Frequent first-trimester pregnancy loss in rhesus macaques infected with African-lineage Zika virus.

In the 2016 Zika virus (ZIKV) pandemic, a previously unrecognized risk of birth defects surfaced in babies whose mothers were infected with Asian-lineage ZIKV during pregnancy. Less is known about the impacts of gestational African-lineage ZIKV infections. Given high human immunodeficiency virus (HIV) burdens in regions where African-lineage ZIKV circulates, we evaluated whether pregnant rhesus macaques infected with simian immunodeficiency virus (SIV) have a higher risk of African-lineage ZIKV-associated birth defects. Remarkably, in both SIV+ and SIV- animals, ZIKV infection early in the first trimester caused a high incidence (78%) of spontaneous pregnancy loss within 20 days. These findings suggest a significant risk for early pregnancy loss associated with African-lineage ZIKV infection and provide the first consistent ZIKV-associated phenotype in macaques for testing medical countermeasures.

Cotyledon-Specific Flow Evaluation of Rhesus Macaque Placental Injury Using Ferumoxytol Dynamic Contrast-Enhanced MRI.

BACKGROUND: Recently, dynamic contrast-enhanced (DCE) MRI with ferumoxytol as contrast agent has recently been introduced for the noninvasive assessment of placental structure and function throughout. However, it has not been demonstrated under pathological conditions. PURPOSE: To measure cotyledon-specific rhesus macaque maternal placental blood flow using ferumoxytol DCE MRI in a novel animal model for local placental injury. STUDY TYPE: Prospective animal model. SUBJECTS: Placental injections of Tisseel (three with 0.5 mL and two with 1.5 mL), monocyte chemoattractant protein 1 (three with 100 µg), and three with saline as controls were performed in a total of 11 rhesus macaque pregnancies at approximate gestational day (GD 101). DCE MRI scans were performed prior (GD 100) and after (GD 115 and GD 145) the injection (term = GD 165). FIELD STRENGTH/SEQUENCE: 3 T, T1-weighted spoiled gradient echo sequence (product sequence, DISCO). ASSESSMENT: Source images were inspected for motion artefacts from the mother or fetus. Placenta segmentation and DCE processing were performed for the dynamic image series to measure cotyledon specific volume, flow, and normalized flow. Overall placental histopathology was conducted for controls, Tisseel, and MCP-1 animals and regions of tissue infarctions and necrosis were documented. Visual inspections for potential necrotic tissue were conducted for the two Tisseelx3 animals. STATISTICAL TESTS: Wilcoxon rank sum test, significance level P < 0.05. RESULTS: No motion artefacts were observed. For the group treated with 1.5 mL of Tisseel, significantly lower cotyledon volume, flow, and normalized flow per cotyledon were observed for the third gestational time point of imaging (day ~145), with mean normalized flow of 0.53 minute-1. Preliminary histopathological analysis shows areas of tissue necrosis from a selected cotyledon in one Tisseel-treated (single dose) animal and both Tisseelx3 (triple dose) animals. DATA CONCLUSION: This study demonstrates the feasibility of cotyledon-specific functional analysis at multiple gestational time points and injury detection in a placental rhesus macaque model through ferumoxytol-enhanced DCE MRI. LEVEL OF EVIDENCE: NA TECHNICAL EFFICACY: Stage 2.

Discrete placental gene expression signatures accompany diabetic disease classifications during pregnancy.

BACKGROUND: Gestational diabetes mellitus affects up to 10% of pregnancies and is classified into subtypes gestational diabetes subtype A1 (GDMA1) (managed by lifestyle modifications) and gestational diabetes subtype A2 (GDMA2) (requiring medication). However, whether these subtypes are distinct clinical entities or more reflective of an extended spectrum of normal pregnancy endocrine physiology remains unclear. OBJECTIVE: Integrated bulk RNA-sequencing (RNA-seq), single-cell RNA-sequencing (scRNA-seq), and spatial transcriptomics harbors the potential to reveal disease gene signatures in subsets of cells and tissue microenvironments. We aimed to combine these high-resolution technologies with rigorous classification of diabetes subtypes in pregnancy. We hypothesized that differences between preexisting type 2 and gestational diabetes subtypes would be associated with altered gene expression profiles in specific placental cell populations. STUDY DESIGN: In a large case-cohort design, we compared validated cases of GDMA1, GDMA2, and type 2 diabetes mellitus (T2DM) to healthy controls by bulk RNA-seq (n=54). Quantitative analyses with reverse transcription and quantitative PCR of presumptive genes of significant interest were undertaken in an independent and nonoverlapping validation cohort of similarly well-characterized cases and controls (n=122). Additional integrated analyses of term placental single-cell, single-nuclei, and spatial transcriptomics data enabled us to determine the cellular subpopulations and niches that aligned with the GDMA1, GDMA2, and T2DM gene expression signatures at higher resolution and with greater confidence. RESULTS: Dimensional reduction of the bulk RNA-seq data revealed that the most common source of placental gene expression variation was the diabetic disease subtype. Relative to controls, we found 2052 unique and significantly differentially expressed genes (-22 thresholds; q<0.05 Wald Test) among GDMA1 placental specimens, 267 among GDMA2, and 1520 among T2DM. Several candidate marker genes (chorionic somatomammotropin hormone 1 [CSH1], period circadian regulator 1 [PER1], phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit beta [PIK3CB], forkhead box O1 [FOXO1], epidermal growth factor receptor [EGFR], interleukin 2 receptor subunit beta [IL2RB], superoxide dismutase 3 [SOD3], dedicator of cytokinesis 5 [DOCK5], suppressor of glucose, and autophagy associated 1 [SOGA1]) were validated in an independent and nonoverlapping validation cohort (q<0.05 Tukey). Functional enrichment revealed the pathways and genes most impacted for each diabetes subtype, and the degree of proximal similarity to other subclassifications. Surprisingly, GDMA1 and T2DM placental signatures were more alike by virtue of increased expression of chromatin remodeling and epigenetic regulation genes, while albumin was the top marker for GDMA2 with increased expression of placental genes in the wound healing pathway. Assessment of these gene signatures in single-cell, single-nuclei, and spatial transcriptomics data revealed high specificity and variability by placental cell and microarchitecture types. For example, at the cellular and spatial (eg, microarchitectural) levels, distinguishing features were observed in extravillous trophoblasts (GDMA1) and macrophages (GDMA2). Lastly, we utilized these data to train and evaluate 4 machine learning models to estimate our confidence in predicting the control or diabetes status of placental transcriptome specimens with no available clinical metadata. CONCLUSION: Consistent with the distinct association of perinatal outcome risk, placentae from GDMA1, GDMA2, and T2DM-affected pregnancies harbor unique gene signatures that can be further distinguished by altered placental cellular subtypes and microarchitectural niches.

Management of twin reversed arterial perfusion (TRAP) sequence with microwave ablation: A case report and review of the literature.

Twin reversed arterial perfusion (TRAP) sequence carries a high mortality risk to the "pump twin." Management involves disrupting blood flow to the acardiac mass. In this case, the pregnant patient presented at 20 weeks 6 days with Stage IIb TRAP Sequence and underwent percutaneous ultrasound-guided microwave ablation (MWA) of the acardiac mass at 21 weeks 0 days. The probe traversed the thorax of the acardiac mass and ablated the confluence of the umbilical vessels. A healthy child was delivered at 33 weeks 5 days gestation. This report demonstrates the utility of MWA in TRAP sequence and describes a novel approach.

Continuous positive airway pressure treatment of obstructive sleep apnea and hypertensive complications in high-risk pregnancy.

PURPOSE: To evaluate whether or not continuous positive airway pressure (CPAP) treatment in pregnancies complicated by obstructive sleep apnea (OSA) is associated with a decrease in hypertensive disorders of pregnancy. METHODS: This was a retrospective cohort study of perinatal outcomes in women who underwent objective OSA testing and treatment as part of routine clinical care during pregnancy. Where diagnostic criteria for OSA were reached (respiratory event index (REI) ≥ 5 events per hour), patients were offered CPAP therapy. Obstetrical outcomes were compared between the control group (no OSA), the group with untreated OSA (OSA diagnosed, not CPAP compliant), and the group with treated OSA (OSA diagnosed and CPAP compliant), with CPAP compliance defined as CPAP use ≥ 4 h, 70% of the time or greater. A composite hypertension outcome combined diagnoses of gestational hypertension (gHTN) and preeclampsia (PreE) of any severity. RESULTS: The study comprised outcomes from 177 completed pregnancies. Our cohort was characterized by obesity, with average body mass indices > 35 kg/m2, and average maternal age > 30 years old. CPAP was initiated at an average gestational age of 23 weeks (12.1-35.3 weeks), and average CPAP use was 5.9 h (4-8.5 h). The composite hypertension outcome occurred in 43% of those without OSA (N = 77), 64% of those with untreated OSA (N = 77), and 57% of those with treated OSA, compliant with CPAP (N = 23) (p = 0.034). CONCLUSION: Real-world data in this small study suggest that CPAP therapy may modulate the increased risk of hypertensive complications in pregnancies complicated by OSA.

Does Daily Self-Weighing Contribute to Postpartum Weight Loss? A Secondary Analysis of Daily Postpartum Weights among Women with Hypertensive Disorders of Pregnancy.

OBJECTIVE: This study was aimed to examine the impact of daily self-weighing via remote monitoring on postpartum weight loss. STUDY DESIGN: This was a secondary analysis of a nonrandomized controlled trial comprised of postpartum women with diagnosed hypertensive-related disorders in pregnancy who received a tablet device linked to Bluetooth-enabled equipment including a scale and blood pressure cuff. In addition to blood pressure monitoring, participants were instructed to perform daily self-weighing. The primary outcome of this study was to determine whether postpartum women who performed daily self-weighing lost more weight than those who did not, with a 42-day endpoint based on a 6-week postpartum visit weight. RESULTS: Overall, 214 women participated in this program and 214 received usual care. Median weight loss for women participating in the remote blood pressure monitoring system was 23.0 (interquartile range [IQR]: 17-30) pounds versus 23.0 (IQR: 17-29) pounds among controls. Weight loss did not vary by prepregnancy obesity (median: 20 pounds [IQR: 17-28 pounds] for nonobese and 23 [IQR: 17-30] pounds for women with obesity, p = 0.16). Women who weighed themselves more than half of follow-up days lost a median of 24 pounds (IQR: 17-30 pounds) compared with 20.5 pounds (IQR: 14-29 pounds), p = 0.06. Women who weighed themselves more than half of follow-up days lost a mean of 11.4% (standard deviation [SD] = 0.41%) of body weight compared with 9.1% (SD = 0.74%; p = 0.01). The amount of weight loss in the telehealth group was correlated with the number of daily weights performed (Pearson's correlation coefficient 0.164, p = 0.025). Postpartum weight loss for daily self-weighing participants was most notable in the first 2 weeks with ongoing weight loss up to the 42-day (6-week) endpoint of this secondary analysis. CONCLUSION: Daily self-weighing alone may be insufficient to promote postpartum weight loss. However, there was a slight trend toward more weight loss with more frequent weighing. KEY POINTS: · Daily self-weighing is insufficient for postpartum weight loss.. · Women who weighed themselves more lost slightly more weight.. · Weight loss was the most notable in the first 2 weeks.. · Its use as one part of a program may be worth studying..

SERUM GLP-2 is Increased in Association with Excess Gestational Weight Gain.

OBJECTIVE: Obesity in pregnancy bears unique maternal and fetal risks. Obesity has also been associated with chronic inflammation, including elevated serum levels of interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α). Higher serum lipopolysaccharide (LPS) levels have been implicated in driving this inflammation, a phenomenon called metabolic endotoxemia (ME). GLP-2, a proglucagon-derived peptide, is believed to be integral in maintaining the integrity of the intestine in the face of LPS-mediated endotoxemia. We hypothesized that obesity and/or excess weight gain in pregnancy would be associated with an increase in maternal and neonatal markers of ME, as well as GLP-2. STUDY DESIGN: Paired maternal and neonatal (cord blood) serum samples (n = 159) were obtained from our pregnancy biobank repository. Serum levels of LPS, endotoxin core antibody-immunoglobulin M (EndoCAb-IgM), and GLP-2 were measured by ELISA. IL-6 and TNF-α were measured using a Milliplex assay. Results were stratified by maternal body mass index (BMI), maternal diabetes, and gestational weight gain (GWG). RESULTS: Maternal IL-6 is significantly decreased in the obese, diabetic cohort compared with the nonobese, nondiabetic cohorts (95.28 vs. 99.48 pg/mL, p = 0.047), whereas GLP-2 is significantly increased (1.92 vs. 2.89 ng/mL, p = 0.026). Neonatal TNF-α is significantly decreased in the obese cohort compared with the nonobese cohort (12.43 vs. 13.93 pg/mL, p = 0.044). Maternal GLP-2 is significantly increased in women with excess GWG compared with those with normal GWG (2.27 vs. 1.48 ng/mL, p = 0.014). We further found that neonatal IL-6 and TNF-α are negatively correlated with maternal BMI (-0.186, p = 0.036 and -0.179, p = 0.044, respectively) and that maternal and neonatal IL-6 showed a positive correlation (0.348, p < 0.001). CONCLUSION: Although we observed altered levels of markers of inflammation (IL-6 and TNF-α) with maternal obesity and diabetes, no changes in LPS or endoCAb-IgM were observed. We hypothesize that the increased GLP-2 levels in maternal serum in association with excess GWG may protect against ME in pregnancy. KEY POINTS: · Maternal serum levels of GLP-2, a proglucagon-derived peptide, are increased in obese, diabetic gravidae.. · Maternal serum GLP-2 levels are also increased in association with excess gestational weight gain compared with normal gestational weight gain.. · GLP-2 may be increased in association with obesity and weight gain to protect against metabolic endotoxemia in pregnancy..

Indications, Resource Allocation, and Outcomes Associated with Ex-Utero Intrapartum Treatment Procedures: A North American Fetal Therapy Network Survey.

INTRODUCTION: Neonates with cardiorespiratory compromise at delivery are at substantial risk of hypoxic neurologic injury and death. Though mitigation strategies such as ex-utero intrapartum treatment (EXIT) exist, the competing interests of neonatal beneficence, maternal non-maleficence, and just distribution of resources require consideration. Due to the rarity of these entities, there are few systematic data to guide evidence-based standards. This multi-institutional, interdisciplinary approach aims to elucidate the current scope of diagnoses that might be considered for such treatments and examine if treatment allocation and/or outcomes could be improved. METHODS: After IRB approval, a survey investigating diagnoses appropriate for EXIT consultation and procedure, variables within each diagnosis, occurrence of maternal and neonatal adverse outcomes, and instances of suboptimal resource allocation in the last decade was sent to all North American Fetal Treatment Network center representatives. One response was recorded per center. RESULTS: We received a 91% response rate and all but one center offer EXIT. Most centers (34/40, 85%) performed 1-5 EXIT consultations per year and 17/40 (42.5%) centers performed 1-5 EXIT procedures in the last 10 years. The diagnoses with the highest degree of agreement between centers surveyed to justify consultation for EXIT are head and neck mass (100%), congenital high airway obstruction (90%), and craniofacial skeletal conditions (82.5%). Maternal adverse outcomes were noted in 7.5% of centers while neonatal adverse outcomes in 27.5%. A large percentage of centers report cases of suboptimal selection for risk mitigation procedures and several centers experienced adverse neonatal and maternal outcomes. CONCLUSION: This study captures the scope of EXIT indications and is the first to demonstrate the mismatch in resource allocation for this population. Further, it reports on attributable adverse outcomes. Given suboptimal allocation and adverse outcomes, further examination of indications, outcomes, and resource use is justified to drive evidence-based protocols.

African-Lineage Zika Virus Replication Dynamics and Maternal-Fetal Interface Infection in Pregnant Rhesus Macaques.

Following the Zika virus (ZIKV) outbreak in the Americas, ZIKV was causally associated with microcephaly and a range of neurological and developmental symptoms, termed congenital Zika syndrome (CZS). The viruses responsible for this outbreak belonged to the Asian lineage of ZIKV. However, in vitro and in vivo studies assessing the pathogenesis of African-lineage ZIKV demonstrated that African-lineage isolates often replicated to high titers and caused more-severe pathology than Asian-lineage isolates. To date, the pathogenesis of African-lineage ZIKV in a translational model, particularly during pregnancy, has not been rigorously characterized. Here, we infected four pregnant rhesus macaques with a low-passage-number strain of African-lineage ZIKV and compared its pathogenesis to those for a cohort of four pregnant rhesus macaques infected with an Asian-lineage isolate and a cohort of mock-inoculated controls. The viral replication kinetics for the two experimental groups were not significantly different, and both groups developed robust neutralizing antibody titers above levels considered to be protective. There was no evidence of significant fetal head growth restriction or gross fetal harm at delivery (1 to 1.5 weeks prior to full term) in either group. However, a significantly higher burden of ZIKV viral RNA (vRNA) was found in the maternal-fetal interface tissues of the macaques exposed to an African-lineage isolate. Our findings suggest that ZIKV of any genetic lineage poses a threat to pregnant individuals and their infants. IMPORTANCE ZIKV was first identified in 1947 in Africa, but most of our knowledge of ZIKV is based on studies of the distinct Asian genetic lineage, which caused the outbreak in the Americas in 2015 to 2016. In its most recent update, the WHO stated that improved understanding of African-lineage ZIKV pathogenesis during pregnancy must be a priority. The recent detection of African-lineage isolates in Brazil underscores the need to understand the impact of these viruses. Here, we provide the first comprehensive assessment of African-lineage ZIKV infection during pregnancy in a translational nonhuman primate model. We show that African-lineage isolates replicate with kinetics similar to those of Asian-lineage isolates and can infect the placenta. However, there was no evidence of more-severe outcomes with African-lineage isolates. Our results highlight both the threat that African-lineage ZIKV poses to pregnant individuals and their infants and the need for epidemiological and translational in vivo studies with African-lineage ZIKV.

Documented ß-Lactam Allergy and Risk for Cesarean Surgical Site Infection.

Objective: To examine the relationship between documented ß-lactam allergy and cesarean delivery (CD) surgical site infection (SSI). Study Design. We conducted a retrospective cohort analysis of women who underwent CD at Ben Taub Hospital and Texas Children's Pavilion for Women (Houston, TX) from August 1, 2011, to December 31, 2019. The primary exposure was a documented ß-lactam allergy, and the second exposure of interest was the type of perioperative antibiotic received. The primary outcome was the prevalence of SSI. Maternal characteristics were stratified by the presence or absence of a documented ß-lactam allergy, and significance was evaluated using Pearson's chi-squared test for categorical variables and t-test for continuous variables. A logistic regression model estimated odds of SSI after adjusting for possible confounders. Results: Of the 12,954 women included, 929 (7.2%) had a documented ß-lactam allergy while 12,025 (92.8%) did not. Among the 929 women with a ß-lactam allergy, 495 (53.3%) received non-ß-lactam perioperative prophylaxis. SSI occurred in 38 (4.1%) of women who had a ß-lactam allergy versus 238 (2.0%) who did not (p ≤ 0.001). ß-Lactam allergy was associated with higher odds of SSI compared to no allergy (adjusted odds ratio (aOR) = 1.97; 95%confidence interval (CI) = 1.24-3.14; p = 0.004) after controlling for age, race, ethnicity, insurance status, delivery body mass index (BMI), tobacco use, intra-amniotic infection in labor, duration of membrane rupture, preterm delivery, delivery indication, diabetes, hypertension, group B Streptococcus colonization, and type of perioperative antibiotic received. Conclusion: The presence of a ß-lactam allergy is associated with increased odds of developing a CD SSI after controlling for possible confounders, including the type of perioperative antibiotic received.

Prenatal care experiences among pregnant women with obesity in Wisconsin, United States: a qualitative quality improvement assessment.

BACKGROUND: Stigma and bias experienced during prenatal care can affect quality of care and, ultimately, the health of pregnant women with obesity and their infants. We sought to 1) better understand the bias and stigma that women with BMIs ≥40 kg/m2 experience while receiving prenatal care, 2) gauge women's interest in group prenatal education for women with obesity, and 3) gather feedback about their preferred weight-related terminology. METHODS: We conducted and thematically content-analyzed 30 semi-structured interviews of women with BMIs ≥40 kg/m2 who received prenatal care at a university-affiliated teaching hospital in the Midwest region of the United States. RESULTS: All women recalled positive experiences during their perinatal care during which they felt listened to and respected by providers. However, many also described a fear of weight-related bias or recalled weight-based discrimination. Women reacted favorably to a proposed group prenatal care option for pregnant women with obesity that focused on nutrition, physical activity, and weight management. Women rated "weight" and "BMI" as the most desirable terms for describing weight, while "large size" and "obesity" were rated least desirable. CONCLUSIONS: Many pregnant women with BMIs ≥40 kg/m2 experience bias in the prenatal care setting. Potential steps to mitigate bias towards weight include improving provider awareness of the experiences and perspectives of this population, expanding prenatal care options targeted towards women with high BMIs, including group care, and using patient-preferred weight-related terminology. Through the remainder of this manuscript, wherever possible, the term "high BMI" will be used in place of the term "obesity" to describe women with BMI ≥ 30 kg/m2 in order to respect the preferred terminology of the women we interviewed.

A Matter of Time: Does Gestational Age Affect the Duration of the Fetal Anatomic Survey?

OBJECTIVE: To assess the average duration of detailed fetal anatomic surveys in pregnancy in relation to gestational age (GA) and the maternal body mass index (BMI) to determine optimal timing of the examination. METHODS: This was a retrospective cohort study of gravidae presenting for detailed fetal anatomic examinations between January 1, 2010, and June 30, 2017. After excluding examinations expected to have longer duration (ie, multifetal, major fetal anomalies), there were a total of 6522 examinations performed between GAs of 18 weeks 0 days and 22 weeks 0 days. Women were grouped by BMI, and results were analyzed by logistic regression. RESULTS: Gravidae of normal weight (BMI, 18.5-24.9 kg/m2 ) had a decrease of 47.47 seconds of the examination time with each increasing week of gestation (P = .036). Overweight (BMI, 25-29.9 kg/m2 ) gravidae similarly had a decrease of 66.31 seconds of the examination time with each additional week of gestation (P = .017). Underweight (BMI, 8.5 kg/m2 ) and obese (BMI, ≥30 kg/m2 ) gravidae did not have differences in the examination time with increasing GA. Increases in suboptimal examinations were noted with an increasing BMI (P < .001). There was a decreased frequency of suboptimal examinations in obese gravidae with a BMI of 40 kg/m2 or higher with increasing GA (P = .037). CONCLUSIONS: The duration of detailed fetal anatomic examinations decreased with increasing GA in normal-weight and overweight gravidae but not in obese gravidae. Performing the anatomy scan earlier in class I and II obese gravidae (BMI, 30-40 kg/m2 ) may enable improved pregnancy management options without increasing the examination duration or likelihood of a suboptimal evaluation.

Maternal Metabolic Biomarkers are Associated with Obesity and Excess Gestational Weight Gain.

OBJECTIVE: The purpose of this study was to evaluate the independent contribution of maternal obesity and gestational weight gain (GWG) in excess of the Institute of Medicine's guidelines on levels of maternal serum inflammatory and metabolic measures. STUDY DESIGN: Banked maternal serum samples from 120 subjects with documented prepregnancy or first trimester body mass index (BMI) were utilized for analyte analyses. Validated, BMI-specific formulas were utilized to categorize GWG as either insufficient, at goal or excess based on the Institute of Medicine guidelines with gestational age adjustments. Serum was analyzed for known inflammatory or metabolic pathway intermediates using the Luminex xMap system with the MILLIPLEX Human Metabolic Hormone Magnetic Bead Panel. Measured analytes included interleukin-6, monocyte chemoattractant protein-1, and tumor necrosis factor-α and metabolic markers amylin, c-peptide, ghrelin, gastric inhibitory polypeptide, glucagon-like peptide-1, glucagon, insulin, leptin, pancreatic polypeptide, and peptide YY. Kruskal-Wallis ANOVA and Pearson's correlation coefficients were calculated for each marker. RESULTS: C-peptide, insulin, and leptin all varied significantly with both obesity and GWG while glucagon-like peptide-1 varied by BMI but not GWG. These analytes covaried with other metabolic analytes, but not with inflammatory analytes. CONCLUSION: Maternal metabolic biomarkers at delivery vary significantly with both obesity and GWG. Taken together, these findings suggest that GWG (with and without comorbid obesity) is an important mediator of measurable metabolites in pregnancy but is not necessarily accompanied by inflammatory measures in serum. These findings are consistent with GWG being an independent risk factor for metabolic disturbances during pregnancy.

Metformin Exposure and Risk of Hypertensive Disorders of Pregnancy in Patients with Type 2 Diabetes.

OBJECTIVE: Metformin has been found to have a role in promoting vascular remodeling and angiogenesis which may reduce the risk of developing preeclampsia. Prior studies have shown a decrease in the incidence of hypertensive disorders of pregnancy in patients with type 2 and gestational diabetes taking metformin. We hypothesize metformin exposure decreases the risk of developing hypertension in patients with type 2 diabetes. STUDY DESIGN: Retrospective cohort study from 2009 to 2019 of singleton pregnancies was complicated by type 2 diabetes. We compared patients who received metformin throughout pregnancy to those with no metformin exposure. The primary outcome was a hypertension composite defined as gestational hypertension, preeclampsia with or without severe features, HELLP syndrome, or eclampsia. Individual hypertensive outcomes and neonatal outcomes were secondarily evaluated. Logistic regression was used to adjust for confounding variables. RESULTS: A total of 254 pregnancies were included. Women exposed to metformin were significantly less likely to develop hypertension composite compared with nonexposed women (22.7 vs. 33.1%, aOR 0.53, 95% CI 0.29-0.96). The incidence of preeclampsia with severe features was also significantly lower in those who received metformin compared with those who did not (12.1 vs. 20.7%, aOR 0.38, 95% CI 0.18-0.81). There were no differences in preterm birth prior to 34 or 37 weeks, fetal growth restriction, or birth weight between the study groups. A subgroup analysis of women without chronic hypertension also had a significantly lower risk of developing preeclampsia with severe features (7.6 vs. 17.8%, aOR 0.35, 95% CI 0.13-0.94). CONCLUSION: Metformin exposure was associated with a decreased risk of composite hypertensive disorders of pregnancy in patients with pregestational type 2 diabetes. These data suggest that there may be benefit to metformin administration beyond glycemic control in this patient population. KEY POINTS: · Metformin use showed a decreased risk of a hypertension composite.. · Results were consistent in patients without chronic hypertension.. · Metformin may show benefit beyond glycemic control in women with type 2 diabetes..

Highly efficient maternal-fetal Zika virus transmission in pregnant rhesus macaques.

Infection with Zika virus (ZIKV) is associated with human congenital fetal anomalies. To model fetal outcomes in nonhuman primates, we administered Asian-lineage ZIKV subcutaneously to four pregnant rhesus macaques. While non-pregnant animals in a previous study contemporary with the current report clear viremia within 10-12 days, maternal viremia was prolonged in 3 of 4 pregnancies. Fetal head growth velocity in the last month of gestation determined by ultrasound assessment of head circumference was decreased in comparison with biparietal diameter and femur length within each fetus, both within normal range. ZIKV RNA was detected in tissues from all four fetuses at term cesarean section. In all pregnancies, neutrophilic infiltration was present at the maternal-fetal interface (decidua, placenta, fetal membranes), in various fetal tissues, and in fetal retina, choroid, and optic nerve (first trimester infection only). Consistent vertical transmission in this primate model may provide a platform to assess risk factors and test therapeutic interventions for interruption of fetal infection. The results may also suggest that maternal-fetal ZIKV transmission in human pregnancy may be more frequent than currently appreciated.

Travel During Pregnancy: Results From an Ultrasound Unit-Based Questionnaire.

BACKGROUND: The frequency of domestic and international travel among women residing in the United States, and specifically Wisconsin, during pregnancy is not known. Given the recent epidemic of Zika virus disease, clinicians should be aware of the frequency of travel during pregnancy and should inquire about travel by pregnant women, women of reproductive age, and their sexual partners. METHODS: Due to the Zika epidemic, our obstetric ultrasound center added questions about international and domestic travel to a general health form that is routinely distributed to all patients presenting for anatomic ultrasounds. The forms were then collected and recorded in order to provide an estimate of the frequency of travel during the first half of pregnancy. RESULTS: Of 1,256 women screened, 64 (5.1%) traveled internationally and 498 (39.6%) traveled domestically prior to their anatomic ultrasound. Additionally, 77 (6.1%) women screened reported international travel by their sexual partner. Among international travelers, 20 (28.1%) traveled to destinations with active ongoing transmission of Zika virus disease, and 16 (25%) traveled after the Centers for Disease Control and Prevention (CDC) issued a travel alert for the area. Among domestic travelers, Florida was the sixth most common destination, and Texas was the 10th most common. CONCLUSIONS: In the population of women screened by this questionnaire, 5.1% traveled internationally and 39.6% traveled domestically prior to their anatomic ultrasound. Notably, Florida and Texas are common travel destinations among women at this clinic, and both have had active local transmission of Zika virus.

Increasing maternal obesity is associated with alterations in both maternal and neonatal thyroid hormone levels.

OBJECTIVE: Obesity is associated with alterations in thyroid hormone (TH) levels in obese, pregnant individuals. The maintenance of TH levels throughout gestation is important for proper foetal development. The aim of this study was to measure levels of fT3, fT4 and TSH in maternal and matched cord blood serum from normal weight, overweight and obese gravidae to determine alterations in maternal and neonatal TH levels by virtue of maternal obesity. DESIGN, SETTING, SUBJECTS, OUTCOME MEASURES: ELISA was utilized to measure fT3, fT4 and TSH levels from banked, matched maternal and neonatal (cord blood) serum (N = 205 matched pairs). Data were stratified according to prepregnancy or first trimester BMI. RESULTS: Both maternal and neonatal fT3 levels consistently increased with increasing maternal obesity, and maternal and neonatal fT3 were significantly correlated (r = 0·422, P < 0·001). Maternal and neonatal fT3 were also significantly associated with birthweight (ß = 0·155, P = 0·027 and ß = 0·171, P = 0·018, respectively). Both the maternal and neonatal fT3 to fT4 ratio significantly increased with increasing maternal obesity. We further found that excess gestational weight gain was associated with a decrease in maternal fT4 compared with gravidae who had insufficient gestational weight gain (0·86 ± 0·17 vs 0·95 ± 0·22, P < 0·01). CONCLUSION: Maternal obesity is not only associated with maternal alterations in TH, but with accompanying neonatal changes. Because both maternal obesity and alterations in TH levels are associated with childhood obesity, based on these findings and our prior analyses in a nonhuman primate model, we propose that changes in fT3 levels in the offspring of obese mothers may be a potential molecular mediator of foetal overgrowth and childhood obesity.

Marijuana use and its effects in pregnancy.

BACKGROUND: It is generally assumed that marijuana is one of the more widely used controlled substances during pregnancy. However, there remains a general paucity of population-based data regarding its use and subsequent perinatal morbidity. We hypothesized that direct patient query during pregnancy regarding marijuana, tobacco, and nicotine use would provide crucial initial population-based data on perinatal risk. OBJECTIVE: Our study sought to examine maternal and neonatal outcomes in pregnancies with reported marijuana exposure, in isolation or in combination with maternal cigarette smoking. STUDY DESIGN: We applied a retrospective cohort study design to subjects (n = 12,069) with available information on marijuana use and pregnancy outcomes. Since 2011, we have routinely and directly questioned all gravidae regarding use of marijuana, tobacco, and nicotine-containing products. We examined perinatal outcomes in marijuana smokers vs nonsmokers, as well as patients reporting both marijuana and cigarette smoking. Multivariate analysis enabled determination of adjusted odds ratios for maternal and fetal outcomes, adjusting for confounders. Significance was determined with Mann-Whitney U, χ(2), and Fischer exact tests (as appropriate). RESULTS: In all, 106/12,069 reported marijuana use (0.88%), with 48/12,069 (0.4%; or 48/106, 45%) concurrently using cigarettes and marijuana. After controlling for potential confounding variables, while marijuana use alone was not associated with significant adverse outcomes, use in combination with cigarette smoking was significantly associated with increased risk of multiple adverse perinatal outcomes (increased occurrence of maternal asthma [adjusted odds ratio, 2.4; 95% confidence interval, 1.0-5.9]; preterm birth [adjusted odds ratio, 2.6; 95% confidence interval, 1.3-4.9]; decreased [<25th percentile] head circumference [adjusted odds ratio, 2.8; 95% confidence interval, 1.3-4.3]; and decreased [<25th percentile] birthweight [adjusted odds ratio, 2.8; 95% confidence interval, 1.6-5.0]). Maternal pregnancy-related hypertension was not increased in marijuana smokers (adjusted odds ratio, 1.30; 95% confidence interval, 0.681-2.498), or in cigarette smokers (adjusted odds ratio, 1.4; 95%, confidence interval, 0.9-1.9). However, co-users had elevated rates of preeclampsia compared to nonusers (adjusted odds ratio, 2.5; 95% confidence interval, 1.4-5.0). CONCLUSION: In our initial cohort analysis, after controlling for potential confounders, while marijuana exposure alone was not associated with significant perinatal adverse outcomes, co-use with cigarette smoking rendered increased risk over either alone. Due to observed prevalence of concurrent cigarette and marijuana use, it is of likely importance to counsel patients regarding use in pregnancy.

Candy twists as an alternative to the glucola beverage in gestational diabetes mellitus screening.

OBJECTIVE: Screening for gestational diabetes mellitus commonly uses an oral glucose challenge test with a 50-g glucola beverage and subsequent venous puncture. However, up to 30% of pregnant women report significant side-effects, and the beverage is costly. We hypothesized that equivalent glucose loads could be achieved from a popular candy twist (Twizzlers; The Hershey Company, Hershey, PA) and tested it as cost-effective, tolerable alternative with a test of equivalency. STUDY DESIGN: The glucose equivalent of the 50-g glucola was calculated as 10 candy twists. We initially used a triple crossover design in nonpregnant patients whereby each subject served as her own control; this ensured the safety and equivalency of this load before using it among pregnant subjects. We then recruited pregnant women with an abnormal screening at 1 hour (glucose challenge test) in a double crossover design study. Subjects consumed 10 candy twists with a 1-hour venous blood glucose assessment. All subjects subsequently completed the confirmatory 3-hour glucose tolerance test. Sensitivity, specificity, positive predictive values, negative predictive values, false-referral rates, and detection rates were calculated. RESULTS: At ≥130 mg/dL, the sensitivity (100%) was the same for candy twists and glucola. However, the false-referral rate (82% vs 90%), positive predictive value (18% vs 10%), and detection rate (18% vs 10%) were improved for candy twists when compared with the 50-g glucola beverage. CONCLUSION: Our results indicate that strawberry-flavored candy twists are potentially an equally effective screening test, compared with the gold standard glucola beverage but lead to fewer false-positive screens and therefore could be a cost-effective alternative.

The preterm placental microbiome varies in association with excess maternal gestational weight gain.

OBJECTIVE: Although a higher maternal body mass index is associated with preterm birth, it is unclear whether excess gestational weight gain (GWG) or obesity drives increased risk. We and others have shown that the placenta harbors microbiota, which is significantly different among preterm births. Our aim in this study was to investigate whether the preterm placental microbiome varies by virtue of obesity or alternately by excess GWG. STUDY DESIGN: Placentas (n=320) were collected from term and preterm pregnancies. Genomic DNA was extracted and subjected to metagenomic sequencing. Data were analyzed by clinical covariates that included the 2009 Institute of Medicine's GWG guideline and obesity. RESULTS: Analysis of 16S recombinant RNA-based metagenomics revealed no clustering of the microbiome by virtue of obesity (P=.161). Among women who spontaneously delivered preterm, there was again no clustering by obesity (P=.480), but there was significant clustering by excess GWG (P=.022). Moreover, among preterm births, detailed analysis identified microbial genera (family and genus level) and bacterial metabolic gene pathways that varied among pregnancies with excess GWG. Notably, excess GWG was associated with decreased microbial folate biosynthesis pathways and decreased butanoate metabolism (linear discriminate analysis, >3.0-fold). CONCLUSION: Although there were no significant alterations in the microbiome by virtue of obesity per se, excess GWG was associated with an altered microbiome and its metabolic profile among those women who experienced a preterm birth.