Genetic Predisposition to Adverse Neurodevelopmental Outcome of Extremely Low Birth Weight Infants.

OBJECTIVE: This study aimed to evaluate whether there are genetic variants associated with adverse neurodevelopmental outcomes in extremely low birth weight (ELBW) infants. STUDY DESIGN: We conducted a candidate gene association study in two well-defined cohorts of ELBW infants (<1,000 g). One cohort was for discovery and the other for replication. The discovery case-control analysis utilized anonymized DNA samples and evaluated 1,614 single-nucleotide polymorphisms (SNPs) in 145 genes concentrated in inflammation, angiogenesis, brain development, and oxidation pathways. Cases were children who died by age one or who were diagnosed with cerebral palsy (CP) or neurodevelopmental delay (Bayley II mental developmental index [MDI] or psychomotor developmental index [PDI] < 70) by 18 to 22 months. Controls were survivors with normal neurodevelopment. We assessed significant epidemiological variables and SNPs associated with the combined outcome of CP or death, CP, mental delay (MDI < 70) and motor delay (PDI < 70). Multivariable analyses adjusted for gestational age at birth, small for gestational age, sex, antenatal corticosteroids, multiple gestation, racial admixture, and multiple comparisons. SNPs associated with adverse neurodevelopmental outcomes with p < 0.01 were selected for validation in the replication cohort. Successful replication was defined as p < 0.05 in the replication cohort. RESULTS: Of 1,013 infants analyzed (452 cases, 561 controls) in the discovery cohort, 917 were successfully genotyped for >90% of SNPs and passed quality metrics. After adjusting for covariates, 26 SNPs with p < 0.01 for one or more outcomes were selected for replication cohort validation, which included 362 infants (170 cases and 192 controls). A variant in SERPINE1, which encodes plasminogen activator inhibitor (PAI1), was associated with the combined outcome of CP or death in the discovery analysis (p = 4.1 × 10-4) and was significantly associated with CP or death in the replication cohort (adjusted odd ratio: 0.4; 95% confidence interval: 0.2-1.0; p = 0.039). CONCLUSION: A genetic variant in SERPINE1, involved in inflammation and coagulation, is associated with CP or death among ELBW infants. KEY POINTS: · Early preterm and ELBW infants have dramatically increased risks of CP and developmental delay.. · A genetic variant in SERPINE1 is associated with CP or death among ELBW infants.. · The SERPINE1 gene encodes the serine protease inhibitor plasminogen activator inhibitor..

Knowledge, Judgment, and Skills in Reproductive Health Care and Abortion Are Essential to the Practice of Obstetrics and Gynecology.

A social contract exists between medicine and society. In fulfilling the social contract to our patients and society, physicians have an obligation to provide the evidence-based care that patients want and need. What do the data regarding knowledge, judgment, and skills required to practice obstetrics and gynecology show? Obstetrics and gynecology job task analyses assess the importance of knowledge, judgment, and skills through surveys asking practicing physicians about the criticality and frequency of a variety of task statements to create an importance score. Excerpts from a 2018 practice analysis survey clearly indicate that reproductive health care and abortion are important components of the knowledge, judgment, and skills to practice obstetrics and gynecology in the United States. These standards help to assure the knowledge, judgment, and skills of current and future generations of ob-gyns, so their patients and the public can be provided the comprehensive reproductive health care they want and need. It is sometimes important to restate principles and standards that have become ingrained in thoughts and practices that guide physicians and serve to protect our patients. This concept is important now, as our country, health care professionals, and patients examine the future of reproductive health care, including abortion.

Prediction of Cerebral Palsy or Death among Preterm Infants Who Survive the Neonatal Period.

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

Fetal Tachycardia in the Setting of Maternal Intrapartum Fever and Perinatal Morbidity.

OBJECTIVE: The fetal consequences of intrapartum fetal tachycardia with maternal fever or clinical chorioamnionitis are not well studied. We evaluated the association between perinatal morbidity and fetal tachycardia in the setting of intrapartum fever. STUDY DESIGN: Secondary analysis of a multicenter randomized control trial that enrolled 5,341 healthy laboring nulliparous women ≥36 weeks' gestation. Women with intrapartum fever ≥ 38.0°C (including those meeting criteria for clinical chorioamnionitis) after randomization were included in this analysis. Isolated fetal tachycardia was defined as fetal heart rate (FHR) ≥160 beats per minute for at least 10 minutes in the absence of other FHR abnormalities. FHR abnormalities other than tachycardia were excluded from the analysis. The primary outcome was a perinatal composite (5-minute Apgar's score ≤3, intubation, chest compressions, or mortality). Secondary outcomes included low arterial cord pH (pH < 7.20), base deficit ≥12, and cesarean delivery. RESULTS: A total of 986 (18.5%) of women in the trial developed intrapartum fever, and 728 (13.7%) met criteria to be analyzed; of these, 728 women 336 (46.2%) had maternal-fetal medicine (MFM) reviewer-defined fetal tachycardia, and 349 of the 550 (63.5%) women during the final hour of labor had validated software (PeriCALM) defined fetal tachycardia. After adjusting for confounders, isolated fetal tachycardia was not associated with a significant difference in the composite perinatal outcome (adjusted odds ratio [aOR] = 3.15 [0.82-12.03]) compared with absence of tachycardia. Fetal tachycardia was associated with higher odds of arterial cord pH <7.2, aOR = 1.48 (1.01-2.17) and of infants with a base deficit ≥ 12, aOR = 2.42 (1.02-5.77), but no significant difference in the odds of cesarean delivery, aOR = 1.33 (0.97-1.82). CONCLUSION: Fetal tachycardia in the setting of intrapartum fever or chorioamnionitis is associated with significantly increased fetal acidemia defined as a pH <7.2 and base excess ≥12 but not with a composite perinatal morbidity. KEY POINTS: · The perinatal outcomes associated with fetal tachycardia in the setting of maternal fever are undefined.. · Fetal tachycardia was not significantly associated with perinatal morbidity although the sample size was limited.. · Fetal tachycardia was associated with an arterial cord pH <7.2 and base deficit of 12 or greater..

Population-Based Estimation of the Preterm Birth Rate in Lilongwe, Malawi: Making Every Birth Count.

Objective The objective of this study was to perform a population-based estimation of the preterm birth (PTB) rate in regions surrounding Lilongwe, Malawi. Study Design We partnered with obstetrician specialists, community health workers, local midwives, and clinicians in a 50 km region surrounding Lilongwe, Malawi, to perform a population-based estimation of the PTB rate during the study period from December 1, 2012 to May 19, 2015. Results Of the 14,792 births captured, 19.3% of births were preterm, including preterm early neonatal deaths. Additional PTB risk factors were similarly prevalent including domestic violence, HIV, malaria, anemia, and malnutrition. Conclusion When performing a population-based estimation of the rate of PTB, including women without antenatal care and women delivering at home, the 19.3% rate of PTB is among the highest recorded globally. This is accompanied by a high rate of risk factors and comorbid conditions.

Sex-Specific Genetic Susceptibility to Adverse Neurodevelopmental Outcome in Offspring of Pregnancies at Risk of Early Preterm Delivery.

OBJECTIVE: To evaluate sex-specific genetic susceptibility to adverse neurodevelopmental outcome (ANO, defined as cerebral palsy [CP], mental, or psychomotor delay) at risk for early preterm birth (EPTB, < 32 weeks). STUDY DESIGN: Secondary case-control analysis of a trial of magnesium sulfate (MgSO4) before anticipated EPTB for CP prevention. Cases are infants who died by the age of 1 year or developed ANO. Controls, matched by maternal race and infant sex, were neurodevelopmentally normal survivors. Neonatal DNA was evaluated for 80 polymorphisms in inflammation, coagulation, vasoregulation, excitotoxicity, and oxidative stress pathways using Taqman assays. The primary outcome for this analysis was sex-specific ANO susceptibility. Conditional logistic regression estimated each polymorphism's odds ratio (OR) by sex stratum, adjusting for gestational age, maternal education, and MgSO4-corticosteroid exposures. Holm-Bonferroni corrections, adjusting for multiple comparisons (p < 7.3 × 10-4), accounted for linkage disequilibrium between markers. RESULTS: Analysis included 211 cases (134 males; 77 females) and 213 controls (130 males; 83 females). An interleukin-6 (IL6) polymorphism (rs2069840) was associated with ANO in females (OR: 2.6, 95% confidence interval [CI]: 1.5-4.7; p = 0.001), but not in males (OR: 0.8, 95% CI: 0.5-1.2; p = 0.33). The sex-specific effect difference was significant (p = 7.0 × 10-4) and was unaffected by MgSO4 exposure. No other gene-sex associations were significant. CONCLUSION: An IL6 gene locus may confer susceptibility to ANO in females, but not males, after EPTB.

Population-Based Estimation of Dental Caries and Periodontal Disease Rates of Gravid and Recently Postpartum Women in Lilongwe, Malawi.

Objectives The objective of this study was to determine the rate of dental caries and periodontal disease among gravid and recently postpartum women at five delivery centers within and surrounding Lilongwe, Malawi. Study Design We partnered with obstetric specialists, community health workers, and dentists to perform dental history interviews and dental examinations during the study period from December 2012 to May 2014. Dental examinations were performed according to World Health Organization standards to assess periodontal and oral health status. Results Among the 387 gravid and recently postpartum women, the rate of dental caries was 69.3% and the rate of composite dental disease (caries and periodontal disease) was 76.7%. The majority (69.5%) of women examined had a decayed-missing-filled (DMF) index greater than or equal to one; the average DMF Index was 2.48. The majority of women had never seen a dentist (62.8%). However, most did perform oral hygiene, two or more times per day (90.2%); most women reported brushing with toothpaste (88.1%). Conclusion When assessing this population for dental caries and periodontal disease, the rate of dental disease was high. Therefore, this may be an ideal setting to test for impactful interventions aimed at reducing caries and periodontal disease.

Cord Blood Haptoglobin, Cerebral Palsy and Death in Infants of Women at Risk for Preterm Birth: A Secondary Analysis of a Randomised Controlled Trial.

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.

Risk of Ischemic Placental Disease in Relation to Family History of Preeclampsia.

OBJECTIVE: To assess the risk of ischemic placental disease (IPD) including preeclampsia, small for gestational age (SGA), and abruption, in relation to preeclampsia in maternal grandmother, mother, and sister(s). STUDY DESIGN: We performed a secondary analysis of data from a randomized trial of vitamins C and E for preeclampsia prevention. Data on family history of preeclampsia were based on recall by the proband. The associations between family history of preeclampsia and the odds of IPD were evaluated from alternating logistic regressions. RESULTS: Of the 9,686 women who delivered nonmalformed, singleton live births, 17.1% had IPD. Probands provided data on preeclampsia in 55.5% (n = 5,374) on all three family members, 26.5% (n = 2,562) in mother and sister(s) only, and 11.6% (n = 1,125) in sister(s) only. The pairwise odds ratio (pOR) of IPD was 1.16 (95% confidence interval [CI]: 1.00-1.36) if one or more of the female relatives had preeclampsia. The pORs of preeclampsia were 1.54 (95% CI: 1.12-2.13) and 1.35 (95% CI: 1.03-1.77) if the proband's mother or sister(s) had a preeclamptic pregnancy, respectively, but no associations were seen for SGA infant or abruption. CONCLUSION: This study suggests that IPD may share a predisposition with preeclampsia, suggesting a familial inheritance.

On the variation in maternal birth canal in vivo viscoelastic properties and their effect on the predicted length of active second stage and levator ani tears.

The pubovisceral muscles (PVM) help form the distal maternal birth canal. It is not known why 13% of vaginal deliveries end in PVM tears, so insights are needed to better prevent them because their sequelae can lead to pelvic organ prolapse later in life. In this paper we provide the first quantification of the variation in in vivo viscoelastic properties of the intact distal birth canal in healthy nulliparous women using Fung's Quasilinear Viscoelastic Theory and a secondary analysis of data from a clinical trial of constant force birth canal dilation to 8 cm diameter in the first stage of labor in 26 nullipara. We hypothesized that no significant inter-individual variation would be found in the long time constant, τ2, which characterizes how long it takes the birth canal to be dilated by the fetal head. That hypothesis was rejected because τ2 values ranged 20-fold above and below the median value. These data were input to a biomechanical model to calculate how such variations affect the predicted length of the active second stage of labor as well as PVM tear risk. The results show there was a 100-fold change in the predicted length of active second stage for the shortest and longest τ2 values, with a noticeable increase for τ2 values over 1000 s. The correlation coefficent between predicted and observed second stage durations was 0.51. We conclude that τ2 is a strong theoretical contributor to the time a mother has to push in order to deliver a fetal head larger than her birth canal, and a weak predictor of PVM tear risk.

Incidence of early-onset sepsis in infants born to women with clinical chorioamnionitis.

Objective To determine the frequency of sepsis and other adverse neonatal outcomes in women with a clinical diagnosis of chorioamnionitis. Methods We performed a secondary analysis of a multi-center placebo-controlled trial of vitamins C/E to prevent preeclampsia in low risk nulliparous women. Clinical chorioamnionitis was defined as either the "clinical diagnosis" of chorioamnionitis or antibiotic administration during labor because of an elevated temperature or uterine tenderness in the absence of another cause. Early-onset neonatal sepsis was categorized as "suspected" or "confirmed" based on a clinical diagnosis with negative or positive blood, urine or cerebral spinal fluid cultures, respectively, within 72 h of birth. Adjusted odds ratios (ORs) and 95% confidence intervals (CIs) were estimated by logistic regression. Results Data from 9391 mother-infant pairs were analyzed. The frequency of chorioamnionitis was 10.3%. Overall, 6.6% of the neonates were diagnosed with confirmed (0.2%) or suspected (6.4%) early-onset sepsis. Only 0.7% of infants born in the setting of chorioamnionitis had culture-proven early-onset sepsis versus 0.1% if chorioamnionitis was not present. Clinical chorioamnionitis was associated with both suspected [OR 4.01 (3.16-5.08)] and confirmed [OR 4.93 (1.65-14.74)] early-onset neonatal sepsis, a need for resuscitation within the first 30 min after birth [OR 2.10 (1.70-2.61)], respiratory distress [OR 3.14 (2.16-4.56)], 1 min Apgar score of ≤3 [OR 2.69 (2.01-3.60)] and 4-7 [OR 1.71 (1.43-2.04)] and 5 min Apgar score of 4-7 [OR 1.67 (1.17-2.37)] (vs. 8-10). Conclusion Clinical chorioamnionitis is common and is associated with neonatal morbidities. However, the vast majority of exposed infants (99.3%) do not have confirmed early-onset sepsis.

Prospective evaluation of the safety and feasibility of a pelvic floor dilator during active labor.

INTRODUCTION AND HYPOTHESIS: The objective was to assess the safety and feasibility of using a pelvic floor dilator during active labor to prevent injuries to the levator ani muscle (LAM) and perineum. METHODS: In a prospective pilot study, a pelvic floor dilator using soft pads was introduced into the vaginal canal to gradually expand the vagina, in 30 nulliparous women and in 10 controls. The primary outcomes were adverse events related to the device. Secondary outcomes were perineal lacerations after delivery, sonographically defined levator ani injury, hiatal area dimensions, and anal sphincter disruption, all at 12-20 weeks postpartum, and maximum pelvic floor dilation, time to achieve maximum dilation, and device retention rate. RESULTS: From October 2014 through November 2016, a total of 494 women were screened, and 61 consented to the study. Thirty women used the device and 27 returned for follow-up. No maternal or neonatal injuries were related to use of the dilator. The average maximum dilation of the vaginal canal was 7.4 cm (SD 0.7, range 5.5-8.0). Dilation time averaged 27 min (SD 13, range 5-60). Device insertion adjustment was needed in 13 out of 30 cases (43%). Similar rates of 3th-4th degree perineal lacerations were seen in both groups. Levator ani avulsion was diagnosed in 2 out of 27 (7%) in the device group and in 1 out of 9 (11%) in the control group (p = 0.2). The rate of partial injury in the device group was 2 out of 27 (7%) vs 2 out of 9 (22%) in the comparison group (p = 0.2). CONCLUSION: The use of the pelvic floor dilator during active labor is feasible. No safety issues were identified.

A constitutive model description of the in vivo material properties of lower birth canal tissue during the first stage of labor.

Remarkable changes must occur in the pelvic floor muscles and tissues comprising the birth canal to allow vaginal delivery. Despite these preparatory adaptations, approximately 13% of women who deliver vaginally for the first time (nulliparas) sustain tears near the origin of the pubovisceral muscle (PVM) which can result in pelvic organ prolapse later in life. To investigate why these tears occur, it is necessary to quantify the viscoelastic behavior of the term pregnant human birth canal. The goal of this study was to quantify the in vivo material properties of the human birth canal, in situ, during the first stage of labor and compare them to published animal data. The results show that pregnant human, ovine and squirrel monkey birth canal tissue can be characterized by the same set of constitutive relations; the interspecies differences were primarily explained by the long time constant, τ2, with its values of 555s, 1110s, and 2777s, respectively. Quantification of these viscoelastic properties should allow for improved accuracy of computer models aimed at understanding birth-related injuries.

Adverse Maternal and Neonatal Outcomes in Indicated Compared with Spontaneous Preterm Birth in Healthy Nulliparas: A Secondary Analysis of a Randomized Trial.

OBJECTIVE: To compare the risks of adverse maternal and neonatal outcomes associated with spontaneous (SPTB) versus indicated preterm births (IPTB). METHODS: A secondary analysis of a multicenter trial of vitamin C and E supplementation in healthy low-risk nulliparous women. Outcomes were compared between women with SPTB (due to spontaneous membrane rupture or labor) and those with IPTB (due to medical or obstetric complications). A primary maternal composite outcome included: death, pulmonary edema, blood transfusion, adult respiratory distress syndrome (RDS), cerebrovascular accident, acute tubular necrosis, disseminated intravascular coagulopathy, or liver rupture. A neonatal composite outcome included: neonatal death, RDS, grades III or IV intraventricular hemorrhage (IVH), sepsis, necrotizing enterocolitis (NEC), or retinopathy of prematurity. RESULTS: Of 9,867 women, 10.4% (N = 1,038) were PTBs; 32.7% (n = 340) IPTBs and 67.3% (n = 698) SPTBs. Compared with SPTB, the composite maternal outcome was more frequent in IPTB-4.4% versus 0.9% (adjusted odds ratio [aOR], 4.0; 95% confidence interval [CI], 1.4-11.8), as were blood transfusion and prolonged hospital stay (3.2 and 3.7 times, respectively). The frequency of composite neonatal outcome was higher in IPTBs (aOR, 1.8; 95% CI, 1.1-3.0), as were RDS (1.7 times), small for gestational age (SGA) < 5th percentile (7.9 times), and neonatal intensive care unit (NICU) admission (1.8 times). CONCLUSION: Adverse maternal and neonatal outcomes were significantly more likely with IPTB than with SPTB.

Cyanotic congenital heart disease following fertility treatments in the United States from 2011 to 2014.

OBJECTIVE: To examine the risk for cyanotic congenital heart diseases (CCHDs) among live births in the USA, resulting from various forms of infertility treatments. METHODS: This study is a cross-sectional analysis of live births in the USA from 2011 to 2014. Infertility treatments are categorised into two of the following groups on birth certificates: assisted reproductive technology (ART) fertility treatment (surgical egg removal; eg, in vitro fertilisation and gamete intrafallopian transfer) and non-ART fertility treatment (eg, medical treatment and intrauterine insemination). We compared the risk for CCHD in ART and non-ART fertility treatment groups with those infants whose mothers received no documented fertility treatment and were naturally conceived (NC). RESULTS: Among 14 242 267 live births from 2011 to 2014, a total of 101 494 live births were in the ART and 81 242 resulted from non-ART fertility treatments. CCHD prevalence in ART, non-ART and NC groups were 393/100 892 (0.39%), 210/80 884 (0.26%) and 10 749/14 020 749 (0.08%), respectively. As compared with naturally conceiving infants, risk for CCHD was significantly higher among infants born in ART (adjusted relative risk (aRR) 2.4, 95% CI 2.1 to 2.7) and non-ART fertility treatment groups (aRR 1.9, 95% CI 1.6 to 2.2). Absolute risk increase in CCHD due to ART and non-ART treatments were 0.03% and 0.02%, respectively. A similar pattern was observed when the analysis was restricted to twins, newborns with birth weights under 1500 g and gestational age of less than 32 weeks. CONCLUSIONS: Our findings suggest an increased risk for CCHD in infants conceived after all types of infertility treatment.

Potential of Metformin to Improve Cardiac Risk in Postpartum Women with Gestational Diabetes.

OBJECTIVE: Pregnancy is associated with an increase in total cholesterol, high density lipoproteins (HDL), and low-density lipoproteins (LDL). Postpartum, HDL and LDL decrease over the first 12 weeks postpartum. Oxidized LDL (ox-LDL) is a marker of oxidative stress-related inflammation, which is associated with obesity and also with development of cardiovascular disease. Cardiovascular protection and weight loss are benefits from metformin, especially in women with diabetes. The objective of this study was to compare changes in lipid profiles and biomarkers for obesity during the initial 6 weeks postpartum between women with gestational diabetes mellitus (GDM) treated with metformin versus placebo. METHODS: This was a planned ancillary study of a randomized controlled trial compares metformin versus placebo in women with GDM for postpartum weight loss. Two 3 mL blood samples were collected within 24 h of delivery and 6 weeks postpartum immediately processed after collection then stored at -20°C until completion of clinical trial prior to analysis. Change in the median plasma concentrations of total cholesterol, HDL, ox-LDL, glucose, insulin, leptin, and unacylated ghrelin were compared between study groups. RESULTS: Of the 77 postpartum women were included, 35 received metformin and 42 received placebo. There was less of a reduction in HDL in the metformin group compared to placebo (-2.3 versus -7.5 mg/dL, p = 0.019). In addition, there was a greater reduction in ox-LDL in those receiving metformin (-12.2 versus -3.8 mg/dL, p = 0.038). No other differences were observed in the selected biomarkers evaluated. CONCLUSION: Biomarker levels of HDL and ox-LDL were positively affected during the initial 6 weeks postpartum in GDM women treated with metformin. Additional studies with a longer duration of metformin treatment in the postpartum period are warranted to evaluate long-term potential benefits.

The association among cytochrome P450 3A, progesterone receptor polymorphisms, plasma 17-alpha hydroxyprogesterone caproate concentrations, and spontaneous preterm birth.

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.