Investigating the origin of the fetal gut and placenta microbiome in twins.

OBJECTIVE: It is widely accepted that the microbiota is critical for human well-being; however, the origin of microbiota in the newborn is not well understood. In this study, we hypothesized that within a maternal-twin dyad (MTD) the meconium microbiome will be similar to the placenta microbiome and the meconium microbiome of within MTD will be similar to one another. METHODS: Prospectively, meconium (proxy for fetal gut), placenta and maternal buccal, skin, vaginal, stool samples were collected from a cohort of MTDs at time of delivery hospitalization. We performed gene sequencing using the V4 region of 16S rRNA with rigorous negative controls. Alpha and beta diversity indices were computed to characterize the microbial community of MTD samples. A p value of <.05 was considered significant. RESULTS: From 17 MTD, 87/132 samples were successfully sequenced. The alpha diversity of the microbiome collected from all the body sites were different (p ≤ .001). The meconium samples when compared to other samples in the MTD microbial community were different (p = .009) and the Bray-Curtis dissimilarity was greater than 0.95 for all of the comparisons (beta diversity). The MTD within-twin placenta microbiome samples were also different, confirmed by Bray-Curtis pairwise dissimilarity distance, 0.83. CONCLUSION: The fetal gut microbiome is different from placenta and maternal buccal, skin, vaginal and stool microbiome. We clearly identified a distinct placenta microbiome. Furthermore, placentas in the same MTD have distinct microbiomes, suggesting that fetal gut and placenta origin is complex and remains unclear.

Fetal gastric area ratio to predict severe neonatal opioid withdrawal syndrome.

OBJECTIVE: Neonatal opioid withdrawal syndrome (NOWS) can occur in newborns exposed to opioids in pregnancy. Opioids delay gastric emptying and inhibit gastric motility in adults, but little is known about their effect in the fetus. We sought to assess gastric area ratio (GAR) in opioid-exposed fetuses. STUDY DESIGN: Retrospective cohort study including opioid-exposed maternal-neonatal dyads between 2007-2017. Primary outcome: severe NOWS (three consecutive Finnegan scores ≥8 or three scores totaling ≥24 within 96 h of life). GAR: (gastric area)/(transverse abdominal area) × 100. Data analysis was by descriptive, parametric, and non-parametric tests. RESULTS: Forty-nine maternal-neonatal dyads were included, 67% (n = 33) with severe NOWS. GAR <95th percentile for gestational age was seen in 80% of neonates (n = 39). However, GAR was not different between groups (p = .90) and did not predict severe NOWS. CONCLUSION: Fetal GAR was <95th percentile in 80% of opioid-exposed neonates. However, fetal GAR may not predict NOWS treatment.

Diabetic nephropathy in pregnancy: Report of two cases progressing to end-stage renal disease within one year postpartum.

BACKGROUND: Diabetes mellitus is a leading cause of nephropathy and end-stage renal disease. However, diabetic nephropathy during pregnancy in patients with normal glomerular filtration rate and subsequent progression to end-stage renal disease has not been well studied. CASES: This report presents two patients with poorly controlled type 1 diabetes mellitus who had diabetic nephropathy with preserved estimated glomerular filtration rate (Case 1: 117 mL/min/1.73m2; Case 2: 79 mL/min/1.73m2) and shared a similar clinical course, with glomerular filtration rates decreasing by approximately one-half during pregnancy and progression to end-stage renal disease within the first year postpartum. Both women had a long history of type 1 diabetes: 18 years and 24 years for case 1 and case 2 respectively. The first patient's course of pregnancy was complicated by difficult-to-control blood glucose and hypertension with subsequent preeclampsia. The second patient's course of pregnancy was complicated by difficult-to-control blood sugars and preterm labor resulting in classical cesarean delivery at 24 weeks. Both patients had renal biopsies shortly after delivery as their renal function continued to worsen postpartum. Both kidney biopsies demonstrated advanced diabetic nephropathy changes and ultimately required chronic renal replacement therapy within 7-9 months postpartum. CONCLUSION: Comprehensive family planning discussions with women who have diabetic nephropathy should include the risks of renal disease progression, even in those patients with preserved renal function at the time of conception.

Placental aromatase expression decreased in severe neonatal opioid withdrawal syndrome.

Background: Severe neonatal opioid withdrawal syndrome (NOWS) cannot be predicted. Placental aromatase metabolizes both methadone and buprenorphine and may contribute to the severity of NOWS.Objectives: To determine whether placental aromatase mRNA expression differs in methadone- or buprenorphine-exposed placentas and is associated with NOWS severity.Study design: Prospective multicenter observational cohort study from July 2016 to December 2017. Inclusion: pregnant, ≥18 years old, singleton fetus, nonanomalous, ≥34 weeks at delivery, documented methadone or buprenorphine use. Exclusion: declined sample collection. Severe NOWS is defined as three consecutive Finnegan scores ≥8 or sum of three consecutive scores ≥24 within 72 hours of birth. Finnegan scoring was correlated with placental mRNA expression and compared to umbilical cord drug and metabolite levels. Data were analyzed using descriptive, parametric, and nonparametric statistics and regression analysis. p-Value <.05 was considered significant.Results: Thirty-eight out of 45 (84%) patients were included. Methadone and buprenorphine were used by 29/38 (76%) and 9/38 (24%) of patients, respectively. 19/38 (50%) infants had severe NOWS. Placental aromatase/actin mRNA expression was significantly lower in the placentas of infants with severe NOWS (p = .04). Mean umbilical cord 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP)/methadone ratios were significantly higher in infants with severe NOWS (p = .03). Placental aromatase mRNA expression was weakly to moderately correlated with umbilical cord methadone, buprenorphine, and their metabolite concentrations (r = 0.4-0.8).Conclusion: Placental aromatase mRNA expression was lower and umbilical cord EDDP/methadone ratios were higher in infants with severe NOWS. Additional investigation of placental aromatase in methadone- and buprenorphine-exposed pregnancies is needed.

Racial/Ethnic Disparities in Morbidity and Mortality for Preterm Neonates Admitted to a Tertiary Neonatal Intensive Care Unit.

OBJECTIVE: The objective of this study was to assess whether in-hospital morbidity or mortality differed by race/ethnicity for preterm neonates admitted to the neonatal intensive care unit (NICU). STUDY DESIGN: In a retrospective cohort study, preterm infants, < 37 weeks, were admitted to the NICU from 1994 to 2009. Exclusions included structural anomalies and aneuploidy. Primary outcome was in-hospital mortality (IHM). Secondary outcomes were respiratory distress syndrome (RDS), interventricular hemorrhage (IVH), necrotizing enterocolitis (NEC), and retinopathy of prematurity (ROP). Sub-analysis of very preterm (VPT) infants, < 28 weeks, was performed. Five racial/ethnic groups (REGs) were compared: White, Black, Hispanic, Asian, and Mixed. Associations were modeled by logistic regression. White neonates (WNs) were the referent group. Unadjusted and adjusted odds ratios and 95% confidence intervals for remaining REGs were reported. p value was significant at 5% for overall tests and at Bonferroni-corrected level < 0.0125 for between-race comparisons with WNs. RESULTS: Four thousand nine hundred fifty-five preterm neonates were identified; 153 were excluded leaving 4802 for analysis. After controlling covariates that were chosen a priori, there was no difference across REGs for IHM (all between-race comparison p values > 0.0125). There was a significant difference in RDS among Black neonates (BNs) (aOR 0.57, 95% CI 0.45-0.73; p < 0.001) and Hispanic neonates (HNs) (aOR 0.67, 95% CI 0.50-0.89; p = 0.005) compared to WNs. The risk of ROP was significantly different across REGs with HNs having a 70% increase in ROP (aOR 1.70, 95% CI 1.15-2.49; p = 0.008) and Mixed neonates (MNs) experiencing a 55% reduction (aOR 0.45, 95% CI 0.29-0.68; p < 0.001) compared to WNs. There was no difference in IVH or NEC across REGs (all p values > 0.0125). In the VPT cohort sub-analysis, BNs experienced a significant 59% reduction in IHM compared to WNs (BNs aOR 0.41, 95% CI 0.22-0.73; p = 0.003). MNs experienced a 46% reduction in ROP compared to WNs (aOR 0.54, 95% CI 0.35-0.81; p = 0.004). There was no difference in RDS, IVH, or NEC in very preterm infants across REGs (all between comparison p values > 0.0125). CONCLUSION: In preterm neonates, in-hospital mortality does not significantly differ across racial and ethnic groups. However, in very preterm infants, in-hospital mortality for Black neonates is improved. There are morbidity differences (RDS, ROP) seen among racial/ethnic groups.

Gender Differences in Respiratory Morbidity and Mortality of Preterm Neonates.

For the past century, researchers have underscored the "disadvantage" observed in respiratory morbidity and mortality of male newborns. In this contemporary review, we examine gender differences in preterm infant respiratory morbidity and mortality specifically appraising differences in the very low birth weight (VLBW) population as well as the late preterm (LPT) population. In the era of postnatal surfactant and antenatal corticosteroids, the gender gap in neonatal outcomes has not narrowed. Structural, physiologic, and hormonal sex differences may be at the root of this disparity. Further exploration into the origin of gender differences in respiratory morbidity and neonatal mortality will shape future therapies. These therapies may need to be gender specific to close the gender gap.

What Is New in Diabetes in Pregnancy?: Best Articles From the Past Year.

This month we focus on current research in diabetes in pregnancy. Dr. Campbell discusses four recent publications, which are concluded with a "bottom line" that is the take-home message. The complete reference for each can be found in on this page, along with direct links to the abstracts.

Seronegative Maternal Ocular Myasthenia Gravis and Delayed Transient Neonatal Myasthenia Gravis.

Background Myasthenia gravis (MG) is an autoimmune disorder with fluctuating muscle weakness, divided into generalized and localized (ocular) forms. Maternal antibodies to acetylcholine receptors cross the placenta and may cause transient neonatal myasthenia gravis (TNMG). We present a case of seronegative maternal ocular MG and delayed TNMG. Case A 29-year-old G3P1011 underwent cesarean birth of a male infant who developed oxygen desaturation requiring supplemental oxygen on day of life (DOL) 3. Based on the clinical course and after exclusion of other diagnoses, the infant was diagnosed with TNMG. Infant's condition improved spontaneously and he was weaned off supplemental oxygen and discharged home on DOL 12. Conclusion Infants born to mothers with seronegative localized (ocular) MG are also susceptible to TNMG which may be late in onset.

What is new in interpregnancy interval and pregnancy outcome? Best articles from the past year.

This month we focus on current research in pregnancy spacing. Dr. Campbell discusses five recent publications, and each is concluded with a "bottom line" that is the take-home message. The complete reference for each can be found in on this page, along with direct links to the abstracts.

Does early second-trimester sonography predict adverse perinatal outcomes in monochorionic diamniotic twin pregnancies?

OBJECTIVES: To determine whether intertwin discordant abdominal circumference, femur length, head circumference, and estimated fetal weight sonographic measurements in early second-trimester monochorionic diamniotic twins predict adverse obstetric and neonatal outcomes. METHODS: We conducted a multicenter retrospective cohort study involving 9 regional perinatal centers in the United States. We examined the records of all monochorionic diamniotic twin pregnancies with two live fetuses at the 16- to 18-week sonographic examination who had serial follow-up sonography until delivery. The intertwin discordance in abdominal circumference, femur length, head circumference, and estimated fetal weight was calculated as the difference between the two fetuses, expressed as a percentage of the larger using the 16- to 18-week sonographic measurements. An adverse composite obstetric outcome was defined as the occurrence of 1 or more of the following in either fetus: intrauterine growth restriction, twin-twin transfusion syndrome, intrauterine fetal death, abnormal growth discordance (≥20% difference), and very preterm birth at or before 28 weeks. An adverse composite neonatal outcome was defined as the occurrence of 1 or more of the following: respiratory distress syndrome, any stage of intraventricular hemorrhage, 5-minute Apgar score less than 7, necrotizing enterocolitis, culture-proven early-onset sepsis, and neonatal death. Receiver operating characteristic and logistic regression-with-generalized estimating equation analyses were constructed. RESULTS: Among the 177 monochorionic diamniotic twin pregnancies analyzed, intertwin abdominal circumference and estimated fetal weight discordances were only predictive of adverse composite obstetric outcomes (areas under the curve, 79% and 80%, respectively). Receiver operating characteristic curves showed that intertwin discordances in abdominal circumference, femur length, head circumference, and estimated fetal weight were not acceptable predictors of twin-twin transfusion syndrome or adverse neonatal outcomes. CONCLUSIONS: In our cohort, only second-trimester abdominal circumference and estimated fetal weight discordances in monochorionic diamniotic twin pregnancies were predictive of adverse composite obstetric outcomes. Twin-twin transfusion syndrome and adverse neonatal outcomes were not predicted by any of the intertwin discordances measured.

First Trimester Aneuploidy Screening Markers in Women with Pre-Gestational Diabetes Mellitus.

OBJECTIVE: To investigate whether maternal serum pregnancy associated plasma protein-A (PAPP-A), total ß human chorionic gonadotropin (hCG) levels and nuchal translucency (NT) measurements differ in women with pre-gestational diabetes mellitus (PGDM) compared to non-diabetic controls and to assess whether correction factors are needed for diabetic women in calculation of aneuploidy risks. STUDY DESIGN: We performed a retrospective study of all women who underwent first trimester aneuploidy screening (11 + 0 to 13 + 6 weeks) from 2005 to 2011. The primary study outcome was the difference in PAPP-A, ß-hCG and NT multiples of median between women with PGDM and non-diabetic women. RESULTS: Of 6741 eligible patients, 103 patients with PGDM were using insulin and 4 patients were using oral hypoglycemic agents; the latter were excluded due to small number. There was 12% reduction of median PAPP-A (p = 0.001) and 18% reduction of median hCG (p = 0.006) in women with PGDM receiving insulin. There was no difference in NT. CONCLUSIONS: In women with PGDM receiving insulin, PAPP-A and ß-hCG levels are significantly lower compared to non-diabetic women. This suggests that when calculating risks for aneuploidy, correction factors should be considered to adjust PAPP-A and ß-hCG concentrations to those seen in non-diabetic women.

Nuchal translucency and cardiac abnormalities in euploid singleton pregnancies.

OBJECTIVE: To investigate different cut-off levels of nuchal translucency (NT) to predict abnormal cardiac findings (ACF) in second trimester ultrasound examination and confirmed postnatal congenital heart defects (CHD) in euploid pregnancies. METHODS: A retrospective analysis was performed on singleton pregnancies examined in our ultrasound units from 2006 to 2011. Fetuses with an abnormal karyotype were excluded. Different cut-off levels of NT thickness were analyzed to evaluate its performance to detect the ACF on second trimester ultrasound (2nd US) examination and also the CHD detected in neonatal follow-up evaluation of ACF cases. RESULTS: Of the 12,840 cases, a total number of 8541 euploid pregnancies were included in the study. Thirty-three had ACFs detected by 2nd US (3.86/1000). The mean NT thickness was found to be higher in fetuses with ACFs (p < 0.0001). Of 33 ACFs, 17 (52%, 1.99/1000) had major CHDs in neonatal follow-up. The area under the ROC curves for NT thickness to predict ACFs and CHDs were 0.67 and 0.65, respectively. CONCLUSIONS: Higher NT thickness is associated with higher risk of ACF. NT is a weak predictor of ACF and major CHD; however, fetuses with an unexplained increase in NT measurement should be referred for further cardiac investigations.

Perinatal outcomes based on the institute of medicine guidelines for weight gain in twin pregnancies.

OBJECTIVE: To estimate the impact of the Institute of Medicine's (IOM) weight gain recommendations on perinatal outcomes in twin pregnancies. METHODS: In this multicenter cohort study, using the 2009 IOM guidelines, we examined pregnancy outcomes in 570 uncomplicated diamniotic twin pregnancies. Subjects were grouped according to pre-pregnancy body mass index. Perinatal outcomes were assessed based on whether maternal weekly weight gain was less than, at, or in excess of the recommended IOM guidelines. RESULTS: In women with a normal pre-pregnancy BMI, patients whose weight gain met the IOM recommendations had a significantly higher mean gestational age at delivery; less prematurity and larger birth weight infants compared to women whose weekly weight gain was less or excess than the recommended IOM guidelines. Similarly, when compared with their low weight gain counterparts, overweight women with appropriate weight gain had improved outcomes including higher mean gestational age at delivery, higher birth weight infants and less prematurity. In obese women, the amount of pregnancy weight gain did not impact perinatal outcomes. CONCLUSION: Our results confirm that weekly maternal weight gain according to the IOM guidelines results in improved outcomes in twin pregnancies. Importantly, women with a normal or overweight pre-pregnancy BMI whose weekly weight gain was less than recommended, had increased risks of prematurity and lower birth weight infants. Similarly, women with a normal pre-pregnancy BMI whose weekly weight gain was excess than recommended had increased risks of prematurity and lower birth weight infants.

Short-term neonatal outcomes in diamniotic twin pregnancies delivered after 32 weeks and indications of late preterm deliveries.

OBJECTIVE: We sought to compare neonatal outcomes in twin pregnancies following moderately preterm birth (MPTB), late preterm birth (LPTB), and term birth and determine the indications of LPTB. STUDY DESIGN: We performed a retrospective cohort study. MPTB was defined as delivery between 32(0/7) and 33(6/7) weeks and LPTB between 34(0/7) and 36(6/7) weeks. The composite neonatal adverse respiratory outcome was defined as respiratory distress syndrome and/or bronchopulmonary dysplasia. The composite neonatal adverse nonrespiratory outcome included early onset culture-proven sepsis, necrotizing enterocolitis, retinopathy of prematurity, intraventricular hemorrhage, or periventricular leukomalacia. LPTB cases were categorized as spontaneous (noniatrogenic), evidence-based iatrogenic, and non-evidence-based (NEB) iatrogenic. RESULTS: Of the 747 twin deliveries during the study period, 453 sets met the inclusion criteria with 22.7% (n = 145) MPTB, 32.1% (n = 206) LPTB, and 15.9% (n = 102) term births. Compared with term neonates, the composite neonatal adverse respiratory outcome was increased following MPTB (relative risk [RR] 24; 95% confidence interval [CI] 3.0 to 193.6) and LPTB (RR 13.7; 95% CI 1.8 to 101.8). Compared with term neonates, the composite neonatal adverse nonrespiratory outcome was increased following MPTB (RR 22.3; 95% CI 3.9 to 127.8) and LPTB (RR 5.5; 95% CI 1.1 to 27.6). Spontaneous delivery of LPTB was 63.6% (n = 131/206) and the rate of iatrogenic delivery was 36.4% (n = 75/206). The majority, 66.6% (n = 50/75), of these iatrogenic deliveries were deemed NEB, giving a total of 24.2% (50/206) NEB deliveries in LPTB group. CONCLUSION: Our data demonstrate a high rate of late preterm birth among twin pregnancies, with over half of nonspontaneous early deliveries due to NEB indications. Although our morbidity data will be helpful to providers in counseling patients, our finding of high NEB indications underscores the need for systematic evaluation of indications for delivery in LPTB twin deliveries. Furthermore, this may lead to more effective LPTB rate reduction efforts.

First-trimester sonographic prediction of obstetric and neonatal outcomes in monochorionic diamniotic twin pregnancies.

OBJECTIVES: The purpose of this study was to investigate whether discordant nuchal translucency and crown-rump length measurements in monochorionic diamniotic twins are predictive of adverse obstetric and neonatal outcomes. METHODS: We conducted a multicenter retrospective cohort study including all monochorionic diamniotic twin pregnancies with two live fetuses at the 11-week to 13-week 6-day sonographic examination who had serial follow-up sonography until delivery. Isolated nuchal translucency, crown-rump length, and combined discordances were correlated with adverse obstetric outcomes, individually and in composite, including the occurrence of 1 or more of the following in either fetus: intrauterine growth restriction (IUGR), twin-twin transfusion syndrome (TTTS), intrauterine fetal death (IUFD), growth discordance (≥ 20%), and preterm birth before 28 weeks' gestation. Correlations with adverse composite neonatal outcomes were also studied. A receiver operating characteristic curve analysis and a logistic regression analysis with a generalized estimating equation were conducted. RESULTS: Fifty-four of the 177 pregnancies included (31%) had an adverse composite obstetric outcome, with TTTS in 19 (11%), IUGR in 21 (12%), discordant growth in 14 (8%), IUFD in 14 (8%), and preterm birth before 28 weeks in 10 (6%). Of the 254 neonates included in the study, 69 (27%) were complicated by adverse composite neonatal outcomes, with respiratory distress syndrome being the most common (n = 59 [23%]). The areas under the curve for the combined discordances to predict composite obstetric and neonatal outcomes were 0.62 (95% confidence interval, 0.52-0.72), and 0.54 (95% confidence interval, 0.46-0.61), respectively. CONCLUSIONS: In our population, nuchal translucency, crown-rump length, and combined discordances in monochorionic diamniotic twin pregnancies were not predictive of adverse composite obstetric and neonatal outcomes.

Efficacy of the genetic sonogram in a stepwise sequential protocol for down syndrome screening.

OBJECTIVES: The purpose of this study was to evaluate the efficacy of the genetic sonogram in Down syndrome screening for women who have received the stepwise sequential test. METHODS: This retrospective cohort study included women with singleton pregnancies who underwent stepwise sequential (first-trimester combined and second-trimester serum) screening and then had a genetic sonogram between March 2005 and January 2010. Stepwise sequential Down syndrome risks were multiplied by either a positive or negative likelihood ratio based on the second-trimester sonographic findings to determine the final Down syndrome risk. A final Down syndrome risk of 1:270 or higher was considered screen positive. RESULTS: A total of 6286 women fulfilled our criteria, including 17 with Down syndrome-affected fetuses. After stepwise sequential testing, the Down syndrome detection rate was 88.2% (15 of 17), and after the genetic sonogram, there was a non-significant reduction in detection to 82.4% (14 of 17; P > .05). For the 6269 unaffected pregnancies, the genetic sonogram converted 58 screen-negative results (1%) to positive and 183 screen-positive results (3.1%) to negative. The net effect was a change in the false-positive rate from 6.2% (390 of 6269) after stepwise sequential screening to 4.2% (266 of 6269) after the genetic sonogram. CONCLUSIONS: The genetic sonogram should be applied cautiously for women who have received prior prenatal screening tests. Women with screen-positive results need to be counseled that a negative sonographic result can be falsely reassuring. Conversely, for women with screen-negative results who have a risk close to the cutoff, a sonographic examination could assist in the decision of whether to accept or reject amniocentesis.

Impact of diabetes on aneuploidy screening.

Maternal pregestational diabetes mellitus is a known risk factor for multiple nonchromosomal congenital anomalies, but there is no clear evidence that diabetes increases the risk for aneuploidy. However, diabetes affects maternal serum analyte concentrations that are used for aneuploidy screening and can alter the false-positive rates of the screening tests. Correction factors are used for women with pregestational diabetes for second-trimester serum analytes used in aneuploidy screening. There is considerable variation in the reported literature regarding the effect of diabetes on first-trimester serum analytes and how it might have an impact on aneuploidy screening.