Effects of medications for opioid use disorder (MOUD) on fetal brain and cranial measurements.

BACKGROUND: The use and misuse of opioids, as well as opioid use disorder (OUD) have increased remarkably among reproductive-aged and pregnant women. As many as 25% of pregnant women who report non-medical opioid use in the past month also report concurrent alcohol use. While teratogenic effects of alcohol are well established, there are limited studies evaluating fetal intracranial effects associated with medications for OUD (MOUD) and concurrent use of MOUD and alcohol during pregnancy. The objective of this study was to determine the effect of MOUD, with and without concomitant alcohol use, on fetal intracranial measurements. The type of maternal MOUD therapy (methadone vs. buprenorphine) was also examined. METHODS: This study was a secondary analysis of a prospective cohort study among participants (n = 196) assigned into three groups (MOUD [n = 94], MOUD+Alcohol [n = 47], and unexposed controls [n = 55]). Co-exposure with either methamphetamines or cocaine were exclusionary criteria; other co-exposures were carefully characterized with prospective repeated self-report measures and biomarkers. Fetal ultrasound measurements at 18-22 weeks (2nd trimester) and 28-32 weeks (early 3rd trimester) were compared among study groups. In addition to standard morphometrics, we performed specialized intracranial measurements of caval-calvarial distance (CCD), frontal lobe width (FLW), frontal lobe length (FLL), and fronto-thalamic distance (FTD). RESULTS: Brain and cranial measurements between MOUD, with or without alcohol co-exposure, and unexposed controls were generally not significantly different in multivariable analyses. Subjects in the MOUD groups had earlier gestational age at delivery and lower birth weight and birth weight percentile compared to unexposed controls with differences driven primarily by the methadone subgroup. Significant differences in standard and specialized intracranial indices at both second and third trimester as well as differences in the change of HC percentile over time were observed in the methadone subgroup compared to controls, while no differences between buprenorphine subgroup and controls were observed for any measures. CONCLUSION: Patients receiving methadone therapy might require closer monitoring during pregnancy; however, detailed imaging of the fetal brain other than the standard measurements might not be warranted.

Effect of prenatal EPA and DHA on maternal and cord blood insulin sensitivity: a secondary analysis of the mothers, omega 3, and mental health study.

BACKGROUND: We sought to determine whether prenatal supplementation with the omega-3 fatty acids eicosapentaenoic acid (EPA) or docosahexaenoic acid (DHA) would increase markers of insulin sensitivity in maternal or cord blood compared with placebo supplementation. A secondary aim was to evaluate the association of serum EPA and DHA fractions with adiponectin, leptin and the adiponectin:leptin ratio (ALR). We hypothesized that omega-3 fatty acid supplementation would increase markers of insulin sensitivity in maternal and umbilical cord plasma. METHODS: We analyzed stored plasma samples collected from a prior 3-arm prospective, double-blinded, randomized controlled trial in which 126 women with singleton pregnancies between 12- and 20-weeks' gestation were randomized to receive: 1) an EPA-rich fish oil supplement, 2) a DHA-rich fish oil supplement, or 3) a soy oil placebo. Maternal venous blood samples were collected at 12-20 weeks gestation (before supplementation) and at 34-36 weeks gestation. At delivery, cord blood was collected. Samples were analyzed using sandwich enzyme-linked immunosorbent assay kits to quantify leptin and adiponectin levels which were utilized to calculate the ALR, a proxy measure for insulin sensitivity. RESULTS: We found no difference in adiponectin, leptin, and the ALR between the treatment and placebo groups at baseline, after supplementation, or in umbilical cord blood. In regression analyses, higher maternal serum DHA fraction was associated with increased ALR before (p = 0.01) and after (p = 0.04) DHA supplementation. There was no association of EPA fraction with any measure of insulin sensitivity. Cord blood DHA fraction was significantly associated with cord plasma leptin (p = 0.02). Early pregnancy BMI was significantly associated with maternal leptin levels at baseline and in late pregnancy (p < 0.001) and was inversely associated with the ALR (p < 0.001). The ALR decreased significantly between the early and late pregnancy visits (p < 0.001). Pregnancy weight gain was inversely associated with the ALR (P. < 0.02). CONCLUSIONS: EPA- and DHA- rich fish oil supplementation had no effect on plasma markers of insulin sensitivity. However, maternal serum DHA fraction was significantly associated with markers of insulin sensitivity. TRIAL REGISTRATION: https://clinicaltrials.gov/, registration number NCT00711971, 7/7/2008.

The association between prenatal alcohol exposure and protein expression in human placenta.

BACKGROUND: The need for earlier recognition of children at risk for neurobehavioral problems associated with prenatal ethanol exposure (PAE) has prompted investigations of biomarkers prognostic for altered fetal development. Here, we examined whether PAE alters the expression of angiogenesis-related proteins and cytokines in human placenta in subjects from an Ethanol, Neurodevelopment, Infant and Child Health prospective cohort. METHODS: PAE was ascertained by screening questionnaires, Time-line Follow-back interviews and a panel of ethanol biomarkers at two study visits. After delivery, placental tissue samples were collected for protein analysis. RESULTS: No significant differences in the prevalence of substance use, demographic or medical characteristics were observed between the No PAE and PAE groups. PAE was associated with significant reductions in placental expression of VEGFR2 and annexin-A4, while the levels of VEGFR1 and CCM-3 trended downward. A trend toward higher expression of the cytokines TNF-α and IL-13 was also observed in the PAE group. Receiver operating characteristic analyses of the data demonstrated a moderate-to-high degree of diagnostic accuracy for individual placental proteins. Combinations of proteins substantially increased their ability to differentiate between PAE and No PAE subjects. CONCLUSIONS: These results establish the feasibility of harvesting placental tissue for protein analyses of PAE in a prospective manner. In addition, given the importance of vascular remodeling in both placenta and developing brain, the role of angiogenic and cytokine proteins in this process warrants further investigation for their utility for predicting alterations in brain development, as well as their mechanistic role in PAE-induced pathology.

Association between prenatal opioid exposure, neonatal opioid withdrawal syndrome, and neurodevelopmental and behavioral outcomes at 5-8 months of age.

BACKGROUND: While use of prescription opioids and medication assisted therapy (MAT) for opioid use disorder in pregnancy, as well as the incidence of neonatal opioid withdrawal syndrome (NOWS) continue to rise, little is known about outcomes for children with NOWS beyond the newborn period. METHODS: We examined 1) prenatal MAT exposure vs. unexposed healthy controls [HC]; and 2) treatment for NOWS and NOWS severity on infant neurodevelopmental and behavioral outcomes at 5-8 months of age in 78 maternal-infant pairs from the ENRICH prospective cohort study. Data were obtained from 3 study visits: prenatal, delivery, and neurodevelopmental evaluation at 5-8 months of age. Neurodevelopmental outcomes included the Bayley Scales of Infant Development [BSID-III], caregiver questionnaires (Parenting Stress Index [PSI-SF], Infant Behavior Questionnaire [IBQ-R], Sensory Profile), and the experimental Still-Face Paradigm (SFP). RESULTS: No differences in the BSID-III, PSI-SF, or IBQ-R scores were observed between MAT and HC groups; however, MAT-exposed and HC infants differed with respect to SFP self-regulation (ß = -18.9; p = 0.01) and Sensory Profile sensation seeking (OR = 4.87; 95% CI: 1.55; 15.30) after adjusting for covariates. No significant differences between Treated-for-NOWS vs. not-Treated-for-NOWS were observed. Shorter timing to NOWS treatment initiation was associated with higher Total Stress (ß = -9.08; p = 0.035), while longer hospitalization was associated with higher Parent-child dysfunctional interaction (p = 0.018) on PSI-SF. CONCLUSIONS: Our results provide additional evidence of little-to-no effect of MAT and pharmacological treatment of NOWS on infant neurodevelopmental and behavioral outcomes at 5-8 months of age. However, prolonged hospitalization might increase family psychosocial stress and requires further examination.

Effect of ibuprofen vs acetaminophen on postpartum hypertension in preeclampsia with severe features: a double-masked, randomized controlled trial.

BACKGROUND: Nonsteroidal antiinflammatory drug use has been shown to increase blood pressure in nonpregnant adults. Because of this, the American College of Obstetricians and Gynecologists suggests avoiding their use in women with postpartum hypertension; however, evidence to support this recommendation is lacking. OBJECTIVE: Our goal was to test the hypothesis that nonsteroidal antiinflammatory drugs, such as ibuprofen, adversely affect postpartum blood pressure control in women with preeclampsia with severe features. STUDY DESIGN: At delivery, we randomized women with preeclampsia with severe features to receive around-the-clock oral dosing with either 600 mg of ibuprofen or 650 mg of acetaminophen every 6 hours. Dosing began within 6 hours after delivery and continued until discharge, with opioid analgesics available as needed for breakthrough pain. Study drugs were encapsulated in identical capsules such that patients, nurses, and physicians were masked to study allocation. Exclusion criteria were serum aspartate aminotransferase or alanine aminotransferase >200 mg/dL, serum creatinine >1.0 mg/dL, infectious hepatitis, gastroesophageal reflux disease, age <18 years, or current incarceration. Our primary outcome was the duration of severe-range hypertension, defined as the time (in hours) from delivery to the last blood pressure ≥160/110 mm Hg. Secondary outcomes were time from delivery to last blood pressure ≥150/100 mm Hg, mean arterial pressure, need for antihypertensive medication at discharge, prolongation of hospital stay for blood pressure control, postpartum use of short-acting antihypertensives for acute blood pressure control, and opioid use for breakthrough pain. We analyzed all outcome data according to intention-to-treat principles. RESULTS: We assessed 154 women for eligibility, of whom 100 met entry criteria, agreed to participate, and were randomized to receive postpartum ibuprofen or acetaminophen for first-line pain control. Seven patients crossed over or did not receive their allocated study drug, and 93 completed the study protocol in their assigned groups. We found no differences in baseline characteristics between groups, including mode of delivery, body mass index, parity, race, chronic hypertension, and maximum blood pressure prior to delivery. We did not find a difference in the duration of severe-range hypertension in the ibuprofen vs acetaminophen groups (35.3 vs 38.0 hours, P = .30). There were no differences between groups in the secondary outcome measures of time from delivery to last blood pressure ≥150/100 mm Hg, postpartum mean arterial pressure, maximum postpartum systolic or diastolic blood pressures, any postpartum blood pressure ≥160/110 mm Hg, short-acting antihypertensive use for acute blood pressure control, length of postpartum stay, need to extend postpartum stay for blood pressure control, antihypertensive use at discharge, or opioid use for inadequate pain control. In a subgroup analysis of patients who experienced severe-range hypertension, the mean time to blood pressure control in the acetaminophen group was 68.4 hours and ibuprofen group was 56.7 hours (P = .26). At 6 weeks postpartum, there were no differences between groups in the rates of obstetric triage visits, hospital readmissions, continued opioid use, or continued antihypertensive use. CONCLUSION: The first-line use of ibuprofen rather than acetaminophen for postpartum pain did not lengthen the duration of severe-range hypertension in women with preeclampsia with severe features.

A Novel Approach to Prenatal Measurement of the Fetal Frontal Lobe Using Three-Dimensional Sonography.

OBJECTIVE: While prenatal 3D ultrasonography results in improved diagnostic accuracy, no data are available on biometric assessment of the fetal frontal lobe. This study was designed to assess feasibility of a standardized approach to biometric measurement of the fetal frontal lobe and to construct frontal lobe growth trajectories throughout gestation. STUDY DESIGN: A sonographic 3D volume set was obtained and measured in 101 patients between 16.1 and 33.7 gestational weeks. Measurements were obtained by two independent raters. To model the relationship between gestational age and each frontal lobe measurement, flexible linear regression models were fit using penalized regression splines. RESULTS: The sample contained an ethnically diverse population (7.9% Native Americans, 45.5% Hispanic/Latina). There was high inter-rater reliability (correlation coefficients: 0.95, 1.0, and 0.87 for frontal lobe length, width, and height; p-values < 0.001). Graphs of the growth trajectories and corresponding percentiles were estimated as a function of gestational age. The estimated rates of frontal lobe growth were 0.096 cm/week, 0.247 cm/week, and 0.111 cm/week for length, width, and height. CONCLUSION: To our knowledge, this is the first study to examine fetal frontal lobe growth trajectories through 3D prenatal ultrasound examination. Such normative data will allow for future prenatal evaluation of a particular disease state by 3D ultrasound imaging.

Hyperparathyroidism in Pregnancy Leading to Pancreatitis and Preeclampsia with Severe Features.

Background. Hyperparathyroidism is underdiagnosed in pregnancy, yet early diagnosis is necessary for the potentially severe sequelae of hypercalcemia for both the woman and fetus. Case. A 31-year-old, gravida 3, para 0-0-2-0 at 32 weeks and 3 days of gestation, presented with preeclampsia with severe features concomitant with acute pancreatitis and known diabetes mellitus type 2. She was stabilized and delivered. In the postpartum period, her total calcium level remained elevated. Ionized calcium levels and parathyroid hormone levels were also elevated, and she was diagnosed with hyperparathyroidism. Conclusion. Hyperparathyroidism and hypercalcemia are risk factors for pancreatitis. Women who develop pancreatitis during pregnancy are at increased risk of developing preeclampsia. If elevated serum calcium is noted, it should be confirmed with ionized calcium level and parathyroid hormones as ionized calcium levels are unaffected by pregnancy.

A Novel Approach to Prenatal Measurement of the Fetal Frontal Lobe Using Three-Dimensional Sonography.

Objective: To assess the feasibility of a standardized approach to biometric measurement of the fetal frontal lobe and to construct frontal lobe growth trajectories throughout gestation. Study Design: A sonographic 3-dimensional (3D) volume set was obtained and measured in 101 patients between 16.1 and 33.7 gestational weeks. Measurements were obtained by 2 independent raters. To model the relationship between gestational age and each frontal lobe measurement, flexible linear regression models were fit using penalized regression splines. Results: The sample contained an ethnically diverse population (7.9% Native Americans, 45.5% Hispanics/Latinas). There was high interrater reliability (correlation coefficients 0.95, 1.0, and 0.87 for frontal lobe length, width, and height; p values <0.001). Graphs of the growth trajectories and corresponding percentiles were estimated as a function of gestational age. The estimated rates of frontal lobe growth were 0.096 cm/week, 0.247 cm/week, and 0.111 cm/week for length, width, and height, respectively. Conclusion: To our knowledge, this is the first study to examine fetal frontal lobe growth trajectories through 3D prenatal ultrasound examination. Such normative data will allow for future prenatal evaluation of a particular disease state by 3D ultrasound imaging.

Retirement Age Ranges from Clinical Practice of Maternal-Fetal Medicine Physicians.

Objectives Retirement of "baby boomer" physicians is a matter of growing concern in light of the shortage of certain physician groups. The objectives of this investigation were to define what constitutes a customary retirement age range of maternal-fetal medicine (MFM) physicians and examine how that compares with other obstetrician-gynecologist (ob-gyn) specialists. Study Design This descriptive study was based on American Medical Association Masterfile survey data from 2010 to 2014. Data from the National Provider Identifier were used to correct for upward bias in reporting retirement ages. Only physicians engaged in direct patient care between ages 55 and 80 years were included. Primary outcomes involved comparisons of retirement ages of male and female physicians with other ob-gyn specialties. Results Interquartile ranges of retirement ages were similar between specialists in MFM (64.1-71.1), gynecologic oncology (62.1-68.9), reproductive endocrinology and infertility (64.1-71.7), and general ob-gyn (61.5-67.9). In every specialty, women retired earlier, while males in MFM were most likely to retire at the oldest age (median 70.0). Conclusion MFM physicians usually retired from clinical practice between ages 64 and 71 years, which is similar to other ob-gyn specialists. Females retired earlier, however, which may impact the overall supply as more females pursue MFM careers.

The effects of nicotine on human fetal development.

Maternal smoking during pregnancy continues to represent a major public health concern. Nicotine is extremely harmful to the developing fetus through many different mechanisms, and the harms increase with later gestational age at exposure. Pregnancies complicated by maternal nicotine use are more likely to have significant adverse outcomes. Nicotine-exposed children tend to have several health problems throughout their lives, including impaired function of the endocrine, reproductive, respiratory, cardiovascular, and neurologic systems. Poor academic performance and significant behavioral disruptions are also common, including ADHD, aggressive behaviors, and future substance abuse. To diminish the adverse effects from cigarette smoking, some women are turning to electronic cigarettes, a new trend that is increasing in popularity worldwide. They are largely perceived as being safer to use in pregnancy than traditional cigarettes, although there is not adequate evidence to support this claim. At this time, electronic cigarette use during pregnancy cannot be recommended. Birth Defects Research (Part C) 108:181-192, 2016. © 2016 Wiley Periodicals, Inc.

Teratogenic risks from exposure to illicit drugs.

Substance use is prevalent in the United States, especially in the reproductive age population. Even though a reduction in substance use may occur during pregnancy, some women may not alter their drug use patterns until at least pregnancy is confirmed. For these reasons, a large number of fetuses are exposed to illicit substances, including during critical stages of organogenesis. Associating illicit drug use with eventual pregnancy outcome is difficult. This article presents issues pertaining to limitations with published investigations about fetal risks and describes the most current information in humans about fetal effects from specific illicit substances.

Umbilical cord prolapse.

Umbilical cord prolapse is an obstetric emergency that can have negative outcomes for the fetus. It is diagnosed by a palpable or visible cord and is often accompanied by severe, rapid fetal heart rate decelerations. Cases of cord prolapse should be delivered as soon as possible, usually by cesarean section. While awaiting delivery, the fetal presenting part should be elevated off the cord either manually or by filling the bladder. Although an untreated case of umbilical cord prolapse can lead to severe fetal morbidity and mortality, prompt and appropriate management leads to good overall outcomes.