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Objective: To estimate the association between lipoprotein particle concentrations in pregnancy and gestational age at delivery.Design: Prospective cohort study.Setting: The study was conducted in the USA at the University of North Carolina.Population: We assessed 715 women enrolled in the Pregnancy, Infection, and Nutrition study from 2001 to 2005.Methods: Fasting blood was collected at two time points (<20 and 24-29 weeks of gestation). Nuclear magnetic resonance (NMR) quantified lipoprotein particle concentrations [low-density lipoprotein (LDL), high-density lipoprotein (HDL), very-low density lipoprotein (VLDL)] and 10 subclasses of lipoproteins. Concentrations were assessed as continuous measures, with the exception of medium HDL which was classified as any or no detectable level, given its distribution. Cox proportional hazards models estimated hazard ratios (HR) for gestational age at delivery adjusting for covariates.Main Outcome Measures: Gestational age at delivery, preterm birth (<37 weeks of gestation), and spontaneous preterm birth.Results: At <20 weeks of gestation, three lipoproteins were associated with later gestational ages at delivery [large LDLNMR (HR 0.78, 95% CI 0.64-0.96), total VLDLNMR (HR 0.77, 95% CI 0.61-0.98), and small VLDLNMR (HR 0.78, 95% CI 0.62-0.98], whereas large VLDLNMR (HR 1.19, 95% CI 1.01-1.41) was associated with a greater hazard of earlier delivery. At 24-28 weeks of gestation, average VLDLNMR (HR 1.25, 95% CI 1.03-1.51) and a detectable level of medium HDLNMR (HR 1.90, 95% CI 1.19-3.02) were associated with earlier gestational ages at delivery.Conclusion: In this sample of pregnant women, particle concentrations of VLDLNMR , LDLNMR , IDLNMR , and HDLNMR were each independently associated with gestational age at delivery for all deliveries or spontaneous deliveries <37 weeks of gestation. These findings may help formulate hypotheses for future studies of the complex relationship between maternal lipoproteins and preterm birth.Tweetable Abstract: Nuclear magnetic resonance spectroscopy may identify lipoprotein particles associated with preterm delivery. [ABSTRACT FROM AUTHOR]

Objective: To compare maternal genotypes between women with and without significant prolongation of pregnancy in the setting of 17-alpha hydroxyprogesterone caproate (17-P) administration for the prevention of recurrent preterm birth (PTB).Design: Case-control.Setting: Three tertiary-care centres across the USA.Population: Women (n = 99) with ≥ 1 prior singleton spontaneous PTB, receiving 17-P.Methods: Women were classified as having successful prolongation of pregnancy during the 17-P treated pregnancy, in two ways: (1) Definition A: success/non-success based on difference in gestational age at delivery between 17-P-treated and untreated pregnancies (success: delivered ≥ 3 weeks later with 17-P) and (2) Definition B: success/non-success based on reaching term (success: delivered at term with 17-P).Main Outcome Measures: To assess genetic variation, all women underwent whole exome sequencing. Between-group sequence variation was analysed with the Variant Annotation, Analysis, and Search Tool (VAAST). Genes scored by VAAST with P < 0.05 were then analysed with two online tools: (1) Protein ANalysis THrough Evolutionary Relationships (PANTHER) and (2) Database for Annotation, Visualization, and Integrated Discovery (DAVID).Results: Using Definition A, there were 70 women with successful prolongation and 29 without; 1375 genes scored by VAAST had P < 0.05. Using Definition B, 47 women had successful prolongation and 52 did not; 1039 genes scored by VAAST had P < 0.05. PANTHER revealed key differences in gene ontology pathways. Many genes from definition A were classified as prematurity genes (P = 0.026), and those from definition B as pharmacogenetic genes (P = 0.0018); (P, non-significant after Bonferroni correction).Conclusion: A novel analytic approach revealed several genetic differences among women delivering early vs later with 17-P.Tweetable Abstract: Several key genetic differences are present in women with recurrent preterm birth despite 17-P treatment. [ABSTRACT FROM AUTHOR]

OBJECTIVE: To measure the effect of prophylactic antibiotics given at time of previable prelabor rupture of membranes (PROM) on latency. METHODS: Single center, retrospective cohort study of singleton pregnancies with previable (<23 0/7weeks) PROM. Antibiotics were given at clinician discretion. The primary outcomewas latency, defined as duration of time between previable PROM and delivery. Secondary outcomes included delivery at ≥ 23weeks, infant survival, and maternal morbidity. Bivariate analysis compared maternal covariates between women who did and did not receive antibiotics. Antibiotic effect on latency was modeled using a Cox proportional hazards ratio. RESULTS: 213 women with previable PROM were identified; 77 (36%) remained pregnant and thus were included in this analysis. Forty (52%) of 77 received antibiotics. Compared to women who did not receive antibiotics, those who did had PROM at a later median (IQR) estimated gestational age, EGA, (22.2weeks [20.7, 22.5] vs. 19.3weeks [18, 20.7], p < 0.01). Median (IQR) latency was not different between women who did and did not receive antibiotics (2.2 [0.7, 3.9] vs. 1.5 [0.5, 4.6] weeks, p = 0.49). More infants survived to discharge among women who received antibiotics compared to those who did not [17(43%) vs. 3(8%), p < 0.01]. When adjusted for EGA at PROM, antibiotics were associated with longer latency (HR 0.57 [95% CI 0.33, 0.97], p = 0.01). Antibiotic use was not associated with differences in maternal morbidity. CONCLUSION: After adjusting for EGA at PROM, antibiotic receiptwas associated with longer latency. Larger prospective studies are needed to define the utility of prophylactic antibiotics in previable PROM. [ABSTRACT FROM AUTHOR]

Objective: The objective of this study was to assess the presence of newly acquired preterm birth (PTB) risk factors among primiparous women with no prior history of PTB.Design: Case-control study.Setting: Deliveries occurring within a large healthcare system from 2002 to 2012.Population: Women with their first two consecutive pregnancies carried to ≥20(0/7)  weeks' gestation.Methods: Those delivering the first pregnancy at term and the second preterm ≥20(0/7) and <37(0/7)  weeks (term-preterm cases) were compared with women with a term birth in their first two pregnancies (term-term controls). Social factors with the potential to change between the first and second pregnancies and intrapartum labour characteristics in the first pregnancy were compared between cases and controls.Main Outcome Measures: Risk factors for term-preterm sequence.Results: About 38 215 women met inclusion criteria; 1353 (3.8%) were term-preterm cases. Cases and controls were similar with regard to race/ethnicity and maternal age at the time of the first and second deliveries. Cases delivered their second pregnancy approximately 3 weeks earlier (35.7 versus 39.1, P < 0.001). In multivariable models accounting for known PTB risk factors, women with a caesarean delivery in the first pregnancy [adjusted odds ratio (aOR) = 2.20; 95% confidence interval (CI) 1.57-3.08], new tobacco use (aOR = 2.33; 95% CI 1.61-3.38), and an interpregnancy interval <18 months (aOR = 1.37; 95% CI 1.21-1.55) were at increased risk of term-preterm sequence.Conclusion: Caesarean delivery in the first pregnancy, new tobacco use, and short interpregnancy interval <18 months are significant risk factors for term-preterm sequence. Women should receive postpartum counselling regarding appropriate interpregnancy interval and cessation of tobacco use.Tweetable Abstract: Caesarean delivery in the 1st pregnancy is a significant risk factor for preterm birth following a term delivery. [ABSTRACT FROM AUTHOR]

Objective: To assess the neuroprotective effect of magnesium sulfate (MgSO4 ) in preterm children exposed to chorioamnionitis.Design: A secondary analysis of a multicentre randomised controlled trial of antenatal MgSO4 administered to women at risk of preterm birth for the prevention of cerebral palsy (CP). Singleton, non-anomalous pregnancies with clinical chorioamnionitis, delivering at ≥24 weeks of gestation, were selected. Cases were exposed to antepartum MgSO4 ; controls received placebo.Setting: Multicentre randomised controlled trial.Population: Singleton, non-anomalous pregnancies with clinical chorioamnionitis, delivering at ≥24 weeks of gestation.Methods: All data were analysed by intention to treat. Univariate and multivariate analyses were performed.Main Outcome Measures: Primary outcome was a composite of stillbirth, death by the age of 1 year, or moderate or severe CP by the age of 2 years. Secondary outcomes included a composite neonatal outcome as well as neurodevelopmental delay, defined as Bayley II mental and psychomotor developmental indices <70 at the age of 2 years. Subgroup analysis assessed these outcomes in children born at <28 weeks of gestation.Results: A total of 396 children were included, with 192 (48.5%) randomised to MgSO4 . Maternal and delivery characteristics were similar between the groups. The primary outcome occurred in 14.1% of children exposed to MgSO4 and 12.7% of children exposed to placebo (relative risk, RR 1.29; 95% CI 0.70-2.38). Rates of stillbirth, death, moderate-severe CP, and neurodevelopmental delay did not differ between groups. In the subgroup analysis of children born at <28 weeks of gestation, there was no difference in the rates of the primary outcome, nor in the secondary outcomes assessed. [Correction added on 02 March 2016 after online publication: There were errors in statistical data analysis and these have been corrected throughout the article.]Conclusions: Among children at risk for early preterm delivery exposed to chorioamnionitis, antenatal administration of MgSO4 was not associated with improved neurodevelopmental outcome. We do not recommend any change in the guidelines on the administration of MgSO4 for neuroprotection based on this study.Tweetable Abstract: MgSO4 was not associated with improved neurodevelopmental outcome in setting of chorioamnionitis. [ABSTRACT FROM AUTHOR]

Further, women with a history of adverse pregnancy outcomes may be less likely to consume substances, but because of their pregnancy history are more likely to deliver preterm, biasing the results against the abstainers. In conclusion, these data underscore the importance of screening for alcohol consumption across gestation, and reinforce continued recommendations for abstention from alcohol during pregnancy. [Extracted from the article]

Background: Spontaneous preterm birth (SPTB) is the leading cause of neonatal morbidity and mortality. It is a final common pathway for multiple etiologies, some of which are well known while others likely remain to be identified. Despite recent advancements in identifying genetic risk factors, the mechanisms of many SPTBs remain poorly understood due to the phenotypic heterogeneity and complexity. Large family-based studies decrease heterogeneity and improve power to identify genetic causes of SPTB., Objective: To identify inherited genetic factors in SPTB etiology using large families., Study Design: Using the Utah Population Database, which links a 4.5 million-person genealogy to state birth certificate and fetal death records, we identified large pedigrees containing multiple women with early SPTB (<34 weeks' gestation) and any SPTB (<37 weeks' gestation). We reviewed birth certificate data to exclude those with maternal and fetal diagnoses associated with iatrogenic preterm birth, resulting in 74 large multiplex pedigrees for early SPTB. Enrolled women with SPTB underwent comprehensive clinical phenotyping with review of primary medical records. Seven pedigrees, each containing at least 3 sampled women with SPTB, were the focus of this genetic study. High-density single-nucleotide polymorphism genotyping was conducted in maternal peripheral blood samples from women in the seven pedigrees. Shared genomic segments analysis was performed to identify genome-wide significant chromosomal regions shared in excess by women with SPTB., Results: We identified two genome-wide significant chromosomal regions. In single-pedigree SGS analysis, a 1.75 Mega base region in chromosome 8 (8q24.23) was shared by 5 out of 6 women with SPTB in a single large pedigree (false positive rate=0.028). In duo-pedigree analysis, a 1.05 Mega base region in the same 8q24.23 locus was identified in a second pedigree (false-positive rate [duo]=0.0019). The intersecting region at the 8q24.23 locus contains FAM135B (family with sequence similarity 135 member B) and KHDRBS3 (KH RNA-binding domain containing, signal transduction associated 3) genes, which have previously been implicated in oncogenesis and ovarian cancer, respectively. Duo-pedigree SPTB analysis also identified a second genome-wide significant 67 kilo base locus in chromosome 12 (12q21.1-q21.2) that was shared by all women with SPTB in two independent pedigrees (false-positive rate [duo]=0.01). The intersecting region at the 12q21.1-q21.2 locus contains CAPS2 (calcyphosine 2) and KCNC2 (potassium voltage-gated channel subfamily C member 2) genes, both implicated in vascular-related complications of pregnancy and preterm labor., Conclusion: Using large SPTB families, we identified shared chromosomal regions (8q24.23 and 12q21.1-q21.2), providing evidence for inherited (segregating) risk loci in SPTB etiology. Further investigation into genes in SPTB etiology, including functional validation may provide avenues for novel therapeutic development and guide efforts for SPTB prevention to prolong pregnancy and improve outcomes., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Objective: Maternal smoking is associated with as much as a 50% reduced risk of preeclampsia, despite increasing risk of other poor pregnancy outcomes that often co-occur with preeclampsia, such as preterm birth and fetal growth restriction. Researchers have long sought to understand whether this perplexing association is biologically based, or a result of noncausal mechanisms. We examined whether smoking-response genes modify the smoking-preeclampsia association to investigate potential biological explanations., Study Design: We conducted a nested case-control study within the Norwegian Mother, Father and Child Birth Cohort (1999-2008) of 2,596 mother-child dyads. We used family-based log-linear Poisson regression to examine modification of the maternal smoking-preeclampsia relationship by maternal and fetal single nucleotide polymorphisms involved in cellular processes related to components of cigarette smoke ( n  = 1,915 with minor allele frequency ≥10%). We further investigated the influence of smoking cessation during pregnancy., Results: Three polymorphisms showed overall ( p  < 0.001) multiplicative interaction between smoking and maternal genotype. For rs3765692 ( TP73 ) and rs10770343 ( PIK3C2G ), protection associated with smoking was reduced with two maternal copies of the risk allele and was stronger in continuers than quitters (interaction p  = 0.02 for both loci, based on testing 3-level smoking by 3-level genotype). For rs2278361 ( APAF1 ) the inverse smoking-preeclampsia association was eliminated by the presence of a single risk allele, and again the trend was stronger in continuers than in quitters (interaction p  = 0.01)., Conclusion: Evidence for gene-smoking interaction was limited, but differences by smoking cessation warrant further investigation. We demonstrate the potential utility of expanded dyad methods and gene-environment interaction analyses for outcomes with complex relationships between maternal and fetal genotypes and exposures., Key Points: · Maternal and fetal genotype may differentially influence preeclampsia.. · Smoking-related genes did not strongly modify smoking-preeclampsia association.. · Smoking cessation reduced strength of gene by smoking interactions.., Competing Interests: None declared., (Thieme. All rights reserved.)

Objective: To evaluate the association of community-level social vulnerability with COVID-19 vaccine hesitancy and vaccination among pregnant and postpartum individuals., Methods: Prospective cohort study assessing COVID-19 vaccine hesitancy among pregnant and postpartum individuals. We performed a baseline survey on COVID-19 vaccine hesitancy from 03/22/21 to 04/02/21, and a follow-up survey on COVD-19 vaccination status 3- to 6-months later. The primary exposure was the Centers for Disease Control and Prevention SVI (Social Vulnerability Index), measured in quartiles. Higher SVI quartiles indicated greater community-level social vulnerability with the lowest quartile (quartile 1) as the referent group. The primary outcome was COVID-19 vaccine hesitancy on the baseline survey (uncertainty or refusal of the vaccine), and the secondary outcome was self-report of not being vaccinated (unvaccinated) for COVID-19 on the follow-up survey., Results: Of 456 assessed individuals, 46% reported COVID-19 vaccine hesitancy on the baseline survey; and of 290 individuals (290/456, 64%) who completed the follow-up survey, 48% (140/290) were unvaccinated. The frequency of baseline vaccine hesitancy ranged from 25% in quartile 1 (low SVI) to 68% in quartile 4 (high SVI), and being unvaccinated at follow-up ranged from 29% in quartile 1 to 77% in quartile 4. As social vulnerability increased, the risk of COVID-19 vaccine hesitancy at baseline increased (quartile 2 aRR (adjusted relative risk): 1.46; 95% CI:0.98 to 2.19; quartile 3 aRR: 1.86; 95% CI:1.28 to 2.71; and quartile 4 aRR: 2.24; 95% CI:1.56 to 3.21), as did the risk of being unvaccinated at follow-up (quartile 2 aRR: 1.00; 95% CI:0.66 to 1.51; quartile 3 aRR: 1.68; 95% CI:1.17 to 2.41; and quartile 4 aRR: 1.82; 95% CI:1.30 to 2.56)., Conclusions: Pregnant and postpartum individuals living in an area with higher community-level social vulnerability were more likely to report COVID-19 vaccine hesitancy and subsequently to be unvaccinated at follow-up., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background: Despite current guidelines recommending universal vaccination, the frequency of vaccination in pregnancy for influenza and tetanus-diphtheria-acellular pertussis remains low., Objective: This study aimed to evaluate the association between community-level social vulnerability and influenza and anticipated tetanus-diphtheria-acellular pertussis vaccinations among pregnant and postpartum individuals., Study Design: We conducted a cross-sectional survey of vaccine hesitancy in the peripartum period among pregnant and postpartum participants enrolled in prenatal care at a single tertiary care center from March 22, 2021, to April 02, 2021. Participant addresses were geocoded using ArcGIS and linked at the census tract level. The primary exposure was community-level social vulnerability as measured by the US Centers for Disease Control and Prevention's Social Vulnerability Index. This index incorporates 15 census variables to produce a composite score and subscores across 4 major thematic domains (socioeconomic status, household composition and disability, minority status and language, and housing type and transportation). The scores range from 0 to 1, with higher values indicating greater social vulnerability. The primary outcomes were self-reported influenza vaccination during the current influenza season and having received or planning to receive the tetanus-diphtheria-acellular pertussis vaccination in pregnancy. We used multivariable logistic regression and adjusted for age, self-reported race and ethnicity, parity, trimester of pregnancy, and chronic comorbid conditions., Results: Of 456 assessed individuals (95% pregnant individuals and 5% postpartum individuals), the frequency of influenza vaccination was 58% (95% confidence interval, 53-62), and the anticipated tetanus-diphtheria-acellular pertussis vaccination was 72% (95% confidence interval, 68-76). Individuals from communities with a higher Social Vulnerability Index were less likely to report vaccination in pregnancy than those from communities with a lower Social Vulnerability Index. Specifically, for each 0.1-unit increase in the Social Vulnerability Index, the odds of influenza vaccination (adjusted odds ratio, 0.23; 95% confidence interval, 0.11-0.46) and anticipated tetanus-diphtheria-acellular pertussis vaccination (adjusted odds ratio, 0.24; 95% confidence interval, 0.11-0.53) decreased by >70%. By domain, the Social Vulnerability Index subscores of socioeconomic status (influenza adjusted odds ratio, 0.20 [95% confidence interval, 0.10-0.40]; tetanus-diphtheria-acellular pertussis adjusted odds ratio, 0.25 [95% confidence interval, 0.12-0.53]) and housing type and transportation (influenza adjusted odds ratio, 0.41 [95% confidence interval, 0.19-0.84; tetanus-diphtheria-acellular pertussis adjusted odds ratio, 0.39 [95% confidence interval, 0.18-0.87) were inversely associated with a lower odds of influenza and tetanus-diphtheria-acellular pertussis vaccinations., Conclusion: Pregnant and postpartum individuals living in areas with higher social vulnerability were less likely to report influenza and anticipated tetanus-diphtheria-acellular pertussis vaccinations in pregnancy. The Social Vulnerability Index could be used as a tool to improve vaccine equity and address disparities in vaccination in pregnancy., (Published by Elsevier Inc.)

The investigation of per- and polyfluorinated alkyl substances (PFAS) in environmental and biological samples relies on both high- and low-resolution mass spectrometry (MS) techniques. While high-resolution MS (HRMS) can be used for identification and quantification of novel compounds, low-resolution MS is the more commonly used and affordable approach for studies examining previously identified PFAS. Of note, perfluorobutanoic acid (PFBA) is one of the smaller PFAS observed in biological and environmental samples and has only one major MS/MS transition, preventing the use of qualitative transitions for verification. Recently, our laboratories undertook a targeted investigation of PFAS in the human placenta from high-risk pregnancies utilizing low-resolution, targeted MS/MS. Examination of placental samples revealed a widespread (n = 93/122 (76%)) chemical interferent in the quantitative ion channel for PFBA (213 → 169). PFBA concentrations were influenced by up to ∼3 ng/g. Therefore, additional chromatographic and HRMS/MS instrumentation was utilized to investigate the suspect peak and putatively assign the identity of the interfering compound as the saturated oxo-fatty acid (SOFA) 3-oxo-dodecanoic acid., Competing Interests: The research presented was not performed or funded by EPA and was not subject to EPA’s quality system requirements. The views expressed in this article are those of the author(s) and do not necessarily represent the views or the policies of the U.S. Environmental Protection Agency. The authors declare no competing financial interest.

Objective: Our objective was to examine if US obstetrician-gynecologists (OBGYNs) practice outside of evidenced-based guidelines and use a combination of interventions to prevent spontaneous preterm birth (sPTB)., Study Design: An electronic survey was distributed to members of the Pregnancy-Related Care Research Network (PRCRN), and also to members of the Society of Maternal-Fetal Medicine (SMFM). The survey consisted of questions regarding physician demographics, and the use of interventions to prevent sPTB in women with 1) a prior sPTB, 2) an incidental short cervix (no prior sPTB), and 3) a history of cervical insufficiency., Results: The PRCRN response rate was 58.6% (283/483) with an additional 143 responses from SMFM members. Among PRCRN responders, 82.7% were general OBGYNs and 17.3% were Maternal-Fetal Medicine subspecialists. Respondents were from all geographic regions of the country; most practiced in a group private practice (42.6%) or academic institution (31.4%). In women with prior sPTB, 45.2% of respondents would consider combination therapy, most commonly weekly intramuscular progesterone (IM-P) and serial cervical length (CL) measurements. If the patient then develops a short cervix, 33.7% would consider adding an ultrasound-indicated cerclage. In women with an incidental short cervix, 66.8% of respondents were likely to recommend single therapy with daily vaginal progesterone (VP). If a patient developed an incidentally dilated cervix, 40.8% of PRCRN respondents would recommend dual therapy, most commonly cerclage + VP, whereas 64.3% of SMFM respondents were likely to continue with VP only. In women with a history of cervical insufficiency, 47% of PRCRN respondents indicated they would consider a combination of IM-P, history-indicated cerclage and serial CL measurements., Conclusion: Although not currently supported by evidence-based medicine, combination therapy is commonly being used by U.S. OBGYNs to prevent sPTB in women with risk factors such as prior sPTB, short or dilated cervix or more than one of these risks., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Prenatal exposure to per- and polyfluoroalkyl substances (PFAS), a ubiquitous class of chemicals, is associated with adverse outcomes such as pre-eclampsia, low infant birth weight, and later-life adiposity. The objectives of this study were to examine PFAS levels in the placenta and identify sociodemographic risk factors in a high-risk pregnancy cohort ( n = 122) in Chapel Hill, North Carolina. Of concern, PFOS, PFHxS, PFHpS, and PFUnA were detected above the reporting limit in 99, 75, 55, and 49% of placentas, respectively. Maternal race/ethnicity was associated with significant differences in PFUnA levels. While the data from this high-risk cohort did not provide evidence for an association with hypertensive disorders of pregnancy, fetal growth, or gestational age, the prevalence of detectable PFAS in the placenta suggests a need to biomonitor for exposure to PFAS during pregnancy. Future research should investigate factors underlying the differences in PFAS levels in association with a mother's race/ethnicity, as well as potential effects on pregnancy and child health.

This document addresses the current coronavirus disease 2019 (COVID-19) pandemic for providers and patients in labor and delivery (L&D). The goals are to provide guidance regarding methods to appropriately screen and test pregnant patients for COVID-19 prior to, and at admission to L&D reduce risk of maternal and neonatal COVID-19 disease through minimizing hospital contact and appropriate isolation; and provide specific guidance for management of L&D of the COVID-19-positive woman, as well as the critically ill COVID-19-positive woman. The first 5 sections deal with L&D issues in general, for all women, during the COVID-19 pandemic. These include Section 1: Appropriate screening, testing, and preparation of pregnant women for COVID-19 before visit and/or admission to L&D Section 2: Screening of patients coming to L&D triage; Section 3: General changes to routine L&D work flow; Section 4: Intrapartum care; Section 5: Postpartum care; Section 6 deals with special care for the COVID-19-positive or suspected pregnant woman in L&D and Section 7 deals with the COVID-19-positive/suspected woman who is critically ill. These are suggestions, which can be adapted to local needs and capabilities., (© 2020 Elsevier Inc. All rights reserved.)

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., (U.S. Government work not protected by U.S. copyright.)

Objective: To identify factors associated with previable delivery in second trimester preterm rupture of membranes (PROM)., Study Design: We conducted a single-center retrospective cohort study of women with pregnancies complicated by second trimester PROM (14.0-21.9 weeks' gestation) from 2000 to 2015 who elected expectant pregnancy management and achieved at least 24 hours latency. Maternal characteristics and clinical factors were compared among pregnancies that reached viability (≥ 23.0 weeks) and pregnancies delivered before viability (< 23.0 weeks) using appropriate statistical methods., Results: Of 73 pregnancies complicated by second trimester PROM, 49 (67%) delivered before viability. Maternal race, history of preterm birth, and tobacco use were similar between women who delivered < 23 weeks versus ≥ 23 weeks. Gestational age at PROM, cervical dilation > 1cm, Group B streptococcus carrier status, bacterial vaginosis, and chlamydial infection during pregnancy were similar between groups. Median time to delivery was significantly shorter in women who delivered < 23 weeks compared with those who reached ≥ 23 weeks (6 vs. 46 days, p  < 0.01)., Conclusion: Previable delivery occurred in the majority of women with second trimester PROM. No maternal or clinical factors were associated with delivery prior to viability. Counseling women with second trimester PROM should include the inability to determine which pregnancies will reach viability., Competing Interests: None., (Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.)

Objective: To quantify the effects of operative blood loss during cesarean on tissue and plasma cefazolin concentrations., Study Design: This was a prospective observational study of singleton pregnancies undergoing scheduled cesarean between 34 and 40 weeks. Cefazolin administered prior to skin incision. Maternal plasma samples were obtained (Time 1[T1]: immediately, T2: 20 minutes, T3: 40 minutes, and T4: 60 minutes after cefazolin infusion). Subcutaneous adipose tissue sampled before and after fascia. Primary outcome was subcutaneous adipose cefazolin level after fascial closure. Formal quantitative blood loss (QBL) performed. Women with higher QBL, those at/above 75% of QBL in this population, were compared with those with lower QBL (QBL below 75%). Data analyzed using bivariable statistics., Results: Ninety-two women were screened, 32 were eligible, and 20 enrolled. Median QBL was 630 mL (interquartile range [IQR]: 473-818) and 1,160 mL (IQR: 1,000-1,560) in the low and high QBL groups, respectively. Demographics and operative characteristics were similar. Median adipose cefazolin level after fascial closure did not differ between the groups (3.5 vs. 3.9 μg/g, p  = 0.75). No differences in maternal plasma cefazolin concentrations between the groups at any time point or in pharmacokinetic parameters were seen., Conclusion: Intraoperative maternal plasma concentrations and adipose levels of cefazolin are similar between women with high and low blood loss at the time of cesarean delivery., Competing Interests: None., (Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.)

Objective  This study was aimed to measure the effects of a high-fat diet and metformin on placental mechanistic target of rapamycin (mTOR) signaling in mice. Study Design  Pregnant friend virus B (FVB)-strain mice were allocated on embryonic day (e) 0.5 to one of four groups; group 1: control diet (CD, 10% fat) + control treatment (CT), group 2: CD + metformin treatment (MT), group 3: high-fat diet (HFD, 60% fat) + CT, and group 4: HFD + MT. Metformin (2.5 mg/mL) was provided in water; CT mice received water. Fetuses and placentas were collected. Western blot measured placental p-Akt and p-S6 expression. Results  20 dams (five/group) and 192 fetuses were studied. Compared with CD-fed, HFD-fed dams had higher placental p-Akt protein expression ( p  < 0.0001). Among HFD-dams, placental p-Akt was higher in metformin-treated compared with control-treated ( p  < 0.001). Among CD-fed dams, there was no significant difference in placental p-S6 expression in MT versus CT groups. Among HFD-fed dams placental p-S6 expression was lower in those exposed to metformin-treated versus controls ( p  = 0.001). Conclusion  Increased placental mTOR signaling and metformin inhibition of placental mTOR signaling only occurred in the presence of an HFD exposure. These findings suggest that metformin may modulate placental mTOR signaling in the presence of metabolic exposures during pregnancy.

The objective of this commentary is to describe the background, rationale, and methods of the PROLONG (Progestin's Role in Optimizing Neonatal Gestation) trial, which is a multicenter, multinational, placebo-controlled, randomized clinical trial (RCT) designed to assess the safety and efficacy of Makena (hydroxyprogesterone caproate injection, 250 mg/mL) in reducing the risk of preterm birth (PTB) and neonatal morbidity/mortality in women pregnant with a singleton gestation who had a previous singleton spontaneous PTB. The total sample size of the RCT will include 1,707 women. The trial has two coprimary outcomes: PTB less than 35 weeks and a composite neonatal morbidity and mortality index. This study sample size will provide 90% power to assess for a 35% reduction in neonatal morbidity and mortality. Secondary outcomes will include 2-year follow-up of infants. The trial is ongoing and targeted to complete recruitment in 2018., Competing Interests: C.G.-B. reports grants from AMAG Pharmaceuticals, during the conduct of the study. A.F.D. reports personal fees from InClin, personal fees from personal consulting, during the conduct of the study; personal fees from Hologic, outside the submitted work. R.B. and M.J.J. report being employed by AMAG Pharmaceuticals, who sponsored this clinical trial. J.R.B., S.P.C., B.L.H., J.M.L., T.M., S.C.B., and H.S.M. have nothing to disclose., (Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.)

Postpartum depression (PPD) is one of the most frequent complications of childbirth affecting ~500,000 women annually (prevalence 10% to 15%). Despite the documented adverse outcomes for mother and child, there remains a great need to develop prospective approaches to identify women at risk. This review examines some of the best-characterized molecular and clinical risk factors for PPD. We illustrate that this is a growing literature but there remains a lack of reliable molecular predictors for PPD. Current best predictors are clinical assessments for psychiatric history and adverse life events, highlighting the need for increased depression screening across the perinatal period.

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

Competing Interests: Conflict of interest: None.

Preterm birth remains a major cause of neonatal death and short and long-term disability in the US and across the world. The majority of preterm births are spontaneous and cervical length screening is one tool that can be utilized to identify women at increased risk who may be candidates for preventive interventions. The purpose of this document is to review the indications and rationale for CL screening to prevent preterm birth in various clinical scenarios. The Society for Maternal-Fetal Medicine recommends (1) routine transvaginal cervical length screening for women with singleton pregnancy and history of prior spontaneous preterm birth (grade 1A); (2) routine transvaginal cervical length screening not be performed for women with cervical cerclage, multiple gestation, preterm premature rupture of membranes, or placenta previa (grade 2B); (3) practitioners who decide to implement universal cervical length screening follow strict guidelines (grade 2B); (4) sonographers and/or practitioners receive specific training in the acquisition and interpretation of cervical imaging during pregnancy (grade 2B)., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Objective: This study aims to determine if antibiotics given for latency to women with twins and previable preterm premature rupture of membranes (PPROM) affect the duration from membrane rupture to delivery., Methods: A retrospective cohort study of twin pregnancies at a single center from 2000 to 2015 with previable (14 (0/7)-22 (6/7) weeks) PPROM was conducted. Women who were not candidates for expectant management or who elected for immediate delivery were excluded. Pregnancy complications, delivery data, and neonatal outcomes were compared between women who did and did not receive latency antibiotics. The primary outcome was latency., Results: Of 52 eligible women, 30 (64%) elected expectant management; 17 women received antibiotics and 13 did not. No demographic differences existed between the groups. The median gestational age of rupture was 20 and 20.3 weeks in the antibiotic group and no antibiotic group, respectively. Median latency was 0.8 and 2.4 weeks in the antibiotic and no antibiotic groups correspondingly (p = 0.21). Overall, 58.8 and 23.1% of women who did and didn't receive antibiotics developed chorioamnionitis (p = 0.07). Perinatal mortality and maternal complication rates were high, though not different between the groups., Conclusion: Currently, even though in singletons with previable PPROM there is a recommendation to consider administrating antibiotics, in the setting of twins, no evidence exists to support this.

Background: Although a weekly injection of 17-hydroxyprogestone caproate is recommended for preventing recurrent preterm birth, clinical experience in North Carolina suggested that many eligible patients were not receiving the intervention., Objective: Our study sought to assess how well practices delivering at 2 major hospitals were doing in providing access to 17-hydroxyprogesterone caproate treatment for eligible patients., Study Design: This retrospective cohort analysis studied all deliveries occurring between January 1, 2012, and December 31, 2013, at 2 large hospitals in North Carolina. Women were included if they had a singleton pregnancy and history of a prior spontaneous preterm birth. We extracted demographic, payer, and medical information on each pregnancy, including whether women had been offered, accepted, and received 17-hydroxyprogesterone caproate. Our outcome of 17-hydroxyprogesterone caproate coverage was defined as documentation of ≥1 injection of the drug., Results: Over the 2-year study period, 1216 women with history of a prior preterm birth delivered at the 2 study hospitals, of which 627 were eligible for 17-hydroxyprogesterone caproate eligible after medical record review. Only 296 of the 627 eligible women (47%; 95% confidence interval, 43-51%) received ≥1 dose of the drug. In multivariable analysis, hospital of delivery, later presentation for prenatal care, fewer prenatal visits, later gestation of prior preterm birth, and having had a term delivery immediately before the index pregnancy were all associated with failed coverage. Among those women who were "covered," the median number of 17-hydroxyprogesterone caproate injections was 9 (interquartile range, 4-15), with 84 of 296 charts (28%) not having complete information on the number of doses., Conclusion: Even under our liberal definition of coverage, less than half of eligible women received 17-hydroxyprogesterone caproate in this sample. Low overall use suggests that there is opportunity for improvement. Quality improvement strategies, including population-based measurement of 17-hydroxyprogesterone caproate coverage, are needed to fully implement this evidence-based intervention to decrease preterm birth., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Unlabelled: Pharmacogenomics and personalised medicine incorporate genetic factors, historical data, and environmental exposures to predict individual variation in response to medications. The study of pharmacology and pharmacogenomics is challenging in obstetrics, and our knowledge in this area lags behind other disciplines of medicine. Some preliminary data, however, suggest that some of the interindividual variation seen in response to medications given for the prevention (progesterone) and the treatment (nifedipine, terbutaline, and others) of preterm labour may be caused by pharmacogenomic effects. A comprehensive approach, integrating clinical data, environmental factors, including concomitant medications and genotype, to optimise the prevention and treatment strategies for preterm birth, is urgently needed., Tweetable Abstract: Some of the variation to meds for prematurity prevention/treatment may arise from pharmacogenomic effects., (© 2015 Royal College of Obstetricians and Gynaecologists.)

Objective: The objective of the study is to compare gestational age specific rates, risks and prospective risks of stillbirth., Methods: A retrospective cohort study of women with a singleton non-anomalous pregnancy was conducted. Definitions were chosen to maintain consistency with previous literature., Results: Rate was highest at 20 weeks, nadired at 41 weeks and rose thereafter. Risk was low earlier in gestation, nadired at 29 weeks and rose with increasing gestational age. Prospective risk was highest at 20 weeks, nadired at 40 weeks and rose at 42 weeks., Conclusions: Differences in trends of stillbirth are noted depending on the calculation. All of these calculations are useful in clinical practice.

Antiphospholipid antibodies are associated with a spectrum of pregnancy complications, including preeclampsia and small for gestational age (SGA) fetuses. We sought to assess anticardiolipin and anti-beta2-glycoprotein I (anti-beta2-GPI) IgG and IgM antibody prevalence and the relationship of these antibodies to pregnancy complications in women with the Factor V Leiden (FVL) mutation. The study comprised a secondary analysis of a multicenter, prospective observational study of FVL prevalence among 5188 asymptomatic pregnant women. A subset of 362 women (117 FVL heterozygotes, 245 matched controls) had serum collected at the time of the original study and underwent serum analysis for anticardiolipin and anti-beta2-GPI IgG and IgM as a part of this analysis. The primary outcome was preeclampsia and/or SGA (<10%). The overall prevalence of anticardiolipin and anti-beta2-GPI IgG and IgM antibodies was low and did not vary with FVL status. Forty-seven women (13.0%) developed preeclampsia and/or SGA. There were no differences in primary outcome rates between women with and without aPL antibodies, regardless of FVL mutation status. Among FVL carriers, the presence of antiphospholipid antibodies does not appear to contribute to adverse pregnancy outcome., (Copyright (c) 2010 Elsevier Ireland Ltd. All rights reserved.)

Background: Idiopathic infantile arterial calcification is a rare disorder that often results in fetal or neonatal demise. Few reports have detailed an early diagnosis, complete antenatal and postnatal imaging, and postmortem findings., Case: A patient presented at 33 weeks of gestation with hydrops fetalis. Idiopathic infantile arterial calcification was diagnosed using a fetal echocardiogram, and fetal demise occurred shortly thereafter. A complete postmortem evaluation included radiography and pathology. The patient's postpartum course was complicated by maternal respiratory distress and pulmonary edema., Conclusion: Finding calcified vessels in the context of fetal hydrops should lead one to consider idiopathic infantile arterial calcification. This diagnosis has important maternal and fetal implications. The detailed evaluation in this case is useful to clinicians in making a definitive diagnosis of idiopathic infantile arterial calcification. Clinicians should be aware that serious maternal complications can occur in these types of cases.

We present a 17-year-old Caucasian male with congenital pulmonary lymphangiectasia and an absent thoracic duct. This patient is unique as he did not present with the disorder until age 9.5 years. Since his initial presentation he has had recurrent chylothoraces and has been treated symptomatically. We discuss the possible implications of his disorder as well as some of the limited treatment that is available., (Copyright 2001 Wiley-Liss, Inc.)