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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.

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.

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.

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..

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.

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..

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.

ObjectiveTo characterize prescription and other medication use in a geographically and ethnically diverse cohort of women in their first pregnancy.MethodsIn a prospective, longitudinal cohort study of nulliparous women followed through pregnancy from the first trimester, medication use was chronicled longitudinally throughout pregnancy. Structured questions and aids were used to capture all medications taken as well as reasons they were taken. Total counts of all medications taken including number in each category and class were captured. Additionally, reasons the medications were taken were recorded. Trends in medications taken across pregnancy and in the first trimester were determined.ResultsOf the 9,546 study participants, 9,272 (97.1%) women took at least one medication during pregnancy with 9,139 (95.7%) taking a medication in the first trimester. Polypharmacy, defined as taking at least five medications, occurred in 2,915 (30.5%) women. Excluding vitamins, supplements, and vaccines, 73.4% of women took a medication during pregnancy with 55.1% taking one in the first trimester. The categories of drugs taken in pregnancy and in the first trimester include the following: gastrointestinal or antiemetic agents (34.3%, 19.5%), antibiotics (25.5%, 12.6%), and analgesics (23.7%, 15.6%, which includes 3.6%; 1.4% taking an opioid pain medication).ConclusionIn this geographically and ethnically diverse cohort of nulliparous pregnant women, medication use was nearly universal and polypharmacy was common.Clinical trial registrationClinicalTrials.gov, NCT01322529.

Background Preeclampsia remains a major cause of maternal and neonatal morbidity and mortality. Biologic plausibility, compelling preliminary data, and a pilot clinical trial support the safety and utility of pravastatin for the prevention of preeclampsia. Objective We previously reported the results of a phase I clinical trial using a low dose (10 mg) of pravastatin in high-risk pregnant women. Here, we report a follow-up, randomized trial of 20 mg pravastatin versus placebo among pregnant women with previous preeclampsia who required delivery before 34+6 weeks’ gestation with the objective of evaluating the safety and pharmacokinetic parameters of pravastatin. Study Design This was a pilot, multicenter, blinded, placebo-controlled, randomized trial of women with singleton, nonanomalous pregnancies at high risk for preeclampsia. Women between 12+0 and 16+6 weeks of gestation were assigned to receive a daily pravastatin dose of 20 mg or placebo orally until delivery. In addition, steady-state pravastatin pharmacokinetic studies were conducted in the second and third trimesters of pregnancy and at 4 to 6 months postpartum. Primary outcomes included maternal-fetal safety and pharmacokinetic parameters of pravastatin during pregnancy. Secondary outcomes included maternal and umbilical cord blood chemistries and maternal and neonatal outcomes, including rates of preeclampsia and preterm delivery, gestational age at delivery, and birthweight. Results Of note, 10 women assigned to receive pravastatin and 10 assigned to receive the placebo completed the trial. No significant differences were observed between the 2 groups in the rates of adverse or serious adverse events, congenital anomalies, or maternal and umbilical cord blood chemistries. Headache followed by heartburn and musculoskeletal pain were the most common side effects. We report the pravastatin pharmacokinetic parameters including pravastatin area under the curve (total drug exposure over a dosing interval), apparent oral clearance, half-life, and others during pregnancy and compare it with those values measured during the postpartum period. In the majority of the umbilical cord and maternal samples at the time of delivery, pravastatin concentrations were below the limit of quantification of the assay. The pregnancy and neonatal outcomes were more favorable in the pravastatin group. All newborns passed their brainstem auditory evoked response potential or similar hearing screening tests. The average maximum concentration and area under the curve values were more than 2-fold higher following a daily 20 mg dose compared with a 10 mg daily pravastatin dose, but the apparent oral clearance, half-life, and time to reach maximum concentration were similar, which is consistent with the previously reported linear, dose-independent pharmacokinetics of pravastatin in nonpregnant subjects. Conclusion This study confirmed the overall safety and favorable pregnancy outcomes for pravastatin in women at high risk for preeclampsia. This favorable risk-benefit analysis justifies a larger clinical trial to evaluate the efficacy of pravastatin for the prevention of preeclampsia. Until then, pravastatin use during pregnancy remains investigational.

BACKGROUND: Pregnant women treated with methadone as opioid maintenance therapy are more likely than women treated with buprenorphine to deliver preterm. Preterm birth is associated with less risk of neonatal abstinence syndrome (NAS). We sought to assess the role of preterm birth as a mediator of the relationship between in utero exposure to methadone and NAS compared with buprenorphine. METHODS: We studied 716 women receiving methadone or buprenorphine and delivering live-born infants at Magee-Womens Hospital, Pittsburgh, Pennsylvania (2013-2015). We implemented inverse probability weighted marginal structural models to isolate the role of preterm birth (

Objective We sought to determine if the rate of recurrent spontaneous preterm birth (PTB) in women treated with 17-α hydroxyprogesterone caproate (17-OHPC) is modified by maternal body mass index (BMI). Study Design We performed a secondary analysis of the Maternal-Fetal Medicine Units Network omega-3 fatty acid supplementation to prevent recurrent PTB randomized controlled trial. All women received 17-OHPC. Results A total of 708 women were included. Rates of spontaneous PTB did not vary significantly by BMI category. With stratification by obesity class and gestational age at delivery, the unadjusted risk for PTB using earlier gestational cutoffs (< 35, 32, and 28 weeks) demonstrated an association between preterm delivery and increasing severity of obesity. With adjustment for potential confounders, there was no statistically significant relationship between BMI and spontaneous PTB. Conclusion We demonstrated that the risk of PTB in women receiving 250 mg 17-OHPC is not dependent on maternal BMI after adjustment for confounding variables. Pharmacokinetic studies have demonstrated a wide variation in plasma concentration of 17-OHPC across the population with likely considerable overlap in plasma concentrations among the obese and nonobese population. Further studies are needed to evaluate the impact of BMI on efficacy of 17-OHPC prior to any dose adjustment in this population.

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.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.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.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).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.

Objective The objective of this study was to evaluate the impact of pregnancy history and 17-hydroxyprogesterone caproate (17-OHPC) treatment on cervical fluid cytokines and matrix metalloproteinases (MMPs). Study Design Cervical fluid was obtained between 160/7 and 246/7 weeks from women with only prior term births (controls, n = 26), women with one or more prior spontaneous preterm births (SPTBs) choosing to receive 17-OHPC (17-OHPC, n = 24), or to not receive 17-OHPC (refusers, n = 12). Cervical fluid collections were repeated 2, 4, and 8 weeks after the first sample and concentrations of MMPs and cytokines were measured by multiplex immune assay. Results Among women whose earliest prior delivery occurred between 16 and 23 weeks, cervical fluid concentration of interleukin (IL)-6, IL-10, and tumor necrosis factor (TNF)-α at baseline were significantly elevated when compared with cervical cytokines of women whose earliest delivery occurred between 32 and 36 weeks (relative risk ratio was 3.37 for IL-6 [95% confidence interval, CI, 1.08–10.53, p Conclusion The cervical fluid of women with a history of an early prior SPTB is characterized by inflammation that is unaffected by 17-OHPC.

Objective The objective of this study was to estimate whether the decision-to-incision (DTI) time for cesarean delivery (CD) is associated with differences in maternal and neonatal outcomes. Methods This analysis is of data from women at 25 U.S. medical centers with a term, singleton, cephalic nonanomalous gestation and no prior CD, who underwent an intrapartum CD. Perinatal and maternal outcomes associated with DTI intervals of ≤ 15, 16 to 30, and > 30 minutes were compared. Results Among 3,482 eligible women, median DTI times were 46 and 27 minutes for arrest and fetal indications for CD, respectively (p 30 minutes had similar odds to the referent group (DTI of 16–30 minutes) for the adverse neonatal and maternal composites (odds ratio [OR]: 0.83, 95% confidence interval [CI]: 0.40–1.71 and OR: 0.89, 95% CI: 0.63–1.27). For arrest disorders, the odds of the adverse neonatal composite were lower among women with a DTI of > 30 minutes (OR: 0.25, 95% CI: 0.08–0.77), and the adverse maternal composite was no different (OR: 1.15, 95% CI: 0.81–1.63). Conclusion In this analysis, DTI times longer than 30 minutes were not associated with worse maternal or neonatal outcomes.

Aims Opioid dependence is associated with high morbidity and mortality. Buprenorphine (BUP) is approved by the Food and Drug Administration to treat opioid dependence. There is a lack of clear consensus on the appropriate dosing of BUP due to interpatient physiological differences in absorption/disposition, subjective response assessment and other patient comorbidities. The objective of the present study was to build and validate robust physiologically based pharmacokinetic (PBPK) models for intravenous (IV) and sublingual (SL) BUP as a first step to optimizing BUP pharmacotherapy. Methods BUP-PBPK modelling and simulations were performed using SimCyp® by incorporating the physiochemical properties of BUP, establishing intersystem extrapolation factors-based in vitro–in-vivo extrapolation (IVIVE) methods to extrapolate in vitro enzyme activity data, and using tissue-specific plasma partition coefficient estimations. Published data on IV and SL-BUP in opioid-dependent and non-opioid-dependent patients were used to build the models. Fourteen model-naive BUP-PK datasets were used for inter- and intrastudy validations. Results The IV and SL-BUP-PBPK models developed were robust in predicting the multicompartment disposition of BUP over a dosing range of 0.3–32 mg. Predicted plasma concentration–time profiles in virtual patients were consistent with reported data across five single-dose IV, five single-dose SL and four multiple dose SL studies. All PK parameter predictions were within 75–137% of the corresponding observed data. The model developed predicted the brain exposure of BUP to be about four times higher than that of BUP in plasma. Conclusion The validated PBPK models will be used in future studies to predict BUP plasma and brain concentrations based on the varying demographic, physiological and pathological characteristics of patients.

Objective The objective was to estimate the optimal screen-positive 1-hour 50 g glucose challenge test (GCT) threshold for gestational diabetes (GDM) and predictive characteristics of increasing screen-positive GCT threshold values (135–199 mg/dL) for GDM. Study Design It is a secondary analysis of a multicenter mild GDM study. At 24 to 30 weeks' gestation, women with elevated GCT (135–199 mg/dL) completed a diagnostic 3-hour oral glucose tolerance test (OGTT). A novel change-point analysis method was used to compare the GDM rates for the adjacent GCT values, delineating categories of changing risk such that values within categories have equal risk for GDM. Positive (PPV) and negative (NPV) predictive values for GDM were computed for increasing GCT cut-offs. Results In 7,280 women with both GCT (135–199 mg/dL) and OGTT results, 4 GDM risk-equivalent GCT categories were identified with escalations at 144, 158, and 174 mg/dL (all p-values Conclusion Elevated GCT cut-off values between 135 and 143 mg/dL may carry equivalent GDM risk. No threshold GCT value

Background In the United States, drug addiction has become a nationwide health crisis. Recently, buprenorphine (BUP), a maintenance therapy approved by the Food and Drug Administration, has been increasingly used in pregnant women for the treatment of opioid use disorder. Pregnancy is associated with various anatomic and physiological changes, which may result in altered drug pharmacokinetics (PKs). Previously, we reported that dose-adjusted plasma concentrations of BUP are lower during pregnancy than after pregnancy. The mechanism(s) responsible for this difference has not yet been defined. Our study aimed to evaluate alterations in cytochromes P450 (CYP)- and uridine diphosphate glucunosyltransferases (UGT)-mediated metabolism of BUP during pregnancy to determine the mechanism(s) responsible for this observation. Methods Data from 2 clinical studies were included in the current analysis. Study 1 was a prospective, open-labeled, nonrandomized longitudinal BUP PK study in pregnant women with a singleton gestation, stabilized on twice-daily sublingual BUP opioid substitution therapy. Each subject participated in up to 3 studies during and after pregnancy (the second, third trimester, and postpartum). The design of study 2 was similar to study 1, with patients evaluated at different time points during the pregnancy (first, second-half of pregnancy), as well as during the postpartum period. In addition, the dosing frequency of BUP study 2 participants was not restricted to twice-daily dosing. At each study visit, blood samples were collected before a BUP dose, followed by multiple collection times (10-12) after the dose, for up to 12 hours or till the end of the dosing interval. Plasma concentrations of BUP and 3 metabolites were quantified using validated ultraperformance liquid chromatography-tandem mass spectrometric assays. Results In total, 19, 18, and 14 subjects completed the PK study during 1/2 trimester, third trimester, and postpartum, respectively. The AUC ratios of norbuprenorphine and norbuprenorphine glucuronide to buprenorphine, a measure of CYP3A mediated N-demethylation, were 1.89, 1.84, and 1.33 during the first and second, third trimesters, and postpartum, respectively. The AUC ratios of buprenorphine glucuronide to BUP, indicative of UGT activity, were 0.71, 2.07, and 0.3 at first/second trimesters, third trimester, and postpartum, respectively. Linear mixed-effect modeling analysis indicated that the AUC ratios of CYP- and UGT-mediated metabolism of BUP were significantly higher during pregnancy compared with postpartum. Conclusions The CYP and UGT activities were significantly increased as determined by the metabolic ratios of BUP during pregnancy compared with the postpartum period. The increased UGT activity appeared to account for a substantial part of the observed change in metabolic activity during pregnancy. This is in agreement with the need for BUP dose increment in pregnant women to reach similar BUP exposure and therapeutic effect as in nonpregnant subjects.

Objective To evaluate whether labor is associated with lower odds of respiratory morbidity among neonates born from 36 to 40 weeks of gestation and to assess whether this association varies by gestational age and maternal diabetic status. Methods We conducted a secondary analysis of women in the Assessment of Perinatal Excellence obstetric cohort who delivered across 25 U.S. hospitals over a 3-year period. Women with a singleton liveborn nonanomalous neonate who delivered from 36 to 40 weeks of gestation were included in our analysis. Those who received antenatal corticosteroids, underwent amniocentesis for fetal lung maturity, or did not meet dating criteria were excluded. Our primary outcome was composite neonatal respiratory morbidity, which included respiratory distress syndrome, ventilator support, continuous positive airway pressure, or neonatal death. Maternal characteristics and neonatal outcomes between women who labored and those who did not were compared. Multivariable logistic regression models were used to evaluate the association between labor and the primary outcome. Interactions between labor and diabetes mellitus and labor and gestational age were tested. Results Our analysis included 63,187 women who underwent labor and 10,629 who did not. There was no interaction between labor and diabetes mellitus (P=.90). However, there was a significant interaction between labor and gestational age (P=.01). In the adjusted model, labor was associated with lower odds of neonatal respiratory morbidity compared with no labor for neonates delivered from 36-39 weeks of gestation. A 1-week increase in gestational age was associated with a 1.2 times increase in the adjusted odds ratio for the neonatal outcome comparing labor and no labor. Conclusion Labor was associated with lower odds of the composite outcome among neonates delivered from 36-39 weeks of gestation. The magnitude of this association varied by gestational age. The association was similar for women with or without diabetes mellitus.

This study's primary objective was to fully characterize the pharmacokinetics of metformin in pregnant women with gestational diabetes mellitus (GDM) versus nonpregnant controls. Steady-state oral metformin pharmacokinetics in pregnant women with GDM receiving either metformin monotherapy (n = 24) or a combination with glyburide (n = 30) as well as in nonpregnant women with type 2 diabetes mellitus (T2DM) (n = 24) were determined utilizing noncompartmental techniques. Maternal and umbilical cord blood samples were collected at delivery from 38 women. With both 500- and 1000-mg doses, metformin bioavailability, volume of distribution beta (V β ), clearance, and renal clearance were significantly increased during pregnancy. In addition, in the women receiving metformin 500 mg, significantly higher metformin apparent oral clearance (CL/F) (27%), weight-adjusted renal secretion clearance (64%), and apparent oral volume of distribution beta (V β /F) (33%) were seen during pregnancy. Creatinine clearance was significantly higher during pregnancy. Increasing metformin dose from 500 to 1000 mg orally twice daily significantly increased V β /F by 28%, weight-adjusted V β /F by 32% and CL/F by 25%, and weight-adjusted CL/F by 28% during pregnancy. Mean metformin umbilical cord arterial-to-venous plasma concentration ratio was 1.0 ± 0.1, venous umbilical cord-to-maternal concentration ratio was 1.4 ± 0.5, and arterial umbilical cord-to-maternal concentration ratio was 1.5 ± 0.5. Systemic exposure after a 500-mg dose of metformin was lower during pregnancy compared with the nonpregnant women with T2DM. However, in patients receiving metformin 1000 mg, changes in estimated bioavailability during pregnancy offset the changes in clearance leading to no significant change in CL/F with the higher dose. SIGNIFICANCE STATEMENT: Gestational diabetes mellitus complicates 5%-13% of pregnancies and is often treated with metformin. Pregnant women undergo physiological changes that alter drug disposition. Preliminary data suggest that pregnancy lowers metformin concentrations, potentially affecting efficacy and safety. This study definitively describes pregnancy's effects on metformin pharmacokinetics and expands the mechanistic understanding of pharmacokinetic changes across the dosage range. Here we report the nonlinearity of metformin pharmacokinetics and the increase in bioavailability, clearance, renal clearance, and volume of distribution during pregnancy.