. There was a small increase in the frequency of neonatal intensive care unit admissions with a greater proportion of the shift completed (adjusted P=.009), but the findings did not persist in the sensitivity analysis., Conclusion: Clinically significant differences in obstetrical interventions and outcomes do not seem to exist based on the temporal proximity to the attending physician's shift change. Future work should attempt to directly study unit culture and provider fatigue to further investigate opportunities to improve obstetrical quality of care, and additional studies are needed to corroborate these findings in community settings., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: Short cervix at midgestation, the presence of intraamniotic debris, and cervical funneling are risk factors for preterm birth; however, cervical length measurements and cutoffs are not well documented among pregnant patients of different gestational ages and self-reported races and ethnicities., Objective: This study aimed to describe the distribution of cervical length and frequency of funneling and debris at midgestation in nulliparous women by gestational age and race/ethnicity., Study Design: This secondary analysis of screening data from a multicenter treatment trial of singleton nulliparous patients with short cervix was conducted at 14 geographically distributed, university-affiliated medical centers in the United States. Singleton nulliparous patients with no known risk factors for preterm birth were screened for trial participation and asked to undergo a transvaginal ultrasound to measure cervical length by a certified sonographer. The distribution of cervical length and the frequency of funneling and debris were assessed for each gestational age week (16-22 weeks) and stratified by self-reported race and ethnicity, which for this study were categorized as White, Black, Hispanic, and other. Patients enrolled in the randomized trial were excluded from this analysis., Results: A total of 12,407 nulliparous patients were included in this analysis. The racial or ethnic distribution of the study participants was as follows: White, 41.6%; Black, 29.6%; Hispanic, 24.2%; and others, 4.6%. The 10th percentile cervical length for the entire cohort was 31.1 mm and, when stratified by race and ethnicity, 31.9 mm for White, 30.2 mm for Black, 31.4 mm for Hispanic, and 31.2 mm for patients of other race and ethnicity (P<.001). At each gestational age, the cervical length corresponding to the tenth percentile was shorter in Black patients. The 25 mm value commonly used to define a short cervix and thought to represent the 10th percentile ranged from 1.3% to 5.4% across gestational age weeks and 1.0% to 3.8% across race and ethnicity groups. Black patients had the highest rate of funneling (2.6%), whereas Hispanic and Black patients had higher rates of intraamniotic debris than White and other patients (P<.001)., Conclusion: Black patients had shorter cervical length and higher rates of debris and funneling than White patients. The racial and ethnic disparities in sonographic midtrimester cervical findings may provide insight into the racial disparity in preterm birth rates in the United States., (Copyright © 2021 Elsevier Inc. All rights reserved.)

The data available to inform pregnant and lactating women about drug safety and efficacy are woefully inadequate. This lack of information encompasses every aspect of pharmaceutics, including limited human data about the embryonic risk, limited pharmacokinetic and pharmacodynamic information during and after pregnancy to ensure proper dosing, and a dearth of new medications to treat obstetrical and lactation disorders. This state of affairs has been longstanding and can be attributed to several realities, most of which have withstood any efforts to modify them. The first reality is the disinterest of the pharmaceutical industry to undertake pregnancy and lactation studies because of the considerable disincentives to undertake such studies. The medicolegal risks and the limited opportunity for financial gain are significant barriers to their participation. The US Food and Drug Administration has not mandated that new drugs or drugs "on patent" must include studies in pregnant women. Regulatory constrains that have defined pregnant women as a vulnerable class have greatly limited pharmacologic studies. Another contributing factor to this lack of information is the lack of researchers skilled in pharmacology with an interest in the pregnant woman. In addition, although difficult to measure, there is the hesitancy of pregnant and lactating women to participate in pharmacology research either for fear of fetal risk or an inability to commit the time required for such studies. Research in obstetrical and lactation pharmacology lags far behind that of pediatric pharmacology. Through the efforts of many, research in that field is highly funded and very productive in providing new information on medications used in children who, like pregnant women, have differing pharmacologic needs based on age (chronology for children and gestational age for pregnant women). Recently, the deficiencies and possible remedies for this embarrassing state of affairs in obstetrical and lactation pharmacology have been addressed by the federal government, which led to 15 recommendations from the Task Force on Research Specific to Pregnant Women and Lactating Women. In this article, we address the challenges in providing meaningful information about specific medications used by the mother and how these problems have evolved. We also suggest specific strategies to start the process of remediation., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Medication-assisted treatment is recommended for individuals with an opioid use disorder, including pregnant women. Medication-assisted treatment during pregnancy provides benefits to the mother and fetus, including better pregnancy outcomes, reduced illicit drug use, and improved prenatal care. An alternative approach, medically supervised withdrawal (detoxification), has, in recent reports, demonstrated a low risk of fetal death and low rates of relapse and neonatal abstinence syndrome. The rates of relapse and neonatal abstinence syndrome are questioned by many who view medically supervised withdrawal as unacceptable based on the concern for the potential adverse consequences of relapse to mother and baby. The impact of opioids on the fetal brain have not been integrated into this debate. Studies in animals and human brain tissues demonstrate opioid receptors in neurons, astroglia, and oligodendrocytes. Age-specific normative data from infants, children, and adults have facilitated investigation of the impact of opioids on the human brain in vivo. Collectively, these studies in animals, human neural tissue, adult brains, and the brains of children and newborns demonstrate that opioids adversely affect the human brain, primarily the developing oligodendrocyte and the processes of myelinization (white matter microstructure), connectivity between parts of the brain, and the size of multiple brain regions, including the basal ganglia, thalamus, and cerebellar white matter. These in vivo studies across the human lifespan suggest vulnerability of specific fronto-temporal-limbic and frontal-subcortical (basal ganglia and cerebellum) pathways that are also likely vulnerable in the human fetal brain. The long-term impact of these reproducible changes in the fetal brain in vivo is unclear, but the possibility of lasting injury has been suggested. In light of the recent data on medically supervised withdrawal and the emerging evidence suggesting adverse effects of opioids on the developing fetal brain, a new paradigm of care is needed that includes the preferred option of medication-assisted treatment but also the option of medically supervised opioid withdrawal for a select group of women. Both these treatment options should offer mental health and social services support throughout pregnancy. More research on both opioid exposure on the developing human brain and the impact of medically supervised withdrawal is required to identify appropriate candidates, optimal dose reduction regimens, and gestational age timing for initiating medically supervised withdrawal., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: Studies of early-term birth after demonstrated fetal lung maturity show that respiratory and other outcomes are worse with early-term birth (37 0 -38 6 weeks) even after demonstrated fetal lung maturity when compared with full-term birth (39 0 -40 6 weeks). However, these studies included medically indicated births and are therefore potentially limited by confounding by the indication for delivery. Thus, the increase in adverse outcomes might be due to the indication for early-term birth rather than the early-term birth itself., Objective: We examined the prevalence and risks of adverse neonatal outcomes associated with early-term birth after confirmed fetal lung maturity as compared with full-term birth in the absence of indications for early delivery., Study Design: This is a secondary analysis of an observational study of births to 115,502 women in 25 hospitals in the United States from 2008 through 2011. Singleton nonanomalous births at 37-40 weeks with no identifiable indication for delivery were included; early-term births after positive fetal lung maturity testing were compared with full-term births. The primary outcome was a composite of death, ventilator for ≥2 days, continuous positive airway pressure, proven sepsis, pneumonia or meningitis, treated hypoglycemia, hyperbilirubinemia (phototherapy), and 5-minute Apgar <7. Logistic regression and propensity score matching (both 1:1 and 1:2) were used., Results: In all, 48,137 births met inclusion criteria; the prevalence of fetal lung maturity testing in the absence of medical or obstetric indications for early delivery was 0.52% (n = 249). There were 180 (0.37%) early-term births after confirmed pulmonary maturity and 47,957 full-term births. Women in the former group were more likely to be non-Hispanic white, smoke, have received antenatal steroids, have induction, and have a cesarean. Risks of the composite (16.1% vs 5.4%; adjusted odds ratio, 3.2; 95% confidence interval, 2.1-4.8 from logistic regression) were more frequent with elective early-term birth. Propensity scores matching confirmed the increased primary composite in elective early-term births: adjusted odds ratios, 4.3 (95% confidence interval, 1.8-10.5) for 1:1 and 3.5 (95% confidence interval, 1.8-6.5) for 1:2 matching. Among components of the primary outcome, CPAP use and hyperbilirubinemia requiring phototherapy were significantly increased. Transient tachypnea of the newborn, neonatal intensive care unit admission, and prolonged neonatal intensive care unit stay (>2 days) were also increased with early-term birth., Conclusion: Even with confirmed pulmonary maturity, early-term birth in the absence of medical or obstetric indications is associated with worse neonatal respiratory and hepatic outcomes compared with full-term birth, suggesting relative immaturity of these organ systems in early-term births., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: While there are well-accepted standards for the diagnosis of arrested active-phase labor, the definition of a "failed" induction of labor remains less certain. One approach to diagnosing a failed induction is based on the duration of the latent phase. However, a standard for the minimum duration that the latent phase of a labor induction should continue, absent acute maternal or fetal indications for cesarean delivery, remains lacking., Objective: The objective of this study was to determine the frequency of adverse maternal and perinatal outcomes as a function of the duration of the latent phase among nulliparous women undergoing labor induction., Study Design: This study is based on data from an obstetric cohort of women delivering at 25 US hospitals from 2008 through 2011. Nulliparous women who had a term singleton gestation in the cephalic presentation were eligible for this analysis if they underwent a labor induction. Consistent with prior studies, the latent phase was determined to begin once cervical ripening had ended, oxytocin was initiated, and rupture of membranes had occurred, and was determined to end once 5-cm dilation was achieved. The frequencies of cesarean delivery, as well as of adverse maternal (eg, postpartum hemorrhage, chorioamnionitis) and perinatal (eg, a composite frequency of seizures, sepsis, bone or nerve injury, encephalopathy, or death) outcomes, were compared as a function of the duration of the latent phase (analyzed with time both as a continuous measure and categorized in 3-hour increments)., Results: A total of 10,677 women were available for analysis. In the vast majority (96.4%) of women, the active phase had been reached by 15 hours. The longer the duration of a woman's latent phase, the greater her chance of ultimately undergoing a cesarean delivery (P < .001, for time both as a continuous and categorical independent variable), although >40% of women whose latent phase lasted ≥18 hours still had a vaginal delivery. Several maternal morbidities, such as postpartum hemorrhage (P < .001) and chorioamnionitis (P < .001), increased in frequency as the length of latent phase increased. Conversely, the frequencies of most adverse perinatal outcomes were statistically stable over time., Conclusion: The large majority of women undergoing labor induction will have entered the active phase by 15 hours after oxytocin has started and rupture of membranes has occurred. Maternal adverse outcomes become statistically more frequent with greater time in the latent phase, although the absolute increase in frequency is relatively small. These data suggest that cesarean delivery should not be undertaken during the latent phase prior to at least 15 hours after oxytocin and rupture of membranes have occurred. The decision to continue labor beyond this point should be individualized, and may take into account factors such as other evidence of labor progress., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background: Dose-adjusted plasma concentrations of buprenorphine are significantly decreased during pregnancy compared with the nonpregnant state. This observation suggests that pregnant women may need a higher dose of buprenorphine than nonpregnant individuals to maintain similar drug exposure (plasma concentrations over time after a dose). The current dosing recommendations for buprenorphine during pregnancy address the total daily dose of buprenorphine to be administered, but the frequency of dosing is not clearly addressed. Based on buprenorphine's long terminal half-life, once-daily or twice-daily dosing has generally been suggested., Objective: The objective of the study was to assess the impact of dosing frequency on buprenorphine plasma concentration time course during pregnancy., Study Design: We utilized 3 data sources to determine an optimal frequency for dosing of buprenorphine during pregnancy: data from a pharmacokinetic study of 14 pregnant and postpartum women on maintenance buprenorphine in a supervised clinical setting; data from pregnant women attending a buprenorphine clinic; and data from a physiologically based pharmacokinetic modeling of buprenorphine pharmacokinetics in nonpregnant subjects., Results: Among the 14 women participating in the pharmacokinetic study during and after pregnancy, plasma concentrations of buprenorphine were <1 ng/mL (the theoretical concentration required to prevent withdrawal symptoms) for 50-80% of the 12 hour dosing interval while at steady state. Among 62 women followed up in a opioid agonist treatment program, in which dosing frequency is determined in part by patient preference, 10 (16%) were on once-daily dosing, 10 (16%) were on twice-daily dosing, 28 (45%) were on thrice-daily dosing, and 14 (23%) were on four-times-daily dosing. A physiologically based pharmacokinetic model in nonpregnant subjects demonstrated that dosing frequency has an impact on the duration over which the plasma concentrations are below a specified plasma concentration threshold., Conclusion: A more frequent dosing interval (ie, three-times-daily or four-times-daily dosing) may be required in pregnant women to sustain plasma concentrations above the threshold of 1 ng/mL to prevent withdrawal symptoms and to improve adherence., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background: Infants born <37 weeks' gestation are of public health concern since complications associated with preterm birth are the leading cause of mortality in children <5 years of age and a major cause of morbidity and lifelong disability. The administration of 17-alpha hydroxyprogesterone caproate reduces preterm birth by 33% in women with history of spontaneous preterm birth. We demonstrated previously that plasma concentrations of 17-alpha hydroxyprogesterone caproate vary widely among pregnant women and that women with 17-alpha hydroxyprogesterone caproate plasma concentrations in the lowest quartile had spontaneous preterm birth rates of 40% vs rates of 25% in those women with higher concentrations. Thus, plasma concentrations are an important factor in determining drug efficacy but the reason 17-alpha hydroxyprogesterone caproate plasma concentrations vary so much is unclear. Predominantly, 17-alpha hydroxyprogesterone caproate is metabolized by CYP3A4 and CYP3A5 enzymes., Objective: We sought to: (1) determine the relation between 17-alpha hydroxyprogesterone caproate plasma concentrations and single nucleotide polymorphisms in CYP3A4 and CYP3A5; (2) test the association between progesterone receptor single nucleotide polymorphisms and spontaneous preterm birth; and (3) test whether the association between plasma concentrations of 17-alpha hydroxyprogesterone caproate and spontaneous preterm birth varied by progesterone receptor single nucleotide polymorphisms., Study Design: In this secondary analysis, we evaluated genetic polymorphism in 268 pregnant women treated with 17-alpha hydroxyprogesterone caproate, who participated in a placebo-controlled trial to evaluate the benefit of omega-3 supplementation in women with history of spontaneous preterm birth. Trough plasma concentrations of 17-alpha hydroxyprogesterone caproate were measured between 25-28 weeks of gestation after a minimum of 5 injections of 17-alpha hydroxyprogesterone caproate. We extracted DNA from maternal blood samples and genotyped the samples using TaqMan (Applied Biosystems, Foster City, CA) single nucleotide polymorphism genotyping assays for the following single nucleotide polymorphisms: CYP3A4*1B, CYP3A4*1G, CYP3A4*22, and CYP3A5*3; and rs578029, rs471767, rs666553, rs503362, and rs500760 for progesteronereceptor. We adjusted for prepregnancy body mass index, race, and treatment group in a multivariable analysis. Differences in the plasma concentrations of 17-alpha hydroxyprogesterone caproate by genotype were evaluated for each CYP single nucleotide polymorphism using general linear models. The association between progesterone receptor single nucleotide polymorphisms and frequency of spontaneous preterm birth was tested using logistic regression. A logistic model also tested interaction between 17-alpha hydroxyprogesterone caproate concentrations with each progesterone receptor single nucleotide polymorphism for the outcome of spontaneous preterm birth., Results: The association between CYP single nucleotide polymorphisms *22, *1G, *1B, and *3 and trough plasma concentrations of 17-alpha hydroxyprogesterone caproate was not statistically significant (P = .68, .44, .08, and .44, respectively). In an adjusted logistic regression model, progesterone receptor single nucleotide polymorphisms rs578029, rs471767, rs666553, rs503362, and rs500760 were not associated with the frequency of spontaneous preterm birth (P = .29, .10, .76, .09, and .43, respectively). Low trough plasma concentrations of 17-alpha hydroxyprogesterone caproate were statistically associated with a higher frequency of spontaneous preterm birth (odds ratio, 0.78; 95% confidence ratio, 0.61-0.99; P = .04 for trend across quartiles), however no significant interaction with the progesterone receptor single nucleotide polymorphisms rs578029, rs471767, rs666553, rs503362, and rs500760 was observed (P = .13, .08, .10, .08, and .13, respectively)., Conclusion: The frequency of recurrent spontaneous preterm birth appears to be associated with trough 17-alpha hydroxyprogesterone caproate plasma concentrations. However, the wide variation in trough 17-alpha hydroxyprogesterone caproate plasma concentrations is not attributable to polymorphisms in CYP3A4 and CYP3A5 genes. Progesterone receptor polymorphisms do not predict efficacy of 17-alpha hydroxyprogesterone caproate. The limitations of this secondary analysis include that we had a relative small sample size (n = 268) and race was self-reported by the patients., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background: Opioid use disorder among pregnant women is associated with adverse perinatal outcomes and is increasing in the United States. The standard of care for pregnant women with opioid use disorder is opioid maintenance therapy including either methadone or buprenorphine, which can be initiated at any time during pregnancy. These medications are known to cross the placenta but their placental and fetal effects have not been well characterized. Delayed villous maturation, a placental finding associated with stillbirth, was observed in placentas exposed to opioid maintenance therapy. Given the association of delayed villous maturation with stillbirth, and the possible relationship between opioid maintenance therapy and delayed villous maturation, this study was undertaken to explore the association between opioid maintenance therapy and this placental finding. Delayed villous maturation was not previously reported in placentas exposed to opioids or opioid maintenance therapy., Objective: This study sought to compare risk of delayed villous maturation in term placentas exposed and unexposed to opioid maintenance therapy with buprenorphine or methadone., Study Design: This was a retrospective cohort study conducted between 2010 through 2012 at Magee-Womens Hospital comparing delayed villous maturation in placentas of women with opioid use disorder exposed to either buprenorphine (n = 86) or methadone (n = 268) versus women without opioid use disorder (n = 978). Potential covariates were assessed in univariate analyses with none significantly associated with delayed villous maturation. The final model used conditional logistic regression adjusting for smoking status alone., Results: Among women without opioid use disorder (and therefore not exposed to opioid maintenance therapy), delayed villous maturation was identified in 5.7% of placentas while the prevalence among women treated with buprenorphine or methadone was 8.1% and 10.8%. Overall, the crude odds of being diagnosed with delayed villous maturation were significantly greater in those exposed to opioid maintenance therapy compared to those not exposed (odds ratio, 1.86; 95% confidence interval, 1.20-2.89). When considered separately, women treated with methadone had significantly greater odds of having a placenta with delayed villous maturation than women without exposure to opioid maintenance therapy (odds ratio, 2.00; 95% confidence interval, 1.52-3.20). Women treated with buprenorphine did not have significantly greater odds of this placental diagnosis when compared to the women unexposed to opioid maintenance therapy (odds ratio, 1.46; 95% confidence interval, 0.64-3.31). Results were similar after accounting for smoking., Conclusion: Delayed villous maturation was more common in the placentas of women exposed to opioid maintenance therapy. Further studies are required to characterize rates and extent of delayed villous maturation in the general population as well as to differentiate between possible effects of opioid exposure (eg, heroin, illicit use of prescription opioids) vs those of opioid maintenance therapy (buprenorphine and methadone)., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Background: Preterm birth has staggering health implications, and yet the causes of most cases are still unknown. Placental features have been understudied as an etiology for preterm birth, and the association between placental pathologic lesions and neonatal outcomes are incompletely understood., Objective: We sought to characterize births according to placental pathology and relate these to adverse neonatal outcomes., Study Design: We studied 20,091 births (15,710 term and 4381 preterm) with placental evaluations. Births were classified according to the presence or absence of placental lesions consistent with malperfusion (vasculopathy, infarct, advanced villous maturation, perivillous fibrin, fibrin deposition) and intrauterine inflammation/infection (chorioamnionitis, funisitis, vasculitis). Outcomes were gestational week of delivery, birthweight z-score, neonatal respiratory distress syndrome, and intraventricular hemorrhage., Results: Among all preterm births, evidence of placental malperfusion was identified more often than inflammation/infection (50.6% vs 27.3%, P < .0001). Placental malperfusion was associated with reduced fetal growth (adjusted birthweight z-score, -0.83, P < .0001) and lesions of inflammation/infection were associated with earlier delivery (adjusted difference -2.08 weeks, P < .0001) than those with no lesions. When both placental lesions were present, earlier delivery (adjusted difference -2.28 weeks, P < .0001) and reduced fetal growth (adjusted birthweight z-score difference, -0.24, P = .001) were observed more often than when neither lesion was present. Findings were similar when restricted to cases of spontaneous preterm birth. Intraventricular hemorrhage was higher in preterm births with malperfusion lesions than cases with no lesions (7.6% vs 3.4%; odds ratio, 1.98; confidence interval, 1.18-3.32), accounting for gestational age and other covariates., Conclusion: Placental pathology provides important insight into subtypes of preterm birth with adverse neonatal outcomes. Co-occurrence of malperfusion and inflammation/infection, especially among spontaneous preterm births, may be a novel pattern of placental injury linked to severe adverse outcomes., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Introduction: Maternal vascular malperfusion (MVM) lesions represent hypoxic-ischemic damage to the placenta, and they are associated with adverse pregnancy outcomes. Women with gestational diabetes (GDM) are at increased risk for pregnancy complications, so we set out to characterize the prevalence and clinical correlates of MVM lesions in this cohort., Methods: This was a retrospective cohort study of 1187/1374 (86.4%) women with GDM delivered between 2009 and 2012 who had placental pathology available. Placental lesions of all types were tabulated and grouped into constructs of related entities. MVM lesions specifically included villous infarcts, decidual vasculopathy, increased syncytial knots, perivillous fibrin, and fibrin deposition. We compared maternal characteristics between women with and without MVM lesions, and we also assessed the impact of these lesions on birth weight, preterm birth, and pre-eclampsia using multivariable logistic regression analysis., Results: MVM lesions were the most common placental lesion type in women with GDM (n = 362, 30.5%). Excess gestational weight gain was independently associated with MVM lesions (aOR 1.42, 95% CI 1.06-1.91, p = 0.02) after adjusting for maternal characteristics. MVM lesions were associated with lower birth weight (-90.3 g, 95% CI -148.0 to -32.7, p = 0.002), as well as a 2-fold increased risk for delivery of a small for gestational age infant (10.8 vs 5.9%, p = 0.01) in overweight and obese women. MVM lesions were also associated with increased risk for preterm birth <34 weeks (adjusted OR 2.36, 95% CI 1.31-4.23, p = 0.004) and hypertensive disorders of pregnancy (HDP; adjusted OR 1.58, 95% CI 1.13-2.22, p = 0.02)., Discussion: Placental maternal vascular malperfusion lesions may be one pathway linking excess gestational weight gain to adverse pregnancy outcomes in women with GDM, and future studies are needed to identify metabolic factors that may explain this association., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Background: Buprenorphine is a Food and Drug Administration-approved maintenance therapy for opioid use disorders and is increasingly being used in pregnant women with opioid use disorders as an alternative to methadone. Dosing of buprenorphine in pregnant women is based on the regimen recommended for nonpregnant females and males. Limited data are available defining the pharmacokinetic properties of sublingual buprenorphine administered during pregnancy., Objective: This study evaluated the impact of physiological changes associated with pregnancy on the pharmacokinetics of sublingual buprenorphine during and after pregnancy., Study Design: Pregnant women (n = 13), between 18 0/7 and 37 6/7 weeks' singleton gestation, receiving sublingual buprenorphine twice daily for opioid use disorders were studied. Pharmacokinetic-2 studies were performed between 18 and 25 weeks (n = 7), pharmacokinetic-3 studies were performed between 31 and 37 weeks (n = 11), and pharmacokinetic-P was performed 4-18 weeks postpartum (n = 10). On the day of the study, blood was withdrawn prior to the daily morning dose of buprenorphine and at 0.25, 0.5, 0.75, 1, 1.5, 2, 4, 8, and 12 hours after the dose. Buprenorphine plasma concentrations were analyzed by liquid chromatography tandem mass spectrometric detection. All pharmacokinetic parameters were observed or estimated using Microsoft Excel. Statistical analyses were performed to identify significant changes in study participants' buprenorphine pharmacokinetic parameter estimates over the duration of the study. Univariate linear and generalized linear mixed models were used to investigate changes in these measures over time, some of which were log transformed for normality., Results: Dose-normalized (plasma concentration per dose) buprenorphine plasma concentrations were significantly lower during pregnancy (pharmacokinetic-2 plus pharmacokinetic-3) than during the postpartum period (pharmacokinetic-P). Specific pharmacokinetic parameters (and level of significance) were as follows: the area under the buprenorphine plasma concentration-time curves (P < .003), maximum buprenorphine concentrations (P < .018), buprenorphine concentrations at 0 hour (P < .002), and buprenorphine concentrations at 12 hours (P < .001). None of these parameters differed significantly during pregnancy (ie, pharmacokinetic-2 vs pharmacokinetic-3). The time to maximum buprenorphine concentrations did not differ significantly between groups., Conclusion: The dose-normalized plasma concentrations during a dosing interval and the overall exposure of buprenorphine (area under the buprenorphine plasma concentration-time curves) are lower throughout pregnancy compared with the postpartum period. This indicates an increase in apparent clearance of buprenorphine during pregnancy. These data suggest that pregnant women may need a higher dose of sublingual buprenorphine compared with postpartum individuals. The dose of buprenorphine should be assessed after delivery to maintain similar buprenorphine exposure during the postpartum period., Competing Interests: Drs Bastian, Rothenberger, Tarter, English, Venkataramanan and Caritis have no conflicts to report. Ms. Chen and Zhang also report no conflicts of interest., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Background: Women with gestational diabetes mellitus (GDM) commonly undergo induction of labor (IOL) at term, but the risks and benefits of IOL are incompletely understood., Objective: We examined the relationship among gestational age, IOL, and the rate of cesarean delivery (CD) in women with GDM., Study Design: We identified 863 women with GDM who underwent either IOL or spontaneous labor ≥37 0/7 weeks. Demographic, cervical favorability, and outcome data were abstracted from the medical record. We compared the CD rate in women undergoing IOL at each week of gestation with expectant management to a later gestational age., Results: When compared to women who were expectantly managed, IOL at 37 weeks (adjusted odds ratio [aOR], 1.53; 95% confidence interval [CI], 0.76-3.06; P = .23), 38 weeks (aOR, 2.07; 95% CI, 0.89-4.80; P = .09), and 39 weeks (aOR, 0.79; 95% CI, 0.44-1.42; P = .43)) was associated with similar risk for CD as expectant management after adjustment for nulliparity, body mass index, baseline simplified Bishop score, and maternal age. CD rates were higher in nulliparous women, but did not differ significantly in those undergoing IOL or expectant management. In multiparous women, IOL was significantly associated with an increased risk for CD at 38 weeks (aOR, 7.47; 95% CI, 1.6-34.8; P = .01) and rates of CD (17.39% vs 2.2%, P = .001) were significantly higher in multiparous women with an unfavorable Bishop score induced <39 weeks. Neonatal morbidity was similar across gestational ages after adjustment for maternal body mass index and maternal glycemic control., Conclusion: IOL results in similar risk for CD as expectant management between 37-40 weeks of gestation. Rates of CD differed based on cervical exam and parity. These findings suggest that gestational age alone does not significantly impact maternal and neonatal outcomes, but that decisions regarding delivery in women with GDM should take into account cervical exam and parity., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Background: Although preterm birth <37 weeks' gestation is the leading cause of neonatal morbidity and mortality in the United States, the majority of data regarding preterm neonatal outcomes come from older studies, and many reports have been limited to only very preterm neonates. Delineation of neonatal outcomes by delivery gestational age is needed to further clarify the continuum of mortality and morbidity frequencies among preterm neonates., Objective: We sought to describe the contemporary frequencies of neonatal death, neonatal morbidities, and neonatal length of stay across the spectrum of preterm gestational ages., Study Design: This was a secondary analysis of an obstetric cohort of 115,502 women and their neonates who were born in 25 hospitals nationwide, 2008 through 2011. All liveborn nonanomalous singleton preterm (23.0-36.9 weeks of gestation) neonates were included in this analysis. The frequency of neonatal death, major neonatal morbidity (intraventricular hemorrhage grade III/IV, seizures, hypoxic-ischemic encephalopathy, necrotizing enterocolitis stage II/III, bronchopulmonary dysplasia, persistent pulmonary hypertension), and minor neonatal morbidity (hypotension requiring treatment, intraventricular hemorrhage grade I/II, necrotizing enterocolitis stage I, respiratory distress syndrome, hyperbilirubinemia requiring treatment) were calculated by delivery gestational age; each neonate was classified once by the worst outcome for which criteria was met., Results: In all, 8334 deliveries met inclusion criteria. There were 119 (1.4%) neonatal deaths. In all, 657 (7.9%) neonates had major morbidity, 3136 (37.6%) had minor morbidity, and 4422 (53.1%) survived without any of the studied morbidities. Deaths declined rapidly with each advancing week of gestation. This decline in death was accompanied by an increase in major neonatal morbidity, which peaked at 54.8% at 25 weeks of gestation. As frequencies of death and major neonatal morbidity fell, minor neonatal morbidity increased, peaking at 81.7% at 31 weeks of gestation. The frequency of all morbidities fell >32 weeks. After 25 weeks, neonatal length of hospital stay decreased significantly with each additional completed week of pregnancy; among babies delivered from 26-32 weeks of gestation, each additional week in utero reduced the subsequent length of neonatal hospitalization by a minimum of 8 days. The median postmenstrual age at discharge nadired around 36 weeks' postmenstrual age for babies born at 31-35 weeks of gestation., Conclusion: Our data show that there is a continuum of outcomes, with each additional week of gestation conferring survival benefit while reducing the length of initial hospitalization. These contemporary data can be useful for patient counseling regarding preterm outcomes., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Background: Preeclampsia complicates approximately 3-5% of pregnancies and remains a major cause of maternal and neonatal morbidity and mortality. It shares pathogenic similarities with adult cardiovascular disease as well as many risk factors. Pravastatin, a hydrophilic, 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase inhibitor, has been shown in preclinical studies to reverse various pathophysiological pathways associated with preeclampsia, providing biological plausibility for its use for preeclampsia prevention. However, human trials are lacking., Objective: As an initial step in evaluating the utility of pravastatin in preventing preeclampsia and after consultation with the US Food and Drug Administration, we undertook a pilot randomized controlled trial with the objective to determine pravastatin safety and pharmacokinetic parameters when used in pregnant women at high risk of preeclampsia., Study Design: We conducted a pilot, multicenter, double-blind, placebo-controlled, randomized trial of women with singleton, nonanomalous pregnancies at high risk for preeclampsia. Women between 12(0/7) and 16(6/7) weeks' gestation were assigned to daily pravastatin 10 mg or placebo orally until delivery. Primary outcomes were maternal-fetal safety and pharmacokinetic parameters of pravastatin during pregnancy. Secondary outcomes included rates of preeclampsia and preterm delivery, gestational age at delivery, birthweight, and maternal and cord blood lipid profile (clinicaltrials.gov identifier NCT01717586)., Results: Ten women assigned to pravastatin and 10 to placebo completed the trial. There were no differences between the 2 groups in rates of study drug side effects, congenital anomalies, or other adverse or serious adverse events. There was no maternal, fetal, or neonatal death. Pravastatin renal clearance was significantly higher in pregnancy compared with postpartum. Four subjects in the placebo group developed preeclampsia compared with none in the pravastatin group. Although pravastatin reduced maternal cholesterol concentrations, umbilical cord cholesterol concentrations and infant birthweight were not different between the groups. The majority of umbilical cord and maternal pravastatin plasma concentrations at the time of delivery were below the lower limit of quantification of the assay. Pravastatin use was associated with a more favorable pregnancy angiogenic profile., Conclusion: This study provides preliminary safety and pharmacokinetic data regarding the use of pravastatin for preventing preeclampsia in high-risk pregnant women. Although the data are preliminary, no identifiable safety risks were associated with pravastatin use in this cohort. This favorable risk-benefit analysis justifies using pravastatin in a larger clinical trial with dose escalation., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Background: Cesarean delivery in the second stage of labor is common, whereas the frequency of operative vaginal delivery has been declining. However, data comparing outcomes for attempted operative vaginal delivery vs cesarean in the second stage are scant. Previous studies that examine operative vaginal delivery have compared it to a baseline risk of complications from a spontaneous vaginal delivery and cesarean delivery. However, when a woman has a need for intervention in the second stage, spontaneous vaginal delivery is not an option she or the provider can choose. Thus, the appropriate clinical comparison is cesarean vs operative vaginal delivery., Objective: Our objective was to compare outcomes by the first attempted operative delivery (vacuum, forceps vs cesarean delivery) in patients needing second-stage assistance at a fetal station of +2 or below., Study Design: We conducted secondary analysis of an observational obstetric cohort in 25 academically affiliated US hospitals over a 3-year period. A subset of ≥37 weeks, nonanomalous, vertex, singletons, with no prior vaginal delivery who reached a station of +2 or below and underwent an attempt at an operative delivery were included. Indications included for operative delivery were: failure to descend, nonreassuring fetal status, labor dystocia, or maternal exhaustion. The primary outcomes included a composite neonatal outcome (death, fracture, length of stay ≥3 days beyond mother's, low Apgar, subgaleal hemorrhage, ventilator support, hypoxic encephalopathy, brachial plexus injury, facial nerve palsy) and individual maternal outcomes (postpartum hemorrhage, third- and fourth-degree tears [severe lacerations], and postpartum infection). Outcomes were examined by the 3 attempted modes of delivery. Odds ratios (OR) were calculated for primary outcomes adjusting for confounders. Final mode of delivery was quantified., Results: In all, 2531 women met inclusion criteria. No difference in the neonatal composite outcome was observed between groups. Vacuum attempt was associated with the lowest frequency of maternal complications (postpartum infection 0.2% vs 0.9% forceps vs 5.3% cesarean, postpartum hemorrhage 1.4% vs 2.8% forceps vs 3.8% cesarean), except for severe lacerations (19.1% vs 33.8% forceps vs 0% cesarean). When confounders were taken into account, both forceps (OR, 0.16; 95% confidence interval, 0.05-0.49) and vacuum (OR, 0.04; 95% confidence interval, 0.01-0.17) were associated with a significantly lower odds of postpartum infection. The neonatal composite and postpartum hemorrhage were not significantly different between modes of attempted delivery. Cesarean occurred in 6.4% and 4.4% of attempted vacuum and forceps groups (P = .04)., Conclusion: In patients needing second-stage delivery assistance with a station of +2 or below, attempted operative vaginal delivery was associated with a lower frequency of postpartum infection, but higher frequency of severe lacerations., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Objective: The objective of the study was to compare the pharmacokinetics of 2 g and 3 g doses of cefazolin when used for perioperative prophylaxis in obese gravidae undergoing cesarean delivery., Study Design: We performed a double-blinded, randomized controlled trial from August 2013 to April 2014. Twenty-six obese women were randomized to receive either 2 or 3 g intravenous cefazolin within 30 minutes of a skin incision. Serial maternal plasma samples were obtained at specific time points up to 8 hours after drug administration. Umbilical cord blood was obtained after placental delivery. Maternal adipose samples were obtained prior to fascial entry, after closure of the hysterotomy, and subsequent to fascial closure. Pharmacokinetic parameters were determined via noncompartmental analysis., Results: The median area under the plasma concentration vs time curve was significantly greater in the 3 g group than in the 2 g group (27204 μg/mL per minute vs 14058 μg/mL per minute; P = .001). Maternal plasma concentrations had an impact by body mass index. For every 1 kg/m(2) increase in body mass index at the time of the cesarean delivery, there was an associated 13.77 μg/mL lower plasma concentration of cefazolin across all time points (P = .01). By the completion of cesarean delivery, cefazolin concentrations in maternal adipose were consistently above the minimal inhibitory concentration for both Gram-positive and Gram-negative bacteria with both the 2 g and 3 g doses. The median umbilical cord blood concentrations were significantly higher in the 3 g vs the 2 g group (34.5 μg/mL and 21.4 μg/mL; P = .003)., Conclusion: Cefazolin concentrations in maternal adipose both at time of hysterotomy closure and fascial closure were above the minimal inhibitory concentration for both Gram-positive and Gram-negative bacteria when either 2 g or 3 g cefazolin was administered as perioperative surgical prophylaxis. Maternal cefazolin concentrations in plasma and maternal adipose tissue are related to both dose and body mass index., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Objective: The purpose of this study was to examine the association between gestational age (GA) at the time of treatment initiation for gestational diabetes mellitus (GDM) and maternal and perinatal outcomes., Study Design: We conducted a secondary analysis of a multicenter randomized treatment trial of mild GDM in which women with mild GDM were assigned randomly to treatment vs usual care. The primary outcome of the original trial, as well as this analysis, was a composite perinatal adverse outcome that included neonatal hypoglycemia, hyperbilirubinemia, hyperinsulinemia, and perinatal death. Other outcomes that were examined included the frequency of large for GA, birthweight, neonatal intensive care unit admission, gestational hypertension/preeclampsia, and cesarean delivery. The interaction between GA at treatment initiation (stratified as 24-26, 27, 28, 29, and ≥30 weeks of gestation) and treatment group (treated vs routine care), with the outcomes of interest, was used to determine whether GA at treatment initiation was associated with outcome differences., Results: Of 958 women whose cases were analyzed, those who initiated treatment at an earlier GA did not gain an additional treatment benefit compared with those who initiated treatment at a later GA (probability value for interaction with the primary outcome, .44). Similarly, there was no evidence that other outcomes were improved significantly by earlier initiation of GDM treatment (large for GA, P = .76; neonatal intensive care unit admission, P = .8; cesarean delivery, P = .82). The only outcome that had a significant interaction between GA and treatment was gestational hypertension/preeclampsia (P = .04), although there was not a clear cut GA trend where this outcome improved with treatment., Conclusion: Earlier initiation of treatment of mild GDM was not associated with stronger effect of treatment on perinatal outcomes., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Objective: We sought to describe the prevalence of serious maternal complications following early preterm birth by gestational age (GA), delivery route, and type of cesarean incision., Study Design: Trained personnel abstracted data from maternal and neonatal charts for all deliveries on randomly selected days representing one third of deliveries across 25 US hospitals over 3 years (n = 115,502). All women delivering nonanomalous singletons between 23-33 weeks' gestation were included. Women were excluded for antepartum stillbirth and highly morbid conditions for which route of delivery would not likely impact morbidity including nonreassuring fetal status, cord prolapse, placenta previa, placenta accreta, placental abruption, and severe and unstable maternal conditions (cardiopulmonary collapse, acute respiratory distress syndrome, seizures). Serious maternal complications were defined as: hemorrhage (blood loss ≥1500 mL, blood transfusion, or hysterectomy for hemorrhage), infection (endometritis, wound dehiscence, or wound infection requiring antibiotics, reopening, or unexpected procedure), intensive care unit admission, or death. Delivery route was categorized as classic cesarean delivery (CCD), low transverse cesarean delivery (LTCD), low vertical cesarean delivery (LVCD), and vaginal delivery. Association of delivery route with complications was estimated using multivariable regression models yielding adjusted relative risks (aRR) controlling for maternal age, race, body mass index, hypertension, diabetes, preterm premature rupture of membranes, preterm labor, GA, and hospital of delivery., Results: Of 2659 women who met criteria for inclusion in this analysis, 8.6% of women experienced serious maternal complications. Complications were associated with GA and were highest between 23-27 weeks of gestation. The frequency of complications was associated with delivery route; compared with 3.5% of vaginal delivery, 23.0% of CCD (aRR, 3.54; 95% confidence interval (CI), 2.29-5.48), 12.1% of LTCD (aRR, 2.59; 95% CI, 1.77-3.77), and 10.3% of LVCD (aRR, 2.27; 95% CI, 0.68-7.55) experienced complications. There was no significant difference in complication rates between CCD and LTCD (aRR, 1.37; 95% CI, 0.95-1.97) or between CCD and LVCD (aRR, 1.56; 95% CI, 0.48-5.07)., Conclusion: The risk of maternal complications after early preterm delivery is substantial, particularly in women who undergo cesarean delivery. Obstetricians need to be prepared to manage potential hemorrhage, infection, and intensive care unit admission for early preterm births requiring cesarean delivery., (Published by Elsevier Inc.)

Objective: The primary aim of the "Nulliparous Pregnancy Outcomes Study: monitoring mothers-to-be" is to determine maternal characteristics, which include genetic, physiologic response to pregnancy, and environmental factors that predict adverse pregnancy outcomes., Study Design: Nulliparous women in the first trimester of pregnancy were recruited into an observational cohort study. Participants were seen at 3 study visits during pregnancy and again at delivery. We collected data from in-clinic interviews, take-home surveys, clinical measurements, ultrasound studies, and chart abstractions. Maternal biospecimens (serum, plasma, urine, cervicovaginal fluid) at antepartum study visits and delivery specimens (placenta, umbilical cord, cord blood) were collected, processed, and stored. The primary outcome of the study was defined as pregnancy ending at <37+0 weeks' gestation. Key study hypotheses involve adverse pregnancy outcomes of spontaneous preterm birth, preeclampsia, and fetal growth restriction., Results: We recruited 10,037 women to the study. Basic characteristics of the cohort at screening are reported., Conclusion: The "Nulliparous Pregnancy Outcomes Study: monitoring mothers-to-be" cohort study methods and procedures can help investigators when they plan future projects., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Objective: The purpose of this study was to compare maternal and neonatal outcomes in nulliparous women with nonmedically indicated inductions at term vs those expectantly treated., Study Design: Data were obtained from maternal and neonatal charts for all deliveries on randomly selected days across 25 US hospitals over a 3-year period. A low-risk subset of nulliparous women with vertex nonanomalous singleton gestations who delivered 38 0/7 to 41 6/7 weeks were selected. Maternal and neonatal outcomes for nonmedically indicated induction within each week were compared with women who did not undergo nonmedically indicated induction during that week. Multivariable analysis was used to adjust for hospital, maternal age, race/ethnicity, body mass index, cigarette use, and insurance status., Results: We found 31,169 women who met our criteria. Neonatal complications were either less frequent with nonmedically indicated induction or no different between groups. Nonmedically indicated induction was associated with less frequent peripartum infections (odds ratio [OR], 0.39; 95% confidence interval [CI], 0.16-0.98) at 38 weeks of gestation and less frequent third- and fourth-degree lacerations (OR, 0.60; 95% CI, 0.42-0.86) and less frequent peripartum infections (OR, 0.66; 95% CI, 0.49-0.90) at 39 weeks of gestation. Nonmedically indicated induction was associated with a longer admission-to-delivery time by approximately 3-4 hours and increased odds of cesarean delivery at 38 (OR, 1.50; 95% CI, 1.08-2.08) and 40 weeks (OR, 1.30; 95% CI, 1.15-1.46) of gestation., Conclusion: At 39 weeks of gestation, nonmedically indicated induction is associated with lower maternal and neonatal morbidity than women who are expectantly treated., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Objective: The purpose of this study was to evaluate the relationship between gestational age (GA) and induction of labor (IOL) and the rate of cesarean delivery in women with mild gestational diabetes mellitus., Study Design: We conducted a secondary analysis of data from a multicenter randomized controlled trial of mild gestational diabetes mellitus treatment. Cesarean delivery rate of women delivering at term (≥37 weeks' gestation) was evaluated by 2 complementary approaches: (1) IOL vs spontaneous labor: women who were induced at each GA compared with those who spontaneously labored at the same GA and (2) IOL vs expectant management: women who delivered after IOL at each GA compared with those who delivered after spontaneous labor at the same GA or subsequently after spontaneous or induced labor (outcome at each week compared with expectant management at that week). Logistic regression adjusted for potential confounders., Results: The overall cesarean delivery rate was 13%. When compared with 39 weeks' gestation (either IOL or spontaneous labor) as the referent, there was no significant difference in the cesarean delivery rate in women who delivered at 37, 38, or 40 weeks' gestation. However, IOL was associated with a 3-fold increase in cesarean delivery rate at 41 weeks' gestation and beyond, as compared with IOL at 39 weeks' gestation. Similarly, there was a 3-fold increase in the cesarean delivery rate in women who were induced when compared with those who were treated expectantly at 40 completed weeks' gestation., Conclusion: Induction of labor in women with mild gestational diabetes mellitus does not increase the rate of cesarean delivery at <40 weeks' gestation., (Copyright © 2014 Mosby, Inc. All rights reserved.)

Objective: The purpose of this study was to determine whether hospital differences in the frequency of adverse obstetric outcomes are related to differences in care., Study Design: The Assessment of Perinatal EXcellence cohort comprises 115,502 women and their neonates who were born in 25 hospitals in the United States between March 2008 and February 2011. Hierarchical logistic regression was used to quantify the amount of variation in postpartum hemorrhage, peripartum infection, severe perineal laceration, and a composite adverse neonatal outcome among hospitals that is explained by differences in patient characteristics, hospital characteristics, and obstetric care provided., Results: The study included 115,502 women. For most outcomes, 20-40% of hospital differences in outcomes were related to differences in patient populations. After adjusting for patient-, provider-, and hospital-level factors, multiple care processes were associated with the predefined adverse outcomes; however, these care processes did not explain significant variation in the frequency of adverse outcomes among hospitals. Ultimately, 50-100% of the interhospital variation in outcomes was unexplained., Conclusion: Hospital differences in the frequency of adverse obstetric outcomes could not be explained by differences in frequency of types of care provided., (Copyright © 2014 Mosby, Inc. All rights reserved.)

Objective: 17-alpha hydroxyprogesterone caproate 250 mg weekly reduces recurrent spontaneous preterm birth in women with a prior spontaneous preterm birth by 33%. The dose is not based on pharmacologic considerations. A therapeutic concentration has not been determined hampering any attempt to optimize treatment. This study evaluated the relationship between 17-alpha hydroxyprogesterone caproate plasma concentrations and the rate of spontaneous preterm birth in women with singleton gestation., Study Design: A single blood sample was obtained between 25 and 28 weeks' gestation from 315 women with a spontaneous preterm birth who participated in a placebo-controlled, prospective, randomized clinical trial evaluating the benefit of omega-3 supplementation in reducing preterm birth. All women in the parent study received 17-alpha hydroxyprogesterone caproate and 434 received omega-3 supplementation and 418 received a placebo. Plasma from 315 consenting women was analyzed for 17-alpha hydroxyprogesterone caproate concentration., Results: There were no differences between placebo and omega-3 supplemented groups in demographic variables, outcomes or in mean 17-alpha hydroxyprogesterone caproate concentration. Plasma concentrations of 17-alpha hydroxyprogesterone caproate ranged from 3.7-56 ng/mL. Women with plasma concentrations of 17-alpha hydroxyprogesterone caproate in the lowest quartile had a significantly higher risk of spontaneous preterm birth (P = .03) and delivered at significantly earlier gestational ages (P = .002) than did women in the second to fourth quartiles. The lowest preterm birth rates were seen when median 17-alpha hydroxyprogesterone caproate concentrations exceeded 6.4 ng/mL., Conclusion: Low plasma 17-alpha hydroxyprogesterone caproate concentration is associated with an increased risk of spontaneous preterm birth. This finding validates efficacy of this treatment but suggests that additional studies are needed to determine the optimal dosage., (Copyright © 2014 Mosby, Inc. All rights reserved.)

Objective: The purpose of this study was to evaluate the quality of compounded 17-hydroxyprogesterone caproate (17-OHPC)., Study Design: Compounded 17-OHPC that was obtained from 15 compounding pharmacies throughout the United States was analyzed for potency, impurities, sterility, and pyrogen status., Results: Eighteen samples were supplied by 15 compounding pharmacies. The concentration of 17-OHPC in all samples was within the specification limits, and all tested samples passed sterility and pyrogen testing. Only 1 of 18 samples was out of specification limits for impurities., Conclusion: Compounded 17-OHPC that was obtained from 15 pharmacies throughout the United States did not raise safety concerns when assessed for potency, sterility, pyrogen status, or impurities., (Copyright © 2014 Mosby, Inc. All rights reserved.)

Objective: Regulatory bodies and insurers evaluate hospital quality using obstetrical outcomes, however meaningful comparisons should take preexisting patient characteristics into account. Furthermore, if risk-adjusted outcomes are consistent within a hospital, fewer measures and resources would be needed to assess obstetrical quality. Our objective was to establish risk-adjusted models for 5 obstetric outcomes and assess hospital performance across these outcomes., Study Design: We studied a cohort of 115,502 women and their neonates born in 25 hospitals in the United States from March 2008 through February 2011. Hospitals were ranked according to their unadjusted and risk-adjusted frequency of venous thromboembolism, postpartum hemorrhage, peripartum infection, severe perineal laceration, and a composite neonatal adverse outcome. Correlations between hospital risk-adjusted outcome frequencies were assessed., Results: Venous thromboembolism occurred too infrequently (0.03%; 95% confidence interval [CI], 0.02-0.04%) for meaningful assessment. Other outcomes occurred frequently enough for assessment (postpartum hemorrhage, 2.29%; 95% CI, 2.20-2.38, peripartum infection, 5.06%; 95% CI, 4.93-5.19, severe perineal laceration at spontaneous vaginal delivery, 2.16%; 95% CI, 2.06-2.27, neonatal composite, 2.73%; 95% CI, 2.63-2.84). Although there was high concordance between unadjusted and adjusted hospital rankings, several individual hospitals had an adjusted rank that was substantially different (as much as 12 rank tiers) than their unadjusted rank. None of the correlations between hospital-adjusted outcome frequencies was significant. For example, the hospital with the lowest adjusted frequency of peripartum infection had the highest adjusted frequency of severe perineal laceration., Conclusion: Evaluations based on a single risk-adjusted outcome cannot be generalized to overall hospital obstetric performance., (Copyright © 2013 Mosby, Inc. All rights reserved.)

Objective: Lipoproteins are associated with atherogenic and inflammatory processes, and these processes may be related to adverse pregnancy outcomes. We therefore examined whether variations in lipoprotein particle size and concentration are associated with preterm birth (PTB) <35 weeks' gestation., Study Design: This is a case-control ancillary study to a randomized trial of omega-3 fatty acid supplementation to prevent recurrent PTB. We measured standard lipids and used nuclear magnetic resonance (NMR) spectroscopy to characterize 17 lipoprotein particles from plasma collected at the baseline randomization visit (16-21 weeks' gestation) in 128 cases (PTB <35 weeks' gestation) and 132 term controls. Logistic regression models controlled for study center, race/ethnicity, number of prior PTB, smoking, and treatment group, as well as total low-density lipoprotein (LDL), high-density lipoprotein, and triglyceride concentrations when examining LDLNMR, high-density lipoproteinNMR, and very LDL (VLDL)NMR, respectively., Results: Only 1 of the 17 NMR lipoproteins was associated with recurrent PTB. We observed an increased odds of recurrent PTB of 1.04 (95% confidence interval, 1.01-1.08; P = .02) per nanometer increase in VLDLNMR particle size and an odds ratio of 3.00 (confidence interval, 1.40-6.43; P = .005) for the third tertile of VLDLNMR particle size compared with the first tertile., Conclusion: In women with prior PTB, variations in midpregnancy lipoproteins were not associated with recurrent PTB overall, however the association observed with VLDLNMR particle size is suggestive that PTB may be amenable to lifestyle, nutritional, or pharmacologic interventions., (Copyright © 2013 Mosby, Inc. All rights reserved.)

Objective: Adherence to published criteria for transvaginal imaging and measurement of cervical length is uncertain. We sought to assess adherence by evaluating images submitted to certify research sonographers for participation in a clinical trial., Study Design: We reviewed qualifying test results of sonographers seeking certification to image and measure cervical length in a clinical trial. Participating sonographers were required to access training materials and submit 15 images, 3 each from 5 pregnant women not enrolled in the trial. One of 2 sonologists reviewed all qualifying images. We recorded the proportion of images that did not meet standard criteria (excess compression, landmarks not seen, improper image size, or full maternal bladder) and the proportion in which the cervical length was measured incorrectly. Failure for a given patient was defined as >1 unacceptable image, or >2 acceptable images with incorrect caliper placement or erroneous choice of the "shortest best" cervical length. Certification required satisfactory images and cervical length measurement from ≥4 patients., Results: A total of 327 sonographers submitted 4905 images. A total of 271 sonographers (83%) were certified on the first, 41 (13%) on the second, and 2 (0.6%) on the third submission. Thirteen never achieved certification. Of 314 who passed, 196 submitted 15 acceptable images that were appropriately measured for all 5 women. There were 1277 deficient images: 493 were acceptable but incorrectly measured images from sonographers who passed certification because mismeasurement occurred no more than twice. Of 784 deficient images submitted by sonographers who failed the certification, 471 were rejected because of improper measurement (caliper placement and/or failure to identify the shortest best image), and 313 because of failure to obtain a satisfactory image (excessive compression, required landmarks not visible, incorrect image size, brief examination, and/or full maternal bladder)., Conclusion: Although 83% of sonographers were certified on their first submission, >1 in 4 ultrasound images submitted did not meet published quality criteria. Increased attention to standardized education and credentials is warranted for persons who perform ultrasound examinations of the cervix in pregnancy., (Copyright © 2013 Mosby, Inc. All rights reserved.)

Objective: The purpose of this study was to estimate a gestational age threshold at which the benefits of treatment with weekly courses of antenatal corticosteroids (ACS) during preterm labor outweigh the risks., Study Design: Risk-benefit ratios by gestational age were determined with the use of a Markov microsimulation decision-analysis model with a 1-week cycle length. Single course and multiple (weekly to a maximum of 4) courses of ACS by gestational age of entry (23 weeks to 31 weeks 6 days' gestation) were compared. Benefits were composite events (respiratory distress syndrome, chronic lung disease, severe intraventricular hemorrhage, periventricular leukomalacia, bronchopulmonary dysplasia, or stillbirth) averted. Risks were small head circumference and small for gestational age., Results: More composite events are averted (benefits) than risks acquired (ratio, 6:1) when multiple courses of ACS are initiated at 26 weeks' gestation. When multiple courses of ACS are initiated at 29 weeks' gestation, the risk-benefit ratio is 1. Beyond 29 weeks, there is a suggestion of more risk than benefit., Conclusion: The model suggests that multiple courses of ACS that are initiated at <29 weeks' gestation may have increased benefit compared with risks. Further analyses are needed to determine the long-term clinical significance of these findings., (Copyright © 2013 Mosby, Inc. All rights reserved.)

Objective: The objective of the study was to determine whether an individualized growth standard (IS) improves the identification of preterm small-for-gestational-age (SGA) neonates at risk of developing moderate/severe cerebral palsy (CP) or death., Study Design: This study was a secondary analysis of data from a randomized trial of MgSO4 for the prevention of CP or death among anticipated preterm births. Singleton nonanomalous liveborns delivered before 34 weeks' were classified as SGA (less than the 10th percentile for their gestational age) by a population standard (PS) or an IS (incorporating maternal age, height, weight, parity, race/ethnicity, and neonatal sex). The primary outcome was the prediction of moderate or severe CP or death by age 2 years., Results: Of 1588 eligible newborns, 143 (9.4%) experienced CP (n = 33) or death (n = 110). Forty-four (2.8%) were SGA by the PS and 364 (22.9%) by the IS. All PS-SGA newborns also were identified as IS-SGA. SGA newborns by either standard had a similarly increased risk of CP or death (PS: relative risk [RR], 2.4, 95% confidence interval [CI], 1.3-4.3 vs IS: RR, 1.8, 95% CI, 1.3-2.5, respectively). The similarity of RRs remained after stratification by the MgSO4 treatment group. The IS was more sensitive (36% vs 6%, P < .001) but less specific (78% vs 98%, P < .001) for CP or death. The receiver operating characteristic curve analysis revealed a statistically lower area under the curve for the PS, although the ability of either method to predict which neonates would subsequently develop CP or death was poor (PS: 0.55, 95% CI, 0.49-0.60 vs IS: 0.59, 95% CI, 0.54-0.64, P < .001)., Conclusion: An individualized SGA growth standard does not improve the association with, or prediction of, CP or death by age 2 years., (Copyright © 2013 Mosby, Inc. All rights reserved.)

Objective: 17-alpha hydroxyprogesterone caproate (17-OHPC) is available both as an Food and Drug Administration (FDA)-approved medication and as a product prepared for individual patients by compounding pharmacies. Compounding pharmacies may omit the preservative that is used in the FDA-approved formulation or use an alternate preservative and may dispense 17-OHPC in containers that differ from the FDA-approved product. The objective of this study was to assess the stability and the microbiologic and pyrogen status of 17-OHPC formulations under various compounding and dispensing conditions., Study Design: 17-OHPC was prepared by a local compounding pharmacy. The formulations that were prepared included 1 identical to the FDA-approved product with benzyl alcohol as a preservative, 1 with benzalkonium chloride as a preservative, and 1 without a preservative. These various formulations were dispensed into either single-dose 1-mL plastic syringes or glass vials or 10-mL glass vials. The concentration of 17-OHPC and microbial and pyrogen status were evaluated at various time intervals over the ensuing 19 weeks., Results: The concentration of 17-OHPC did not change over the duration of study, regardless of the dispensing medium that was used or the absence or presence of any preservatives. The preparations remained microbe- and pyrogen-free during the study period, regardless of the dispensing medium that was used or the absence of presence of any preservatives., Conclusion: Products that contained 17-OHPC tested in this study were quite stable over the 19-week period of study in different dispensing containers and in the absence or presence of a different preservative. The compounded products remained sterile and pyrogen-free during the period of observation., (Copyright © 2013 Mosby, Inc. All rights reserved.)

Objective: We sought to evaluate whether 17 alpha-hydroxyprogesterone caproate (17-OHP) reduces preterm birth (PTB) in nulliparous women with a midtrimester cervical length (CL) <30 mm., Study Design: In this multicenter randomized controlled trial, nulliparous women with a singleton gestation between 16 and 22 3/7 weeks with an endovaginal CL <30 mm (<10th percentile in this population) were randomized to weekly intramuscular 17-OHP (250 mg) or placebo through 36 weeks. The primary outcome was PTB <37 weeks., Results: The frequency of PTB did not differ between the 17-OHP (n = 327) and placebo (n = 330) groups (25.1% vs 24.2%; relative risk, 1.03; 95% confidence interval, 0.79-1.35). There also was no difference in the composite adverse neonatal outcome (7.0% vs 9.1%; relative risk, 0.77; 95% confidence interval, 0.46-1.30)., Conclusion: Weekly 17-OHP does not reduce the frequency of PTB in nulliparous women with a midtrimester CL <30 mm., (Copyright © 2012 Mosby, Inc. All rights reserved.)

Objective: The purpose of this study was to estimate pharmacokinetic parameters and to evaluate placental transport of 17-hydroxyprogesterone caproate (17-OHPC) in singleton gestation., Study Design: Sixty-one women who received weekly injections of 17-OHPC underwent 2 pharmacokinetic studies at 20 + 0 to 24 + 6 weeks' gestation (study 1) and 31 + 0 to 34 + 6 weeks' gestation (study 2); daily blood samples were obtained between injections. In 18 women, blood samples were obtained over a 28-day period beyond the last injection (extended study). Maternal and/or cord blood were obtained at delivery., Results: The half-life (median ± SD) of 17-OHPC was 16.2 ± 6 days. Concentrations of 17-OHPC were higher during study 2 than during study 1. Body mass index affected maternal 17-OHPC concentrations. Cord:maternal 17-OHPC concentration ratios averaged 0.2; 17-OHPC was detectible in cord plasma 44 days after the last maternal injection., Conclusion: The apparent half-life of 17-OHPC is long, and pharmacokinetic parameters vary widely between subjects and are affected by maternal body mass index. The drug crosses the placental barrier., (Copyright © 2012 Mosby, Inc. All rights reserved.)

Objective: We sought to evaluate in women with twin gestation the relationship between 17-hydroxyprogesterone caproate (17-OHPC) concentration and gestational age at delivery and select biomarkers of potential pathways of drug action., Study Design: Blood was obtained between 24-28 weeks (epoch 1) and 32-35 weeks (epoch 2) in 217 women with twin gestation receiving 17-OHPC or placebo. Gestational age at delivery and concentrations of 17-OHPC, 17-hydroxyprogesterone, progesterone, C-reactive protein (CRP), and corticotrophin-releasing hormone were assessed., Results: Women with higher concentrations of 17-OHPC delivered at earlier gestational ages than women with lower concentrations (P < .001). Women receiving 17-OHPC demonstrated significantly higher (P = .005) concentrations of CRP in epoch 1 than women receiving placebo but CRP values were similar in epoch 2 in both groups. A highly significant (P < .0001) positive relationship was observed between 17-OHPC concentration and progesterone and 17-hydroxyprogesterone concentrations at both epochs. Corticotropin-releasing hormone concentrations did not differ by treatment group., Conclusion: 17-OHPC may adversely impact gestational age at delivery in women with twin gestation., (Copyright © 2012 Mosby, Inc. All rights reserved.)

Objective: We evaluated whether improvements in pregnancy outcomes after treatment of mild gestational diabetes mellitus differed in magnitude on the basis of fetal gender., Study Design: This is a secondary analysis of a masked randomized controlled trial of treatment for mild gestational diabetes mellitus. The results included preeclampsia or gestational hypertension, birthweight, neonatal fat mass, and composite adverse outcomes for both neonate (preterm birth, small for gestational age, or neonatal intensive care unit admission) and mother (labor induction, cesarean delivery, preeclampsia, or gestational hypertension). After stratification according to fetal gender, the interaction of gender with treatment status was estimated for these outcomes., Results: Of the 469 pregnancies with male fetuses, 244 pregnancies were assigned randomly to treatment, and 225 pregnancies were assigned randomly to routine care. Of the 463 pregnancies with female fetuses, 233 pregnancies were assigned randomly to treatment, and 230 pregnancies were assigned randomly to routine care. The interaction of gender with treatment status was significant for fat mass (P = .04) and birthweight percentile (P = .02). Among women who were assigned to the treatment group, male offspring were significantly more likely to have both a lower birthweight percentile (50.7 ± 29.2 vs 62.5 ± 30.2 percentile; P < .0001) and less neonatal fat mass (487 ± 229.6 g vs 416.6 ± 172.8 g; P = .0005,) whereas these differences were not significant among female offspring. There was no interaction between fetal gender and treatment group with regard to other outcomes., Conclusion: The magnitude of the reduction of a newborn's birthweight percentile and neonatal fat mass that were related to the treatment of mild gestational diabetes mellitus appears greater for male neonates., (Copyright © 2012. Published by Mosby, Inc.)

Objective: The purpose of this study was to determine outcomes, after the use of propensity score techniques, to create balanced groups according to whether a woman undergoes elective repeat cesarean delivery (ERCD) or trial of labor (TOL)., Study Design: Women who were eligible for a TOL with 1 previous low transverse incision were categorized according to whether they underwent an ERCD or TOL. A propensity score technique was used to develop ERCD and TOL groups with comparable baseline characteristics. Outcomes were assessed with conditional logistic regression., Results: The rates of endometritis, operative injury, respiratory distress syndrome, and newborn infant infection were lower and the rates of hysterectomy and wound complication were higher in the ERCD group., Conclusion: Propensity score techniques can be used to generate comparable ERCD and TOL groups. Some types of maternal morbidity (such as hysterectomy) are higher; other types (such as operative injury) are lower in the ERCD group. Although the absolute risk is low, neonatal morbidity appears to be lower in the ERCD group., (Copyright © 2012 Mosby, Inc. All rights reserved.)

Objective: The objective of the study was to compare pregnancy outcomes by completed week of gestation after 39 weeks with outcomes at 39 weeks., Study Design: Secondary analysis of a multicenter trial of fetal pulse oximetry in spontaneously laboring or induced nulliparous women at a gestation of 36 weeks or longer. Maternal outcomes included a composite (treated uterine atony, blood transfusion, and peripartum infections) and cesarean delivery. Neonatal outcomes included a composite of death, neonatal respiratory and other morbidities, and neonatal intensive care unit admission., Results: Among the 4086 women studied, the risks of the composite maternal outcome (P value for trend < .001), cesarean delivery (P < .001), and composite neonatal outcome (P = .047) increased with increasing gestational age from 39 to 41 or more completed weeks. Adjusted odds ratios (95% confidence interval) for 40 and 41 or more weeks, respectively, compared with 39 weeks were 1.29 (1.03-1.64) and 2.05 (1.60-2.64) for composite maternal outcome, 1.28 (1.05-1.57) and 1.75 (1.41-2.16) for cesarean delivery, and 1.25 (0.86-1.83) and 1.37 (0.90-2.09) for composite neonatal outcome., Conclusion: Risks of maternal morbidity and cesarean delivery but not neonatal morbidity increased significantly beyond 39 weeks., (Copyright © 2012 Mosby, Inc. All rights reserved.)