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Fetal electrocardiogram (ECG) ST changes are associated with fetal cardiac hypoxia. Our objective was to evaluate ST changes by maternal diabetic status and stage of labor. This was a secondary analysis of a multicentered randomized-controlled trial in which laboring patients with singleton gestations underwent fetal ECG scalp electrode placement and were randomly assigned to masked or unmasked ST-segment readings. Our primary outcome was the frequency of fetal ECG tracings with ST changes by the stage of labor. ECG tracings were categorized into mutually exclusive groups (ST depression, ST elevation without ST depression, or no ST changes). We compared participants with DM, gestational diabetes mellitus (GDM), and no DM. Of the 5,436 eligible individuals in the first stage of labor (95 with pregestational DM and 370 with GDM), 4,427 progressed to the second stage. ST depression occurred more frequently in the first stage of labor in participants with pregestational DM (15%, adjusted odds ratio [aOR] 2.20, 95% confidence interval [CI] 1.14-4.24) and with GDM (9.5%, aOR 1.51, 95% CI 1.02-2.25) as compared with participants without DM (5.7%). The frequency of ST elevation was similar in participants with pregestational DM (33%, aOR 0.79, 95% CI 0.48-1.30) and GDM (33.2%, aOR 0.91, 95% CI 0.71-1.17) as compared with those without DM (34.2%). In the second stage, ST depression did not occur in participants with pregestational DM (0%) and occurred more frequently in participants with GDM (3.5%, aOR 2.01, 95% CI 1.02-3.98) as compared with those without DM (2.0%). ST elevation occurred more frequently in participants with pregestational DM (30%, aOR 1.81, 95% CI 1.02-3.22) but not with GDM (19.0%, aOR 1.06, 95% CI 0.77-1.47) as compared with those without DM (17.8%). ST changes in fetal ECG occur more frequently in fetuses of diabetic mothers during labor.gov number, NCT01131260. ST changes in fetal ECG, a marker of fetal cardiac hypoxia, occur more frequently in fetuses of diabetic parturients.· Fetal hypertrophic cardiomyopathy (HCM) and cardiac dysfunction occur frequently among fetuses of diabetic patients.. · Fetal ECG changes such as ST elevation and depression reflect cardiac hypoxia.. · Fetuses of diabetic patients demonstrate a higher prevalence of fetal ECG tracings with ST changes..

OBJECTIVE To compare maternal and neonatal outcomes after preterm prelabor rupture of membranes (PROM) from 23 to 34 weeks of gestation in twin compared with singleton gestations. METHODS We conducted a secondary analysis of an obstetric cohort of 115,502 individuals and their singleton or twin neonates born in 25 hospitals nationwide (2008-2011). Those with preterm PROM from 23 0/7 through 33 6/7 weeks of gestation were included; neonates with major fetal anomalies were excluded. The coprimary outcomes for this analysis were composite maternal morbidity (chorioamnionitis, blood transfusion, postpartum endometritis, wound infection, sepsis, venous thromboembolism, intensive care unit admission, or death) and composite major neonatal morbidity (persistent pulmonary hypertension, intraventricular hemorrhage grade III or IV, seizures, hypoxic-ischemic encephalopathy, necrotizing enterocolitis stage II or III, bronchopulmonary dysplasia, stillbirth subsequent to admission, or neonatal death before discharge). Logistic regression was used to estimate unadjusted and adjusted odds ratios (ORs) with 95% CIs for twin compared with singleton gestations. RESULTS Of 1,531 (1.3%) individuals who met eligibility criteria for this analysis, 218 (14.2%) had twin gestations. The median gestational age at preterm PROM was similar between those with twins and singletons (31.2 weeks [interquartile range 27.4-32.9] vs 30.6 weeks [interquartile range 26.9-32.7], P=.23); however, those with twin gestations had a shorter median latency period (2.0 days [interquartile range 1.0-5.0] vs 3.0 days [interquartile range 2.0-8.0], P

Objective To evaluate intrapartum resuscitation interventions and improvement in category II fetal heart rate (FHR) tracings. Methods This secondary analysis of a randomized trial of intrapartum fetal electrocardiographic ST-segment analysis included all participants with category II FHR tracings undergoing intrauterine resuscitation: maternal oxygen, intravenous fluid bolus, amnioinfusion, or tocolytic administration. Fetal heart rate pattern-recognition software was used to confirm category II FHR tracings 30 minutes before intervention and to analyze the subsequent 60 minutes. The primary outcome was improvement to category I within 60 minutes. Secondary outcomes included FHR tracing improvement to category I 30-60 minutes after the intervention and composite neonatal outcome. Results Of 11,108 randomized participants, 2,251 (20.3%) had at least one qualifying intervention for category II FHR tracings: 63.7% improved to category I within 60 minutes and 50.5% improved at 30-60 minutes. Only 3.4% underwent cesarean delivery and 4.1% an operative vaginal delivery for nonreassuring fetal status within 60 minutes after the intervention. Oxygen administration was the most common intervention (75.4%). Among American College of Obstetricians and Gynecologists-defined subgroups that received oxygen, the absent FHR accelerations and absent-minimal FHR variability subgroup (n=332) was more likely to convert to category I within 60 minutes than the FHR accelerations or "moderate FHR variability" subgroup (n=1,919) (77.0% vs 63.0%, odds ratio [OR] 2.0, 95% CI 1.4-2.7). The incidence of composite neonatal adverse outcome for category II tracings was 2.9% (95% CI 2.2-3.7%) overall; 2.8% (95% CI 2.0-3.8%) for improvement to category I within 60 minutes (n=1,433); and 3.2% (95% CI 2.1-4.6%) for no improvement within 60 minutes (n=818). However, the group with improvement had 29% lower odds for higher level neonatal care (11.8% vs 15.9%, OR 0.71, 95% CI 0.55-0.91). Conclusion Nearly two thirds of category II FHR tracings improved to category I within 60 minutes of intervention with a relatively low overall rate of the composite neonatal adverse outcome. Funding source Funded in part by Neoventa Medical.

Objective Administration of antenatal corticosteroids (ANCS) is recommended for individuals expected to deliver between 24 and 34 weeks of gestation. Properly timed administration of ANCS achieves maximal benefit. However, more than 50% of individuals receive ANCS outside the recommended window. This study aimed to examine maternal and hospital factors associated with suboptimal receipt of ANCS among individuals who deliver between 24 and 34 weeks of gestation. Study Design Secondary analysis of the Assessment of Perinatal Excellence (APEX), an observational study of births to 115,502 individuals at 25 hospitals in the United States from March 2008 to February 2011, was conducted. Data from 3,123 individuals who gave birth to a nonanomalous live-born infant between 240/7 to 340/7 weeks of gestation, had prenatal records available at delivery, and data available on the timing of ANCS use were included in this analysis. Eligible individuals' ANCS status was categorized as optimal (full course completed >24 hours after ANCS but not >7 days before birth) or suboptimal (none, too late, or too early). Maternal and hospital-level variables were compared using optimal as the referent group. Hierarchical multinomial logistic regression models, with site as a random effect, were used to identify maternal and hospital-level characteristics associated with optimal ANCS use. Results Overall, 83.6% (2,612/3,123) of eligible individuals received any treatment: 1,216 (38.9%) optimal and 1,907 (61.1%) suboptimal. Within suboptimal group, 495 (15.9%) received ANCS too late, 901 (28.9%) too early, and 511 (16.4%) did not receive any ANCS. Optimal ANCS varied depending on indication for hospital admission (p Conclusion Optimal ANCS use varied by maternal and hospital factors and by hospital site, indicating opportunities for improvement. Key Points

Aims Indomethacin is used for the treatment of preterm labour, short cervices and idiopathic polyhydramnios during pregnancy. Few studies have described the pharmacokinetics (PK) of indomethacin during pregnancy. This study aimed to determine maternal and fetal PK of indomethacin during different trimesters of pregnancy using physiologically based PK (PBPK) modelling and simulations. Methods Full PBPK simulations were performed in nonpregnant subjects and pregnant subjects from each trimester of pregnancy at steady state using Simcyp's healthy volunteers and pregnancy PBPK model, respectively. The fetal exposures were predicted using a fetoplacental pregnancy PBPK model. The models were verified by comparing PBPK-based predictions with observed PK profiles. Results Predicted exposure (AUC0-6h ) and clearance of indomethacin in nonpregnant women and pregnant women are similar to the clinical observations. AUC0-6h of indomethacin is approximately 14, 24 and 32% lower, consistent with 18, 34 and 52% higher clearance in the first, second and third trimesters of pregnancy, respectively, compared to nonpregnant women. Predicted fetal plasma exposures increased by approximately 30% from the second trimester to the third trimester of pregnancy. Conclusion A mechanistic PBPK model adequately described the maternal and the fetal PK of indomethacin during pregnancy. As the pregnancy progresses, a modest decrease (≤32%) in systemic exposures in pregnant women and a 33% increase in fetal exposures to indomethacin were predicted. Higher fetal exposures in the third trimester of pregnancy may pose safety risks to the fetus. Additional studies are warranted to understand the exposure-response relationship and provide appropriate dosing recommendations during pregnancy that consider both safety and efficacy.

Objective In the antenatal late preterm steroids (ALPS) trial betamethasone significantly decreased short-term neonatal respiratory morbidity but increased the risk of neonatal hypoglycemia, diagnosed only categorically ( Study Design Secondary analysis of infants from ALPS, a multicenter trial randomizing women at risk for late preterm delivery to betamethasone or placebo. This study was a reabstraction of all available charts from the parent trial, all of which were requested. Unreviewed charts included those lost to follow-up or from sites not participating in the reabstraction. Duration of hypoglycemia ( Results Of 2,831 randomized, 2,609 (92.2%) were included. There were 387 (29.3%) and 223 (17.3%) with hypoglycemia in the betamethasone and placebo groups, respectively (relative risk [RR]: 1.69, 95% confidence interval [CI]: 1.46–1.96). Hypoglycemia generally occurred in the first 24 hours in both groups: 374/385 (97.1%) in the betamethasone group and 214/222 (96.4%) in the placebo group (p = 0.63). Of 387 neonates with hypoglycemia in the betamethasone group, 132 (34.1%) received treatment, while 73/223 (32.7%) received treatment in placebo group (p = 0.73). The lowest recorded blood sugar was similar between groups. Most hypoglycemia resolved by 24 hours in both (93.0 vs. 89.3% in the betamethasone and placebo groups, respectively, p = 0.18). Among infants with hypoglycemia in the first 24 hours, the time to resolution was shorter in the betamethasone group (2.80 [interquartile range: 2.03–7.03) vs. 3.74 (interquartile range: 2.15–15.08) hours; p = 0.002]. Persistence for >72 hours was rare and similar in both groups, nine (2.4%, betamethasone) and four (1.9%, placebo, p = 0.18). Conclusion In this cohort, hypoglycemia was transient and most received no treatment, with a quicker resolution in the betamethasone group. Prolonged hypoglycemia was uncommon irrespective of steroid exposure. Key Points

BACKGROUND: Preterm birth is a global health priority. Using a progestogen during high-risk pregnancy could reduce preterm birth and adverse neonatal outcomes.METHODS: We did a systematic review of randomised trials comparing vaginal progesterone, intramuscular 17-hydroxyprogesterone caproate (17-OHPC), or oral progesterone with control, or with each other, in asymptomatic women at risk of preterm birth. We identified published and unpublished trials that completed primary data collection before July 30, 2016, (12 months before data collection began), by searching MEDLINE, Embase, CINAHL, the Maternity and Infant Care Database, and relevant trial registers between inception and July 30, 2019. Trials of progestogen to prevent early miscarriage or immediately-threatened preterm birth were excluded. Individual participant data were requested from investigators of eligible trials. Outcomes included preterm birth, early preterm birth, and mid-trimester birth. Adverse neonatal sequelae associated with early births were assessed using a composite of serious neonatal complications, and individually. Adverse maternal outcomes were investigated as a composite and individually. Individual participant data were checked and risk of bias assessed independently by two researchers. Primary meta-analyses used one-stage generalised linear mixed models that incorporated random effects to allow for heterogeneity across trials. This meta-analysis is registered with PROSPERO, CRD42017068299.FINDINGS: Initial searches identified 47 eligible trials. Individual participant data were available for 30 of these trials. An additional trial was later included in a targeted update. Data were therefore available from a total of 31 trials (11 644 women and 16185 offspring). Trials in singleton pregnancies included mostly women with previous spontaneous preterm birth or short cervix. Preterm birth before 34 weeks was reduced in such women who received vaginal progesterone (nine trials, 3769 women; relative risk [RR] 0·78, 95% CI 0·68-0·90), 17-OHPC (five trials, 3053 women; 0·83, 0·68-1·01), and oral progesterone (two trials, 181 women; 0·60, 0·40-0·90). Results for other birth and neonatal outcomes were consistently favourable, but less certain. A possible increase in maternal complications was suggested, but this was uncertain. We identified no consistent evidence of treatment interaction with any participant characteristics examined, although analyses within subpopulations questioned efficacy in women who did not have a short cervix. Trials in multifetal pregnancies mostly included women without additional risk factors. For twins, vaginal progesterone did not reduce preterm birth before 34 weeks (eight trials, 2046 women: RR 1·01, 95% CI 0·84-1·20) nor did 17-OHPC for twins or triplets (eight trials, 2253 women: 1·04, 0·92-1·18). Preterm premature rupture of membranes was increased with 17-OHPC exposure in multifetal gestations (rupture INTERPRETATION: Vaginal progesterone and 17-OHPC both reduced birth before 34 weeks' gestation in high-risk singleton pregnancies. Given increased underlying risk, absolute risk reduction is greater for women with a short cervix, hence treatment might be most useful for these women. Evidence for oral progesterone is insufficient to support its use. Shared decision making with woman with high-risk singleton pregnancies should discuss an individual's risk, potential benefits, harms and practicalities of intervention. Treatment of unselected multifetal pregnancies with a progestogen is not supported by the evidence.FUNDING: Patient-Centered Outcomes Research Institute.

Major depressive disorder (MDD) is a common disorder in pregnancy. Although sertraline is the most frequently prescribed antidepressant for pregnant people in the United States, limited information about its pharmacokinetics in pregnancy is available. Our objectives were to characterize plasma sertraline concentration to dose (C/D) ratios across pregnancy and postpartum and investigate the effect of pharmacogenetic variability on sertraline elimination. We performed a prospective observational cohort study in people with a singleton pregnancy ≤ 18 weeks gestation and a lifetime diagnosis of MDD at the 3 Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)-funded Obstetrical-Fetal Pharmacology Research Center sites. Subjects (N = 47) were receiving maintenance sertraline therapy and chose to continue it during pregnancy. Blood samples were obtained 24-hours postdose every 4 weeks across pregnancy and twice postpartum for measurement of plasma concentrations of sertraline and desmethylsertraline. Overall mean sertraline C/D ratios were decreased at study onset and remained consistently low until after delivery. During the last 4 weeks of pregnancy the mean sertraline C/D ratio (95% confidence interval (CI)), 0.25 (95% CI, 0.19, 0.3) ng/mL/dose (mg/day), was smaller than the mean ratio at ≥ 8 weeks after delivery, 0.32 (95% CI, 0.27, 0.37) ng/mL/dose (mg/day), a 22% difference. Mean sertraline/desmethylsertraline ratios were highest after birth, which confirmed increased sertraline elimination during pregnancy. Sertraline C/D ratios in participants with functional CYP2C19 activity did not change significantly during pregnancy, whereas ratios in participants with poor or intermediate CYP2C19 activity decreased by 51%. Exploratory pharmacogenomic analysis indicated that pregnant people with poor or intermediate CYP2C19 activity are at risk for subtherapeutic sertraline concentrations during pregnancy.

Objective This study aimed to assess the association of maternal body mass index (BMI) with a composite of severe maternal outcomes. Study Design Secondary analysis of a cohort of deliveries on randomly selected days at 25 hospitals from 2008 to 2011. Data on comorbid conditions, intrapartum events, and postpartum course were collected. The reference group (REF, BMI: 18.5–29.9kg/m2), obese (OB; BMI: 30–39.9kg/m2), morbidly obese (MO; BMI: 40–49.9kg/m2), and super morbidly obese (SMO; BMI ≥ 50kg/m2) women were compared. The composite of severe maternal outcomes was defined as death, intensive care unit (ICU) admission, ventilator use, deep venous thrombosis/pulmonary embolus (DVT/PE), sepsis, hemorrhage, disseminated intravascular coagulation (DIC), unplanned operative procedure, or stroke. Patients in the REF group were matched 1:1 with those in all other obesity groups based on propensity score using the baseline characteristics of age, race/ethnicity, previous cesarean, preexisting diabetes, chronic hypertension, parity, cigarette use, and insurance status. Multivariable Poisson's regression was used to estimate adjusted relative risks (aRRs) and 95% confidence intervals (CIs) for the association between BMI and the composite outcome. Because cesarean delivery may be in the causal pathway between obesity and adverse maternal outcomes, models were then adjusted for mode of delivery to evaluate potential mediation. Results A total of 52,162 pregnant patients are included in the analysis. Risk of composite maternal outcomes was increased for SMO compared with REF but not for OB and MO [OB: aRR=1.06, 95% CI: 0.99–1.14; MO: aRR=1.10, 95% CI: 0.97–1.25; SMO: aRR=1.32, 95% CI: 1.02–1.70]. However, in the mediation analysis, cesarean appears to mediate 46% (95% CI: 31–50%) of the risk of severe morbidity for SMO compared with REF. Conclusion Super morbid obesity is significantly associated with increased serious maternal morbidity and mortality; however, cesarean appears to mediate this association. Obesity and morbid obesity are not associated with maternal morbidity and mortality. Key Points

We sought to (1) use the Robson 10-Group Classification System (TGCS), which classifies deliveries into 10 mutually exclusive groups, to characterize the groups that are primary contributors to cesarean delivery frequencies, (2) describe inter-hospital variations in cesarean delivery frequencies, and (3) evaluate the contribution of patient characteristics by TGCS group to hospital variation in cesarean delivery frequencies. This was a secondary analysis of an observational cohort of 115,502 deliveries from 25 hospitals between 2008 and 2011. The TGCS was applied to the cohort and each hospital. We identified and compared the TGCS groups with the greatest relative contributions to cohort and hospital cesarean delivery frequencies. We assessed variation in hospital cesarean deliveries attributable to patient characteristics within TGCS groups using hierarchical logistic regression. A total of 115,211 patients were classifiable in the TGCS (99.7%). The cohort cesarean delivery frequency was 31.4% (hospital range: 19.1-39.3%). Term singletons in vertex presentation with a prior cesarean delivery (group 5) were the greatest relative contributor to cohort (34.8%) and hospital cesarean delivery frequencies (median: 33.6%; range: 23.8-45.5%). Nulliparous term singletons in vertex (NTSV) presentation (groups 1 [spontaneous labor] and 2 [induced or absent labor]: 28.9%), term singletons in vertex presentation with a prior cesarean delivery (group 5: 34.8%), and preterm singletons in vertex presentation (group 10: 9.8%) contributed to 73.2% of the relative cesarean delivery frequency for the cohort and were correlated with hospital cesarean delivery frequencies (Spearman's rho = 0.96). Differences in patient characteristics accounted for 34.1% of hospital-level cesarean delivery variation in group 2. The TGCS highlights the contribution of NTSV presentation to cesarean delivery frequencies and the impact of patient characteristics on hospital-level variation in cesarean deliveries among nulliparous patients with induced or absent labor.· We report on the cesarean delivery frequencies in a multicenter U.S.. · NTSV gestations (groups 1 and 2) are a primary driver of cesarean deliveries.. · Patient characteristics contributed most to hospital variation in cesarean deliveries in group 2..

OBJECTIVE To study the association between nicotine or cannabis metabolite presence in maternal urine and child neurodevelopmental outcomes. METHODS We conducted a secondary analysis of two parallel multicenter randomized controlled trials of treatment for hypothyroxinemia or subclinical hypothyroidism among pregnant individuals enrolled at 8-20 weeks of gestation. All maternal-child dyads with a maternal urine sample at enrollment and child neurodevelopmental testing were included (N=1,197). Exposure was urine samples positive for nicotine (cotinine) or cannabis 11-nor-9-carboxy-delta-9-tetrahydrocannabinol [THC-COOH]) or both metabolites. Primary outcome was child IQ at 60 months. Secondary outcomes included cognitive, motor and language, attention, behavioral and social competency, and differential skills assessments at 12, 24, 36, and 48 months. Quantile regression analysis was performed with confounder adjustment. RESULTS Of 1,197 pregnant individuals, 99 (8.3%) had positive cotinine samples and 47 (3.9%) had positive THC-COOH samples; 33 (2.8%) were positive for both. Groups differed in self-reported race and ethnicity, education, marital status, insurance, and thyroid status. Median IQ was similar between cotinine-exposed and -unexposed children (90 vs 95, adjusted difference in medians -2.47, 95% CI -6.22 to 1.29) and THC-COOH-exposed and -unexposed children (89 vs 95, adjusted difference in medians -1.35, 95% CI -7.76 to 5.05). In secondary outcome analysis, children with THC-COOH exposure compared with those unexposed had higher attention scores at 48 months of age (57 vs 49, adjusted difference in medians 6.0, 95% CI 1.11-10.89). CONCLUSIONS Neither prenatal nicotine nor cannabis exposure was associated with a difference in IQ. Cannabis exposure was associated with worse attention scores in early childhood. Longitudinal studies assessing associations between child neurodevelopmental outcomes and prenatal nicotine and cannabis exposure with a focus on timing and quantity of exposure are needed. CLINICAL TRIAL REGISTRATION ClinicalTrials.gov, NCT00388297.

Objective This study aimed to develop and validate a model to predict the probability of vaginal delivery (VD) in low-risk term nulliparous patients, and to determine whether it can predict the risk of severe maternal and neonatal morbidity. Methods Secondary analysis of an obstetric cohort of patients and their neonates born in 25 hospitals across the United States (n = 115,502). Trained and certified research personnel abstracted the maternal and neonatal records. Nulliparous patients with singleton, nonanomalous vertex fetuses, admitted with an intent for VD ≥ 37 weeks were included in this analysis. Patients in active labor (cervical exam > 5 cm), those with prior cesarean and other comorbidities were excluded. Eligible patients were randomly divided into a training and test sets. Based on the training set, and using factors available at the time of admission for delivery, we developed and validated a logistic regression model to predict the probability of VD, and then estimated the prevalences of severe morbidity according to the predicted probability of VD. Results A total of 19,611 patients were included. Based on the training set (n = 9,739), a logistic regression model was developed that included maternal age, body mass index (BMI), cervical dilatation, and gestational age on admission. The model was internally validated on the test set (n = 9,872 patients) and yielded a receiver operating characteristic-area under the curve (ROC-AUC) of 0.71 (95% confidence interval [CI]: 0.70–0.72). Based on a subset of 18,803 patients with calculated predicted probabilities, we demonstrated that the prevalences of severe morbidity decreased as the predicted probability of VD increased (p Conclusion In a large cohort of low-risk nulliparous patients in early labor or undergoing induction of labor, at term with singleton gestations, we developed and validated a model to calculate the probability of VD, and maternal and neonatal morbidity. If externally validated, this calculator may be clinically useful in helping to direct level of care, staffing, and adjustment for case-mix among various systems. Key Points

Background Gestational diabetes mellitus (GDM) is associated with fetal overgrowth, and certain treatments are associated with an increased risk of macrosomia. However, there are limited data about the long-term effect of GDM treatment on childhood growth. Methods Cohort study of 816 women with GDM and their offspring delivered between 2009 and 2012. Childhood height and weight through age 3 were collected from the medical record and z-scores and body mass index (BMI) were calculated. We assessed the association between GDM treatment and childhood growth using linear mixed modeling. Results Treatment was divided into medical nutritional therapy (MNT) (n = 293), glyburide (n = 421), and insulin (n = 102). At delivery, birthweight, z-score, and BMI were higher in the offspring of women treated with either glyburide or insulin compared to MNT. However, weight, z-score, and BMI were similar among all offspring at 6 months and 1, 2, and 3 years of age. After controlling for covariates, there were differences in the weight z-score (P = 0.01) over the 3-year period by treatment group, but no differences in weight (P = 0.06) or change in BMI (P = 0.28). Pairwise comparisons indicated that insulin was associated with more weight gain compared with MNT (0.69 kg; 95% CI, 0.10-1.28; P = 0.02) and glyburide was associated with a trend toward lower weight z-score compared with MNT (−0.24; 95% CI, −0.47 to 0.003; P = 0.05). Conclusion Despite growth differences detected at birth, we observed no meaningful differences in childhood growth from 6 months to 3 years among treatment groups, including in the offspring of women with GDM treated with glyburide.

Objective To estimate whether the frequency of adverse maternal and neonatal outcomes differs between low-risk nulliparous and multiparous women at 39-41 weeks of gestation. Methods This is a secondary analysis of an observational obstetrics cohort of maternal-neonatal dyads at 25 hospitals. Low-risk women with nonanomalous singletons who delivered between 39 0/7 and 41 6/7 weeks of gestation were included. The composite neonatal adverse outcome included 5-minute Apgar score less than five, ventilator support or cardiopulmonary resuscitation, seizure, hypoxic ischemic encephalopathy, sepsis, bronchopulmonary dysplasia, persistent pulmonary hypertension, necrotizing enterocolitis, birth injury or perinatal death. The composite maternal adverse outcome included infection, third- or fourth-degree perineal laceration, thromboembolism, transfusion of blood products, or maternal death. Small for gestational age (SGA), large for gestational age (LGA), and shoulder dystocia requiring maneuvers were also evaluated. Multivariable regression was used to estimate adjusted relative risks (aRRs) and adjusted odds ratios (aORs) with 95% CIs. Results Of the 115,502 women in the overall cohort, 39,870 (34.5%) met eligibility criteria for this analysis; 18,245 (45.8%) were nulliparous. The risk of the composite neonatal adverse outcome (1.5% vs 1.0%, aRR 1.80, 95% CI 1.48-2.19), composite maternal adverse outcome (15.1% vs 3.3%, aRR 5.04, 95% CI 4.62-5.49), and SGA (8.9% vs 5.8%, aOR 1.45, 95% CI 1.33-1.57) was significantly higher in nulliparous than multiparous patients. The risk of LGA (aOR 0.65, 95% CI 0.60-0.71) and shoulder dystocia with maneuvers (aRR 0.68, 95% CI 0.60-0.77) was significantly lower in nulliparous rather than multiparous patients. Conclusion The risk of composite adverse outcomes and SGA among low-risk nulliparous women at 39-41 weeks of gestation is significantly higher than among multiparous counterparts. However, nulliparous women had a lower risk of shoulder dystocia with maneuvers and LGA.

Objective The objective of this study was to determine whether antenatal corticosteroid exposure has a differential association with preterm neonatal morbidity among women with and without diabetes. Study design Secondary analysis of an observational cohort of 115,502 women and their neonates born in 25 U.S. hospitals (2008-2011). Women who delivered at 230/7 to 336/7 weeks' gestation and received antenatal corticosteroids were compared with those who did not receive antenatal corticosteroids. Women with a stillbirth and women who delivered a neonate that was not resuscitated were excluded. The primary outcome was neonatal respiratory distress syndrome or death within 48 hours. Secondary outcomes included composite neonatal morbidity (respiratory distress syndrome, necrotizing enterocolitis, grades 3-4 intraventricular hemorrhage, sepsis, or death) and mechanical ventilation. Multivariable modified Poisson regression was used to estimate the association between antenatal corticosteroid exposure and neonatal outcomes. Maternal diabetes (pregestational and gestational) was evaluated as a potential effect modifier, and sensitivity analyses were conducted to evaluate whether receipt of a partial, single, or multiple course(s) of antenatal corticosteroids influenced results. Results A total of 4,429 women with 5,259 neonates met inclusion criteria: 3,716 (83.9%) women received antenatal corticosteroids and 713 (16.1%) did not. Of the 510 diabetic women (181 pregestational and 329 gestational), 439 (86.1%) received antenatal corticosteroids. Of the 3,919 nondiabetic women, 3,277 (83.6%) received antenatal corticosteroids. Antenatal corticosteroid exposure was not associated with respiratory distress syndrome or early death (adjusted relative risk [aRR] = 0.94, 95% confidence interval [CI]: 0.85-1.04), composite neonatal morbidity (aRR = 0.98, 95% CI: 0.89-1.07), or mechanical ventilation (aRR = 0.95, 95% CI: 0.86-1.05). There was no significant effect modification of maternal diabetes on the relationship between antenatal corticosteroids and neonatal outcomes (p > 0.05), and outcomes were similar in sensitivity analyses of partial, single, or multiple courses of corticosteroids. Discussion Antenatal corticosteroid administered to reduce preterm neonatal morbidity does not appear to have a differential association among women with diabetes compared with those without. Key points · Antenatal corticosteroids are used ubiquitously in women with and without diabetes.. · Maternal diabetes does not appear to modify the neonatal effect of antenatal corticosteroids.. · Larger studies of antenatal corticosteroids are needed to confirm our findings in diabetic women..

Objective To estimate the effect of antenatal treatment of subclinical hypothyroidism on maternal depressive symptoms. Methods We conducted an ancillary study to a multicenter trial in women with singleton pregnancies diagnosed with subclinical hypothyroidism randomized to antenatal thyroxine therapy or placebo. Treatment was discontinued at the end of pregnancy. Women with overt thyroid disease, diabetes, autoimmune disease, and those diagnosed with depression were excluded. Participants were assessed for depressive symptoms using the Center for Epidemiological Studies-Depression scale (CES-D) before starting the study drug (between 11 and 20 weeks of gestation), between 32 and 38 weeks of gestation, and at 1 year postpartum. The primary outcome was maternal depressive symptoms score as assessed using the CES-D. Secondary outcome was the percentage of women who scored 16 or higher on the CES-D, as such a score is considered screen-positive for depression. Results Two hundred forty-five (36.2% of parent trial) women with subclinical hypothyroidism were allocated to thyroxine (n=124) or placebo (n=121). Median CES-D scores and the proportion of participants with positive scores were similar at baseline between the two groups. Treatment with thyroxine was not associated with differences in CES-D scores (10 [5-15] vs 10 [5-17]; P=.46) or in odds of screening positive in the third trimester compared with placebo, even after adjusting for baseline scores (24.3% vs 30.1%, adjusted odds ratio 0.63, 95% CI 0.31-1.28, P=.20). At 1 year postpartum, CES-D scores were not different (6 [3-11] vs 6 [3-12]; P=.79), nor was the frequency of screen-positive CES-D scores in the treated compared with the placebo group (9.7% vs 15.8%; P=.19). Treatment with thyroxine during pregnancy was also not associated with differences in odds of screening positive at the postpartum visit compared with placebo even after adjusting for baseline scores. Sensitivity analysis including women who were diagnosed with depression by the postpartum visit did not change the results. Conclusions This study did not achieve its planned sample size, thus our conclusions may be limited, but in this cohort of pregnant women with subclinical hypothyroidism, antenatal thyroxine replacement did not improve maternal depressive symptoms.

Objective To assess whether neonatal morbidities evident by the time of hospital discharge are associated with subsequent cerebral palsy (CP) or death. Study Design This is a secondary analysis of data from a multicenter placebo-controlled trial of magnesium sulfate for the prevention of CP. The association between prespecified intermediate neonatal outcomes (n = 11) and demographic and clinical factors (n = 10) evident by the time of discharge among surviving infants (n = 1889) and the primary outcome of death or moderate/severe CP at age 2 (n = 73) was estimated, and a prediction model was created. Results Gestational age in weeks at delivery (odds ratio [OR]: 0.74, 95% confidence interval [CI]: 0.67–0.83), grade III or IV intraventricular hemorrhage (IVH) (OR: 5.3, CI: 2.1–13.1), periventricular leukomalacia (PVL) (OR: 46.4, CI: 20.6–104.6), and male gender (OR: 2.5, CI: 1.4–4.5) were associated with death or moderate/severe CP by age 2. Outcomes not significantly associated with the primary outcome included respiratory distress syndrome, bronchopulmonary dysplasia, seizure, necrotizing enterocolitis, neonatal hypotension, 5-minute Apgar score, sepsis, and retinopathy of prematurity. Using all patients, the receiver operating characteristic curve for the final prediction model had an area under the curve of 0.84 (CI: 0.78–0.89). Using these data, the risk of death or developing CP by age 2 can be calculated for individual surviving infants. Conclusion IVH and PVL were the only neonatal complications evident at discharge that contributed to an individual infant's risk of the long-term outcomes of death or CP by age 2. A model that includes these morbidities, gestational age at delivery, and gender is predictive of subsequent neurologic sequelae. Key Points

The rate of recurrent spontaneous preterm birth (PTB) was reduced by 33% in the Maternal-Fetal Medicine Unit (MFMU) Network trial of 17α-hydroxyprogesterone caproate (17-OHPC), but the mechanism of action, 17 years later, remains elusive. The robustness of the interleukin-10 (IL-10) response to lipopolysaccharide (LPS) stimulation of leukocytes in pregnant women with a prior PTB correlates with gestational age at delivery. This study sought to determine if there is a relationship between the concentration of 17-OHPC and response to LPS stimulation. We performed a secondary analysis of data from the Omega-3 MFMU trial which evaluated the effectiveness of omega-3 fatty acid supplementation in reducing recurrent PTB. We utilized previously characterized data from a subanalyses of the Omega-3 trial of IL-10 and tumor necrosis factor alpha (TNF-α) levels from peripheral blood mononuclear cells stimulated with LPS. Blood was obtained from enrolled women at 16 to 22 weeks' gestation (baseline) and 25 to 28 weeks' gestation (posttreatment). All women received 17-OHPC and plasma 17-OHPC concentrations were measured at 25 to 28 weeks' gestation. We analyzed these data to determine if there was a relationship between 17-OHPC concentration and cytokine production. We then performed an in vitro study to determine if 17-OHPC could directly alter cytokine production by THP-1-derived macrophages. In the clinical samples, we found that 17-OHPC plasma concentrations were correlated with the quantity of the LPS-stimulated production of IL-10. TNF-α production after LPS stimulation was unrelated to 17-OHPC concentration. In the in vitro study, we demonstrate a 17-OHPC concentration dependent increase in IL-10 production. In women receiving 17-OHPC for PTB prevention, we demonstrate a relationship between plasma 17-OHPC and LPS-stimulated IL-10 production by circulating leukocytes. We also demonstrate that, in vitro, 17-OHPC treatment affects IL-10 production by LPS-stimulated macrophages. Collectively, these findings support an immunomodulatory mechanism of action of 17-OHPC in the prevention of recurrent PTB.· 17-OHPC plasma concentrations and LPS-stimulated IL-10 levels correlate in clinical samples in women at risk for recurrent preterm birth.. · 17-OHPC can modulate the response of LPS-stimulated macrophages to increase IL-10 production.. · There was no relationship between TNF-α and plasma concentration of 17-OHPC in clinical samples or in vitro..

BACKGROUND: The existence of the “July phenomenon” (worse outcomes related to the presence of new physician trainees in teaching hospitals) has been debated in the literature and media. Previous studies of the phenomenon in obstetrics are limited by the quality and detail of data. OBJECTIVE: To evaluate whether the months of June to August, when transitions in trainees occur, are associated with increased maternal and neonatal morbidity. STUDY DESIGN: Secondary analysis of an observational cohort of 115,502 mother–infant pairs that delivered at 25 hospitals from March 2008 to February 2011. Inclusion criteria were an individual who had a singleton, nonanomalous live fetus at the onset of labor, and delivered at a hospital with trainees. The primary outcomes were composites of maternal and neonatal morbidity. We evaluated the outcomes by academic quarter during which the delivery occurred, beginning July 1, and by duration of the academic year as a continuous variable. To account for clustering in outcomes at a given delivery location, we applied hierarchical logistic regression with adjustment for hospital as a random effect. RESULTS: Of 115,502 deliveries, 99,929 met the inclusion criteria. Race and ethnicity, insurance, body mass index, drug use, and the availability of 24/7 maternal-fetal medicine, anesthesia, and neonatology varied by quarter. In adjusted analysis, the frequency of the composite maternal and neonatal morbidity did not differ by quarter. No differences in composite morbidity were observed when using day of the year as a continuous variable (maternal morbidity adjusted odds ratio, 1.00; 95% confidence interval, 0.99–1.00 and neonatal morbidity adjusted odds ratio, 1.00; 95% confidence interval, 1.00–1.01) and after adjustment for hospital as a random effect. Odds of major surgical complications in quarter 2 were twice those in quarter 1. Neonatal injury and intensive care unit were less frequent in later quarters. CONCLUSION: Maternal and neonatal morbidity in teaching hospitals was not associated with the academic quarter during which delivery occurred, and there was no evidence of a “July phenomenon”.

This study aimed to evaluate whether intrapartum fetal electrocardiogram (ECG) tracings with ST-elevation or depression occur more frequently in each stage of labor in small-for-gestational age (SGA) or large-for-gestational age (LGA), as compared with appropriate-for-gestational age (AGA) fetuses.We conducted a secondary analysis of a large, multicenter trial in which laboring patients underwent fetal ECG waveform-analysis. We excluded participants with diabetes mellitus and major fetal anomalies. Birth weight was categorized as SGA (10th percentile), LGA (90th percentile), or AGA (10-90th percentile) by using a gender and race/ethnicity specific nomogram. In adjusted analyses, the frequency of ECG tracings with ST-depression or ST-elevation without depression was compared according to birthweight categories and labor stage.Our study included 4,971 laboring patients in the first stage and 4,074 in the second stage. During the first stage of labor, there were no differences in the frequency of ST-depression in SGA fetuses compared with AGA fetuses (6.7 vs. 5.5%; adjusted odds ratio [aOR]: 1.41, 95% confidence interval [CI]: 0.93-2.13), or in ST-elevation without depression (35.8 vs. 34.1%; aOR: 1.17, 95% CI: 0.94-1.46). During the second stage, there were no differences in the frequency of ST-depression in SGA fetuses compared with AGA fetuses (1.6 vs. 2.0%; aOR: 0.69, 95% CI: 0.27-1.73), or in ST-elevation without depression (16.2 vs. 18.1%; aOR: 0.90, 95% CI: 0.67-1.22). During the first stage of labor, there were no differences in the frequency of ST-depression in LGA fetuses compared with AGA fetuses (6.3 vs. 5.5%; aOR: 0.97, 95% CI: 0.60-1.57), or in ST-elevation without depression (33.1 vs. 34.1%; aOR: 0.80, 95% CI: 0.62-1.03); during the second stage of labor, the frequency of ST-depression in LGA compared with AGA fetuses (2.5 vs. 2.0%, aOR: 1.36, 95% CI: 0.61-3.03), and in ST-elevation without depression (15.5 vs. 18.1%; aOR: 0.83, 95% CI: 0.58-1.18) were similar as well.The frequency of intrapartum fetal ECG tracings with ST-events is similar among SGA, AGA, and LGA fetuses.· SGA and LGA neonates are at increased risk of cardiac dysfunction.. · Fetal ECG has been used to evaluate fetal response to hypoxia.. · Fetal ST-elevation and ST-depression occur during hypoxia.. · Frequency of intrapartum ST-events is similar among SGA, AGA and LGA fetuses..

BackgroundLiterature is divided regarding the risk of neonatal ventricular septal defect (VSD) associated with first trimester ondansetron use in pregnancy.MethodsWe evaluated the risk of VSD associated with first trimester exposure to intravenous or oral ondansetron in 33 677 deliveries at Magee–Womens Hospital in Pittsburgh, PA (2006–2014). Using log-binomial regression, we evaluated the risk: (1) in the full cohort, (2) using propensity score designs with both matching and inverse probability weighting and (3) utilizing clustered trajectory analysis evaluating the role of dose. Sensitivity analyses assessed the association between ondansetron and all recorded birth defects in aggregate.ResultsA total of 3733 (11%) pregnancies were exposed to ondansetron in the first trimester (dose range: 2.4–1008 mg). Ondansetron was associated with increased risk of VSD with risk ratios ranging from 1.7 [95% confidence interval (CI) 1.0–2.9] to 2.1 (95% CI 1.1–4.0) across methods. Risks correspond to one additional VSD for approximately every 330 pregnancies exposed in the first trimester. The association was dose-dependent with increased risk in women receiving highest cumulative doses compared with lowest doses [adjusted risk ratio: 3.2 (95% CI 1.0–9.9)]. The association between ondansetron and congenital malformations was diluted as the outcome included additional birth defects.ConclusionsFirst trimester ondansetron use is associated with an increased risk of neonatal VSD potentially driven by higher doses. This risk should be viewed in the context of risks attributable to severe untreated nausea and vomiting of pregnancy.

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.

Gestational diabetes mellitus is a condition similar to type 2 diabetes mellitus (T2DM) in that patients are unable to compensate for the degree of insulin resistance, and both conditions are often treated with metformin. The comparative pharmacodynamic response to metformin in these 2 populations has not been studied. This study characterized insulin sensitivity, β-cell responsivity, and disposition index following a mixed-meal tolerance test utilizing a minimal model of glucose, insulin, and C-peptide kinetics before and during treatment with metformin. The study included women with gestational diabetes mellitus (n = 34), T2DM (n = 14), and healthy pregnant women (n = 30). Before treatment, the gestational diabetes mellitus group had significantly higher baseline (45%), dynamic (68%), static (71%), and total β-cell responsivity (71%) than the T2DM group. Metformin significantly increased insulin sensitivity (51%) as well as disposition index (97%) and decreased mixed-meal tolerance test peak glucose concentrations (8%) in women with gestational diabetes mellitus after adjustment for gestational age-dependent effects; however, in women with T2DM metformin only significantly affected peak glucose concentrations (22%) and had no significant effect on any other parameters. Metformin had a greater effect on the change in disposition index (Δ disposition index) in women with gestational diabetes mellitus than in those with T2DM (P = .01). In conclusion, response to metformin in women with gestational diabetes mellitus is significantly different from that in women with T2DM, which is likely related to the differences in disease severity.

Objective This study aimed to evaluate the association between clinical and examination features at admission and late preterm birth. Study Design The present study is a secondary analysis of a randomized trial of singleton pregnancies at 340/7 to 365/7 weeks' gestation. We included women in spontaneous preterm labor with intact membranes and compared them by gestational age at delivery (preterm vs. term). We calculated a statistical cut-point optimizing the sensitivity and specificity of initial cervical dilation and effacement at predicting preterm birth and used multivariable regression to identify factors associated with late preterm delivery. Results A total of 431 out of 732 (59%) women delivered preterm. Cervical dilation ≥ 4 cm was 60% sensitive and 68% specific for late preterm birth. Cervical effacement ≥ 75% was 59% sensitive and 65% specific for late preterm birth. Earlier gestational age at randomization, nulliparity, and fetal malpresentation were associated with late preterm birth. The final regression model including clinical and examination features significantly improved late preterm birth prediction (81% sensitivity, 48% specificity, area under the curve = 0.72, 95% confidence interval [CI]: 0.68–0.75, and p-value Conclusion Four in 10 women in late-preterm labor subsequently delivered at term. Combination of examination and clinical features (including parity and gestational age) improved late-preterm birth prediction.

To evaluate whether inadequate or excessive gestational weight gain before the third trimester is associated with adverse pregnancy outcomes, and to evaluate the association of weight gain in the third trimester with fetal growth.This was a retrospective cohort study of all eligible overweight and obese women with singleton pregnancies delivered at an academic institution between 2012 and 2014. Our primary exposure was inadequate or excess gestational weight gain during the first and second trimesters. Outcomes included small- (SGA) or large- (LGA) for-gestational-age birth weight as well adverse maternal outcomes and composite neonatal morbidity. Multivariable logistic regression was used to assess the relationship between weight gain and perinatal outcomes, and stratified analyses evaluated the relationship between third trimester weight gain and birth weight category.Of the 5,814 women, 1,280 (22%) had adequate, 1,428 (24.6%) had inadequate, and 3,106 (53.4%) had excessive weight gain in the first and second trimesters. Women with inadequate early gestational weight gain were more likely to deliver an SGA neonate (adjusted odds ratio [aOR] 1.59, 95% CI 1.23-2.06) and less likely to deliver an LGA neonate (aOR 0.73, 95% CI 0.54-0.98), whereas those with excessive early gestational weight gain were less likely to deliver an SGA neonate (aOR 0.66, 95% CI 0.52-0.85) and more likely to deliver an LGA neonate (aOR 1.66, 95% CI 1.32-2.1). Higher weight gain in the third trimester was associated with increased risk for LGA birth weight, but third trimester weight gain was not related to SGA birth weight.Early gestational weight gain is associated with birth weight category. Modifying weight gain in the third trimester may limit the risk for LGA birth weight, but higher weight gain in late gestation does not alter the association between inadequate early weight gain and the risk for SGA.

Objective This study aimed to evaluate whether the number of vacuum pop-offs, the number of forceps pulls, or the duration of operative vaginal delivery (OVD) is associated with adverse maternal and perinatal outcomes. Study Design This is a secondary analysis of a multicenter observational cohort of women who underwent an attempted OVD. Women were stratified by the duration of OVD and the number of pop-offs (vacuum) or pulls (forceps) attempted. Severe perineal lacerations, failed OVD, and a composite adverse neonatal outcome were compared by the duration of OVD and number of pop-offs or pulls. Results Of the 115,502 women in the primary cohort, 5,325 (4.6%) underwent an attempt at OVD: 3,594 (67.5%) with vacuum and 1,731 (32.5%) with forceps. After adjusting for potential confounders, an increasing number of pop-offs was associated with an increased odds of the composite adverse neonatal outcome. However, an increasing duration of vacuum exhibited a stronger association with the composite adverse neonatal outcome. Similarly, the number of forceps pulls was less strongly associated with the composite adverse neonatal outcome compared with the duration of forceps application. Conclusion The duration of OVD may be more associated with adverse neonatal outcomes than the number of pop-offs or pulls.

Background Antenatal exposure to intra-uterine inflammation results in precocious Haptoglobin (Hp) expression (switch-on status). We investigated the relationships between foetal Hp expression at birth with newborn and childhood outcomes. Methods We evaluated cord blood samples from 921 newborns of women at imminent risk for preterm delivery randomised to either placebo (n = 471, birth gestational age (GA) median [min-max]: 31 [24–41] weeks) or magnesium sulphate (n = 450, GA 31 [24–42] weeks]). Primary outcome was infant death by 1 year and/or cerebral palsy (CP) ≥ 2 years of corrected age. Adjusted odd ratios (aOR) for neonatal and childhood outcomes were calculated controlling for GA, birth weight, sex, and magnesium exposure. Findings Primary outcome occurred in 2.8% of offspring. Newborns were classified in three pre-defined categorisation groups by cord blood Hp switch status and IL-6 levels: inflammation-nonexposed (Category 1, n = 432, 47%), inflammation-exposed haptoglobinemic (Category 2, n = 449, 49%), and inflammation-exposed anhaptoglobinemic or hypohaptoglobinemic (Category 3, n = 40, 4%). Newborns, found anhaptoglobinemic or hypohaptoglobinemic (Category 3) had increased OR for intraventricular haemorrhage (IVH) and/or death (aOR: 7.0; 95% CI: 1.4–34.6, p = 0.02) and for CP and/or death (aOR: 6.27; 95% CI: 1.7–23.5, p = 0.006) compared with Category 2. Foetal ability to respond to inflammation by haptoglobinemia resulted in aOR similar to inflammation-nonexposed newborns. Hp1-2 or Hp2-2 phenotypes protected against retinopathy of prematurity (aOR = 0.66; 95% CI 0.48–0.91, p = 0.01). Interpretation Foetal ability to switch-on Hp expression in response to inflammation was associated with reduction of IVH and/or death, and CP and/or death. Foetuses unable to mount such a response had an increased risk of adverse outcomes. Trial Registration: clinicaltrials.gov Identifier: NCT00014989

OBJECTIVE This study aimed to evaluate whether racial and ethnic disparities in adverse perinatal outcomes exist at term. STUDY DESIGN We performed a secondary analysis of a multicenter observational study of 115,502 pregnant patients and their neonates (2008-2011). Singleton, nonanomalous pregnancies delivered from 37 to 41 weeks were included. Race and ethnicity were abstracted from the medical record and categorized as non-Hispanic White (White; referent), non-Hispanic Black (Black), non-Hispanic Asian (Asian), or Hispanic. The primary outcome was an adverse perinatal composite defined as perinatal death, Apgar score

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.

The use of birthweight standards to define small for gestational age may fail to identify neonates affected by poor fetal growth as they include births associated with suboptimal fetal growth.This study aimed to compare intrauterine vs birthweight-derived standards to define newborn small for gestational age to predict neonatal morbidity and mortality.This was a secondary analysis of a multicenter observational study of 118,422 births. Live-born singleton, nonanomalous newborns born at 23 to 41 weeks of gestation were included. Those with missing gestational age estimation or without a first- or second-trimester ultrasound to confirm dating, birthweight, or neonatal outcome data were excluded. Birthweight percentile was computed using an intrauterine standard (Hadlock) and a birthweight-derived standard (Olsen). We compared the test characteristics of small for gestational age (birthweight of10th percentile) by each standard to predict a composite neonatal morbidity and mortality outcome (death before discharge, neonatal intensive care unit admission48 hours, respiratory distress syndrome, sepsis, necrotizing enterocolitis, grade 3 or 4 intraventricular hemorrhage, or seizures). Severe composite morbidity was analyzed as a secondary outcome and was defined as death, neonatal intensive care unit admission7 days, necrotizing enterocolitis, grade 3 or 4 intraventricular hemorrhage, or seizures. The areas under the curve using receiver-operating characteristic methodology and proportions of the primary outcome by small for gestational age status were compared by gestational age category at birth (34, 34 0/7 to 36 6/7, ≥37 weeks).Of 115,502 mother-newborn dyads in the parent study, 78,203 (67.7%) were included, with most exclusions occurring because of missing or inadequate dating information, multiple gestations, or delivery outside the gestational age range. The primary composite outcome occurred in 9.5% (95% confidence interval, 9.3-9.7), and the severe composite outcome occurred in 5.3% (95% confidence interval, 5.1-5.4). Small for gestational age was diagnosed by intrauterine and birthweight-derived standards in 14.8% and 7.4%, respectively (P.001). Neonates considered small for gestational age only by the intrauterine standard experienced the primary outcome more than twice as often as those considered non-small for gestational age by both standards (18.4% vs 7.9%; P.001). For the prediction of the primary outcome, small for gestational age by the intrauterine standard had higher sensitivity (29% vs 15%; P.001) but lower specificity (87% vs 93%; P.001) than by the birthweight standard. Both standards had weak performance overall, although the intrauterine standard had a higher area under the curve (0.58 vs 0.53; P.001). When subanalyzed by gestational age at birth, the difference in areas under the curve was only present among preterm deliveries 34 to 36 competed weeks. Neither standard demonstrated any discrimination for morbidity prediction among term births (area under the curve, 0.50 for both). When the prediction of severe morbidity was compared, the intrauterine still had better overall prediction than the birthweight standard (areas under the curve, 0.65 vs 0.57; P.001), although this also varied by gestational age at birth.Among nonanomalous neonates, neither intrauterine nor birthweight-derived standards for small for gestational age accurately predicted neonatal morbidity and mortality, with no discriminatory ability at term. Small for gestational age intrauterine standards performed better than birthweight standards.

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.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.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 of4, 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 of4 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.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.

Objective The study aimed to evaluate the impact of 17-hydroxyprogesterone caproate (17-OHPC) on recurrent preterm birth (PTB) in women with a prior PTB and a current dichorionic/diamniotic twin gestation. Study design We combined individual patient-level data from two prospective randomized placebo-controlled trials of prophylactic 17-OHPC in twin gestation and compared the rates of recurrent spontaneous PTB in those women with a prior singleton PTB randomized to placebo or 17-OHPC (250 mg weekly). Results Only 7.4% of women with dichorionic/diamniotic twin gestation experienced a prior PTB. Among these 66 women, spontaneous delivery prior to 34 weeks occurred significantly less often (p = 0.03) in those randomized to 17-OHPC (20.6%) than in those randomized to placebo (46.9%). However, mean gestational length was not significantly different, and there was no statistically significant difference in composite neonatal outcome. Conclusion 17-OHPC may be beneficial to women with a prior PTB and a current dichorionic/diamniotic twin gestation. These findings along with those reported by the Maternal Fetal Medicine Units Network in singletons suggest a common mechanism of action and a specific target population, those with a prior PTB, that may benefit from 17-OHPC treatment. A large prospective trial is needed to validate these findings. Key points · 17-OHPC reduces recurrent PTB in women with dichorionic/diamniotic twins.. · PTB risk and response to 17-OHPC may differ according to the type of twinning.. · 17-OHPC may affect a common pathway in twins and singletons with a prior PTB..

To evaluate whether breastfeeding and its duration are associated with a reduced risk of low IQ scores or other neurodevelopmental problems.We conducted a secondary analysis of two parallel multicenter, double-blinded randomized controlled trials in which participants with a singleton pregnancy and either subclinical hypothyroidism or hypothyroxinemia were treated with thyroxine or placebo. Our primary outcome was a low IQ score (less than 85 on the WPPSI-III [Wechsler Preschool and Primary Scale of Intelligence III] at age 5 years). Secondary outcomes included performance measures on other validated neurodevelopmental tests. Univariable and multivariable analyses were performed to evaluate the association between breastfeeding and neurodevelopmental outcomes. Stepwise backward proceeding linear and logistic regression models were used to develop the final adjusted models.Of the 772 participants studied, 614 (80%) reported breastfeeding. Of these, 31% reported breastfeeding for less than 4 months, 19% for 4-6 months, 11% for 7-9 months, 15% for 10-12 months and 23% for more than 12 months. IQ scores were available for 756 children; mean age-5 scores were higher with any breastfeeding (96.7±15.1) than without (91.2±15.0, mean difference 5.5, 95% CI 2.8-8.2), and low IQ scores were less frequent with any breastfeeding (21.5%) than with no breastfeeding (36.2%, odds ratio 0.48, 95% CI 0.33-0.71). In adjusted analyses, breastfeeding remained associated with reduced odds of low IQ score (adjusted odds ratio [aOR] 0.62, 95% CI 0.41-0.93), and each additional month of breastfeeding was associated with lower odds of a low IQ scores (aOR 0.97, 95% CI 0.939-0.996). No significant associations between breastfeeding and other neurodevelopmental outcomes were identified in adjusted analyses.Breastfeeding and its duration are associated with lower odds of low IQ score at age 5 years.

Pregnancy is associated with several physiological changes that can alter the pharmacokinetics (PK) and pharmacodynamics of drugs. These may require dosing changes in pregnant women to achieve drug exposures comparable to the nonpregnant population. There is, however, limited information available on the PK and pharmacodynamics of drugs used during pregnancy. Practical difficulties in performing PK studies and potential liability issues are often the reasons for the availability of limited information. Over the past several years, there has been a rapid development in the application of various modeling strategies such as population PK and physiologically based PK modeling to provide guidance on drug dosing in this special patient population. Population PK models rely on measured PK data, whereas physiologically based PK models integrate physiological, preclinical, and clinical data to quantify changes in PK of drugs in various patient populations. These modeling strategies offer a promising approach to identify the drugs with PK changes during pregnancy and guide dose adjustment in pregnant women. This review focuses on PBPK modeling to guide drug therpay in pregnancy.

Objective To assess whether postpartum hemorrhage management or subsequent morbidity differs based on whether delivery occurred during the day or night. Methods We conducted a secondary analysis of a multicenter observational obstetric cohort of more than 115,000 mother-neonate pairs from 25 hospitals (2008-2011). This analysis included women delivering singleton or twin births who experienced postpartum hemorrhage (estimated blood loss greater than 500 cc for vaginal delivery, estimated blood loss greater than 1,000 cc for cesarean delivery, or documented treatment for postpartum hemorrhage). Nighttime delivery was defined as that occurring between 8 PM and 6 AM. The primary outcome was a composite of maternal morbidity (death, hysterectomy, intensive care unit admission, transfusion, or unanticipated procedure for bleeding). Secondary outcomes included estimated blood loss, uterotonic use, and procedures to treat bleeding that occurred during the postpartum hospitalization. Multivariable logistic, linear, quantile, and multinomial regression models were used to assess associations between nighttime delivery and outcomes, adjusting for potential patient-level confounders and hospital as a fixed effect. Results In total, 2,709 (34.2%) of 7,917 women with postpartum hemorrhage delivered at night. Women who delivered at night were younger, had a lower body mass index, and were more likely to have government-sponsored insurance, be nulliparous, have hypertension, use neuraxial analgesia, and deliver vaginally. After adjusting for potential confounders, the primary composite outcome of maternal morbidity was similar regardless of night compared with day delivery (15.5% night vs 17.5% day; adjusted odds ratio 0.89, 95% CI 0.77-1.03). Some secondary outcomes, including mean EBL, frequency of uterotonic use, and time from delivery to first uterotonic dose, differed on unadjusted analyses, but these associations did not persist in multivariable analysis. The study had limited power to assess differences in uncommon outcomes. Conclusion Nighttime delivery was not associated with significant differences in postpartum hemorrhage-related management or morbidity.

OBJECTIVE: To examine whether the decision and indications for performing intrapartum cesarean delivery vary by time of day. METHODS: We conducted a secondary analysis of a multicenter observational cohort of 115,502 deliveries (2008–2011), including nulliparous women with term, singleton, nonanomalous live gestations in vertex presentation who were attempting labor. Those who attempted home birth, or underwent cesarean delivery scheduled or decided less than 30 minutes after admission were excluded. Time of day was defined as cesarean delivery decision time among those who delivered by cesarean and delivery time among those who delivered vaginally, categorized by each hour of a 24-hour day. Primary outcomes were decision to perform cesarean delivery and the indications for cesarean delivery (labor dystocia, nonreassuring fetal status, or other indications). Secondary outcomes included whether a dystocia indication adhered to standards promoted to reduce cesarean delivery rates. Bivariate analyses were performed using χ(2) and Kruskal-Wallis tests for categorical and continuous outcomes, respectively, and generalized additive models with smoothing splines explored nonlinear associations without adjustment for other factors. RESULTS: Seven thousand nine hundred fifty-six (22.1%) of 36,014 eligible women underwent cesarean delivery. Decision for cesarean delivery (P.05). CONCLUSION: Among nulliparous women who were attempting labor at term, the decision to perform cesarean delivery, particularly for dystocia, varied with time of day. Some of these differences correlate with labor management differences, given the changing frequency of latent phase cesarean delivery and median time in active phase.

Objective We assessed if the initial response to medical nutritional therapy (MNT) can help predict the need for pharmacological therapy in women with gestational diabetes mellitus (GDM). Study Design We identified 1,174 women with GDM who underwent standardized dietary counseling and reported glucose values from the first week of MNT. We compared women who required pharmacological therapy with those who did not use bivariate statistics, and used multivariable logistic regression modeling to assess for factors predicting the need for pharmacological therapy. Results We identified 819 women (69.8%) who needed pharmacological therapy. They had higher prepregnancy body mass index, higher rates of GDM diagnosis before 24 weeks, and higher oral glucose tolerance test values. After adjustment for covariates, age (odds ratio [OR]: 1.04; 95% confidence interval [CI]: 1.01–1.08), obesity (OR: 2.49; 95% CI: 1.70–3.66), and ≥33% of abnormal glucose values from the first week of MNT (OR: 13.84; 95% CI: 9.4–20.20) were associated with the need for pharmacological therapy. Area under the curve of the regression model was 0.83, with a sensitivity of 72.2%, a specificity of 86.8%, and a positive predictive value of 92.5%. Conclusion Glucose values from the first week of MNT were the strongest predictor of needing pharmacological therapy. Further studies are needed to define metabolic predictors of response to MNT in women with GDM.

OBJECTIVE To study the association of prepregnancy body mass index (BMI) and gestational weight gain with child neurodevelopmental outcomes. METHODS We performed a secondary analysis of data from two parallel, multicenter, randomized, double-blind, placebo-controlled thyroxine replacement trials in pregnant women with either hypothyroxinemia or subclinical hypothyroidism who delivered at term. Body mass index was categorized as normal (18.5-24.9), overweight (25.0-29.9), or obese (30 or greater). We also evaluated early (20 weeks of gestation or less), late (greater than 20 weeks of gestation), and total gestational weight gain and categorized gestational weight gain as inadequate, adequate, and excessive per 2009 Institute of Medicine guidelines. Neurodevelopmental outcomes included 5-year Wechsler Preschool and Primary Scale of Intelligence and 3-year Differential Ability Scales-II. Linear and logistic regression analyses were performed and adjusted for maternal age, race-ethnicity, education, insurance status, parity, smoking and alcohol use, thyroid status (subclinical hypothyroidism or hypothyroxinemia), treatment group, gestational age at delivery, and neonatal sex. RESULTS Of the 948 women included, 380 (40%), 305 (32%), and 263 (28%) had normal, overweight, and obese prepregnancy BMI, respectively. A total of 106 (11%), 212 (22%), and 630 (66%) of women had inadequate, adequate, and excessive total rates of gestational weight gain, respectively. Maternal differences among the BMI categories included race-ethnicity, education, insurance type, parity, and thyroid status (all P

To compare fetal heart rate (FHR) patterns during the last hour of labor between small-for-gestational-age (SGA; birth weight less than the 10th percentile for gestational age) and appropriate-for-gestational-age (AGA; birth weight at the 10-90th percentile) neonates at 36 weeks of gestation or greater. We also compared the rate of cesarean delivery and composite neonatal morbidity among SGA and AGA newborns.This is a secondary analysis of a randomized trial of intrapartum fetal electrocardiographic ST-segment analysis. We excluded women with chorioamnionitis, insufficient duration of FHR tracing in the hour before delivery, and anomalous newborns. Fetal heart rate patterns were categorized by computerized pattern recognition software (PeriCALM Patterns). Composite neonatal morbidity was defined as any of the following: intrapartum fetal death, Apgar score 3 or less at 5 minutes, cord artery pH 7.05 or less, base deficit 12 mmol/L or greater, neonatal seizure, intubation at delivery, neonatal encephalopathy, and neonatal death. Logistic regression was used to evaluate the association between FHR patterns and SGA adjusted for magnesium sulfate exposure and stage of labor.Of the 11,108 women randomized, 85% (n=9,402) met inclusion criteria, of whom 9% were SGA. In the last hour, the likelihood of accelerations was significantly lower among SGA than AGA neonates (72.4% vs 66.8%; P=.001). Variable decelerations lasting greater than 60 seconds, with depth greater than 60 beats per minute (bpm) or nadir less than 60 bpm, were significantly more common with SGA than AGA (all P.001). The rate of late decelerations, prolonged decelerations, or bradycardia were similar between SGA and AGA (all P.05). Cesarean delivery for fetal indications was significantly more common with SGA (7.0%) than AGA (4.0%; P.001). The composite neonatal morbidity was 1.4% among SGA and 1.0% among AGA (odds ratio 1.40, 95% CI 0.74-2.64).Although the FHR patterns in the last hour of labor differ among SGA and AGA neonates, as does the rate of cesarean delivery, the composite neonatal morbidity was similar.

To evaluate the association between gestational weight gain and maternal and neonatal outcomes in a large, geographically diverse cohort.Trained chart abstractors at 25 hospitals obtained maternal and neonatal data for all deliveries on randomly selected days over 3 years (2008-2011). Gestational weight gain was derived using weight at delivery minus prepregnancy or first-trimester weight and categorized as below, within, or above the Institute of Medicine (IOM) guidelines in this retrospective cohort study. Maternal (primary or repeat cesarean delivery, third- or fourth-degree lacerations, severe postpartum hemorrhage, hypertensive disease of pregnancy) and neonatal (preterm birth, shoulder dystocia, macrosomia, hypoglycemia) outcomes were compared among women in the gestational weight gain categories in unadjusted and adjusted analyses with odds ratios (ORs) and 95% CI reported. Covariates included age, race-ethnicity, tobacco use, insurance type, parity, prior cesarean delivery, pregestational diabetes, hypertension, and hospital type.Of the 29,861 women included, 51% and 21% had gestational weight gain above and below the guidelines, respectively. There was an association between gestational weight gain above the IOM guidelines and cesarean delivery in both nulliparous women (adjusted OR 1.44, 95% CI 1.31-1.59) and multiparous women (adjusted OR 1.26, 95% CI 1.13-1.41) and hypertensive diseases of pregnancy in nulliparous and multiparous women combined (adjusted OR 1.84, 95% CI 1.66-2.04). For the neonatal outcomes, gestational weight gain above the IOM guidelines was associated with shoulder dystocia (adjusted OR 1.74, 95% CI 1.41-2.14), macrosomia (adjusted OR 2.66, 95% CI 2.03-3.48), and neonatal hypoglycemia (adjusted OR 1.60, 95% CI 1.16-2.22). Gestational weight gain below the guidelines was associated with spontaneous (adjusted OR 1.50, 95% CI 1.31-1.73) and indicated (adjusted OR 1.34, 95% CI 1.12-1.60) preterm birth.In a large, diverse cohort with prospectively collected data, gestational weight gain below or above guidelines is associated with a variety of adverse pregnancy outcomes.

OBJECTIVE: To evaluate maternal and neonatal outcomes in healthy, nulliparous women classified with stage 1 hypertension under the revised American College of Cardiology (ACC) and American Heart Association Guidelines (AHA) and to evaluate the effects of low-dose aspirin on maternal and neonatal outcomes in this population. METHODS: We conducted a secondary analysis of data from a multicenter randomized, double blind, placebo-controlled trial of low-dose aspirin for prevention of preeclampsia in nulliparous, low-risk women recruited between 13 and 25 weeks of gestation. Of the 3,134 nulliparous women enrolled in the original study, 2,947 women with singleton pregnancies and without missing data were included in this analysis. Blood pressure was measured at enrollment between 13 and 25 weeks of gestation and outcomes were adjudicated from the medical record. RESULTS: One hundred sixty-four participants were identified with lower range stage 1 hypertension (5.6%), systolic blood pressure 130–135 mmHg and/or diastolic blood pressure 80–85mmHg, by the new ACC–AHA guidelines. Within the placebo group (n=1482), women with stage 1 hypertension had a significantly increased incidence of preeclampsia compared to normotensive women, 15.3% (15/98) versus 5.4% (75/1384), RR 2.66; 95%CI 1.56–4.54, p

Objective: To assess whether treatment of pregnant women with subclinical hypothyroidism or hypothyroxinemia alters neonatal TSH results. Study Design: A planned secondary analysis of data from two multi-center randomized, double-masked, placebo-controlled thyroxine replacement trials in pregnant women with either subclinical hypothyroidism or hypothyroxinemia. Infant heel-stick specimens were obtained before discharge. We compared TSH levels between neonates born to mothers allocated to treatment or placebo within each trial and between neonates in the placebo groups. Multiples of means were generated for day-of-life-specific data. Results: Neonatal TSH values were available for 573/677 (84.6%) newborns from the subclinical hypothyroidism trial and 461/526 (87.6%) newborns from the hypothyroxinemia trial. Neonatal TSH values did not differ in either trial by treatment group or between placebo groups (P > 0.05 for all comparisons). Conclusions: Neonatal TSH values did not differ with thyroid hormone replacement in pregnancies diagnosed with subclinical hypothyroidism or hypothyroxinemia., Precis: Thyroid hormone replacement in pregnant women with subclinical hypothyroidism or hypothyroxinemia does not significantly affect neonatal TSH values. (18 words)

Recently, the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines revised the recommendations for diagnosis of chronic hypertension. The new classification system includes a diagnosis of stage 1 hypertension in adults with blood pressures 130 to 139/80 to 89 mm Hg. We sought to compare outcomes among women at high risk for preeclampsia with stage 1 hypertension and assessed whether women with stage 1 hypertension had benefit from aspirin treatment compared with high-risk normotensive women. We performed a secondary analysis of the high-risk aspirin trial and included women with prior preeclampsia or diabetes mellitus. Among these women, 827 (81%) were classified as normotensive, whereas 193 (19%) were classified as stage 1 hypertensive. Among women receiving placebo, preeclampsia occurred significantly more often in women with stage 1 hypertension compared with normotensive high-risk women after adjustment for maternal age and body mass index (39.1% versus 15.1%; risk ratio, 2.49; 95% confidence interval, 1.74–3.55). Further, women with stage 1 hypertension had a significant risk reduction related to aspirin prophylaxis (risk ratio, 0.61; 95% confidence interval, 0.39–0.94) that was not seen in normotensive high-risk women (risk ratio, 0.97; 95% confidence interval, 0.70–1.34). Application of the American College of Cardiology/American Heart Association guidelines in a high-risk population demonstrates that in the setting of other risk factors, the presence of stage 1 hypertension is associated with a significantly increased risk of preeclampsia when compared with high-risk normotensive women. These findings emphasize the importance of recognition of stage 1 hypertension as an additive risk factor in women at high risk for preeclampsia and the benefit of aspirin.

Aims Buprenorphine (BUP) is approved by the US Food and Drug Administration for the treatment of opioid addiction. The current dosing regimen of BUP in pregnant women is based on recommendations designed for nonpregnant adults. However, physiological changes during pregnancy may alter BUP exposure and efficacy. The objectives of this study were to develop a physiologically-based pharmacokinetic (PBPK) model for BUP in pregnant women, to predict changes in BUP exposure at different stages of pregnancy, and to demonstrate the utility of PBPK modelling in optimizing BUP pharmacotherapy during pregnancy. Methods A full PBPK model for BUP was initially built and validated in healthy subjects. A fetoplacental compartment was included as a combined compartment in this model to simulate pregnancy induced anatomical and physiological changes. Further, gestational changes in physiological parameters were incorporated in this model. The PBPK model predictions of BUP exposure in pregnancy and during the postpartum period were compared to published data from a prospective clinical study. Results The predicted BUP plasma concentration-time profiles in the virtual pregnant populations are consistent with the observed data in the 2nd and 3rd trimesters, and the postpartum period. The differences in the predicted means of dose normalized area under the plasma drug concentration-time curve up to 12 h, average concentration and maximum concentration were within ±25% of the corresponding observed means with the exception of average concentration in the 3rd trimester (-26.3%). Conclusion PBPK model-based simulation may be a useful tool to optimize BUP pharmacotherapy during pregnancy, obviating the need to perform pharmacokinetic studies in each trimester and the postpartum period that normally require intensive blood sampling.

Objective To estimate the contributions of patient and health care provider-hospital characteristics to the variation in the frequency of nulliparous, term, singleton, vertex cesarean delivery in a multi-institutional U.S. cohort. Methods We performed a secondary analysis of the multicenter Assessment of Perinatal Excellence cohort of 115,502 mother and neonatal pairs who were delivered at 25 hospitals between March 2008 and February 2011. Women met inclusion criteria if they were nulliparous and delivered a singleton in vertex presentation at term. Hospital ranks for nulliparous, term, singleton, vertex cesarean delivery frequency were determined after risk adjustment. The fraction of variation in nulliparous, term, singleton, vertex cesarean delivery frequency attributable to patient and health care provider-hospital characteristics was assessed using hierarchical logistic regression. Results Of the 115,502 deliveries in the initial cohort, 38,275 nulliparous, term, singleton, vertex deliveries met inclusion criteria. The median hospital nulliparous, term, singleton, vertex cesarean delivery frequency was 25.3% with a range from 15.0% to 35.2%. The majority of hospitals (16/25) changed rank quintiles after risk adjustment; overall the changes in rank were not statistically significant (P=.53). Patient characteristics accounted for 24% of the nulliparous, term, singleton, vertex cesarean delivery variation. The analyzed health care provider-hospital characteristics were not significantly associated with cesarean delivery frequency. Conclusion Although patient characteristics accounted for some of the variation in nulliparous, term, singleton, vertex cesarean delivery frequency and accounting for case mix had implications for hospital cesarean delivery rankings, the majority of the variation was not explained by the characteristics evaluated. These findings emphasize the importance of continued efforts to understand aspects of obstetric care, including case mix, that contribute to cesarean delivery variation.