Plasma soluble fms-like tyrosine kinase 1 to placental growth factor ratio of 11.5 multiples of median predicts preeclampsia with severe features within 2 weeks of testing.

BACKGROUND: Angiogenic imbalances, characterized by an excess of antiangiogenic factors (soluble fms-like tyrosine kinase 1) and reduced angiogenic factors (vascular endothelial growth factor and placental growth factor), contribute to the mechanisms of disease in preeclampsia. The ratio of soluble fms-like tyrosine kinase 1 to placental growth factor has been used as a biomarker for preeclampsia, but the cutoff values may vary with gestational age and assay platform. OBJECTIVE: This study aimed to compare multiples of the median of the maternal plasma soluble fms-like tyrosine kinase 1 to placental growth factor ratio, soluble fms-like tyrosine kinase 1, placental growth factor, and conventional clinical and laboratory values in their ability to predict preeclampsia with severe features. STUDY DESIGN: We conducted a cohort study across 18 United States centers involving hospitalized individuals with hypertension between 23 and 35 weeks' gestation. Receiver operating characteristic curve analyses of maternal plasma biomarkers, highest systolic or diastolic blood pressures, and laboratory values at enrollment were performed for the prediction of preeclampsia with severe features. The areas under the curve were compared, and quasi-Poisson regression models were fitted to estimate relative risks. The primary outcome was preeclampsia with severe features within 2 weeks of enrollment. Secondary outcomes were a composite of severe adverse maternal outcomes (elevated liver enzymes, low platelets count, placental abruption, eclampsia, disseminated intravascular coagulation, and pulmonary edema) and a composite of severe adverse perinatal outcomes (birth weight below the third percentile, very preterm birth [<32 weeks' gestation], and fetal or neonatal death). RESULTS: Of the 543 individuals included in the study, preeclampsia with severe features within 2 weeks was observed in 33.1% (n=180) of them. A receiver operating characteristic curve-derived cutoff of 11.5 multiples of the median for the soluble fms-like tyrosine kinase 1 to placental growth factor plasma ratio provided good sensitivity (90.6%), specificity (76.9%), positive predictive value (66.0%), negative predictive value (94.3%), positive likelihood ratio (3.91), negative likelihood ratio (0.12), and accuracy (81.4%) for preeclampsia with severe features within 2 weeks. This cutoff was used to compare test positive cases (≥ cutoff) and test negative cases (< cutoff). Preeclampsia with severe features (66.0% vs 5.7%; P<.001) and composites of severe adverse maternal (8.11% vs 2.7%; P=.006) or perinatal (41.3% vs 10.14%; P=.001) outcomes within 2 weeks were more frequent in test positive cases than in test negative cases. A soluble fms-like tyrosine kinase 1 to placental growth factor plasma ratio ≥11.5 multiples of the median was independently associated with preeclampsia with severe features (adjusted incidence rate ratio, 9.08; 95% confidence interval, 6.11-14.06; P<.001) and a composite of severe adverse perinatal outcomes (adjusted incidence rate ratio, 9.42; 95% confidence interval, 6.36-14.53; P<.001) but not with a composite of severe adverse maternal outcomes (adjusted incidence rate ratio, 2.20; 95% confidence interval, 0.95-5.54; P=.08). The area under the curve for the soluble fms-like tyrosine kinase 1 to placental growth factor plasma ratio in multiples of the median (0.91; 95% confidence interval, 0.89-0.94) for preeclampsia with severe features within 2 weeks was significantly higher (P<.001 for all comparisons) than either plasma biomarker alone or any other parameter with the exception of absolute soluble fms-like tyrosine kinase 1 to placental growth factor plasma ratio values. CONCLUSION: A soluble fms-like tyrosine kinase 1 to placental growth factor plasma ratio ≥11.5 multiples of the mean among hospitalized patients with hypertension between 23 and 35 week's gestation predicts progression to preeclampsia with severe features and severe adverse perinatal outcomes within 2 weeks.

Prediction of Neonatal Growth Restriction in Fetuses With Gastroschisis by Early Third Trimester Ultrasonography Utilizing Contemporary Birth Weight Percentiles.

OBJECTIVE: To identify the estimated fetal weight (EFW) formula and threshold for the optimal prediction of fetal growth restriction (FGR) at 26-34 weeks' in fetuses with gastroschisis. METHODS: Late second and third trimester ultrasound data were used to calculate the EFW utilizing eight different formulas: Hadlock I-IV, Honarvar, Shepard, Siemer, and Warsof. EFW and birth weight percentiles were assigned from US population growth curves. FGR and small for gestational age (SGA) were defined as EFW and birth weight less than the tenth percentile for gestational age; Receiver operating characteristic (ROC) curves were used to compare formula performance for FGR diagnosis at 26-34 weeks' to identify an SGA birth weight. RESULTS: There were 170 newborns with gastroschisis; 46 (27%) were SGA. The mean gestational age at the time of ultrasound was 30.8 ± 1.7 weeks. The mean gestational age at birth was 36.3 ± 1.7 weeks. ROC curve analysis found the Hadlock III formula had the largest area under the curve (AUC) of 0.813 closely followed by Hadlock IV (AUC = 0.811) and Hadlock II (AUC = 0.808) for diagnosis of FGR correlating to neonatal SGA diagnosis. Hadlock II, Hadlock III, and Hadlock IV had the highest diagnostic accuracies when compared to the other EFW formulas. CONCLUSIONS: The Hadlock II, Hadlock III, and Hadlock IV formulas have comparable predictive performance in the optimal identification of FGR in fetuses with gastroschisis at 26-34 weeks'. A threshold of an EFW less than the 25.2th percentile is suggested.

Attitudes and Knowledge of Maternal-Fetal Medicine Fellows Regarding Noninvasive Prenatal Testing.

Using cell-free DNA in maternal serum to detect fetal aneuploidy has been shown to have high sensitivity and specificity. The purpose of this study was to assess attitudes and knowledge of Maternal-Fetal Medicine (MFM) fellows regarding noninvasive prenatal testing (NIPT). A 13 question survey was sent via listserv to US-based MFM fellows. One hundred sixteen fellows responded, a 42.3% response rate, with >75% reporting they are comfortable ordering NIPT. Most (82%) preferred that a patient discuss options with a provider or genetic counselor. Three common methods used to learn about NIPT were: formal educational activities (n = 78, 69%), self-review of the literature (n = 76, 67%), and discussions with peers (n = 73, 65%). On questions related to trisomy 21, accuracy was >70%. However, accuracy was lower regarding use in twin pregnancies (42%) and monosomy X screening (50%).

Idiopathic Polyhydramnios: Severity and Perinatal Morbidity.

Objective To estimate the association between the severity of idiopathic polyhydramnios and adverse outcomes. Study Design Retrospective cohort study of deliveries at one hospital from 2000 to 2012 with an amniotic fluid index (AFI) measurement ≥24 + 0 weeks' gestation. Pregnancies complicated by diabetes, multiples, or fetal anomalies were excluded. Exposure was the degree of polyhydramnios: normal (AFI 5-24 cm), mild (≥ 24-30 cm), and moderate-severe (> 30 cm). Primary outcomes were perinatal mortality, neonatal intensive care unit (NICU) admission, and postpartum hemorrhage. Results There were 10,536 pregnancies: 10,188 with a normal AFI, 274 mild (78.74%), and 74 moderate-severe polyhydramnios (21.26%). Adverse outcomes were increased with idiopathic polyhydramnios: NICU admission (adjusted odds ratio [AOR] 3.71, 95% confidence interval [CI] 2.77-4.99), postpartum hemorrhage (AOR 15.81, 95% CI 7.82-31.96), macrosomia (AOR 3.41, 95% CI 2.61-4.47), low 5-minute Apgar score (AOR 2.60, 95% CI 1.57-4.30), and cesarean (AOR 2.16, 95% CI 1.74-2.69). There were increasing odds of macrosomia (mild: AOR 3.19, 95% CI 2.36-4.32; moderate-severe: AOR 4.44, 95% CI 2.53-7.79) and low 5-minute Apgar score (mild: AOR 2.24, 95% CI 1.23-4.08; moderate-severe: AOR 3.93, 95% CI 1.62-9.55) with increasing severity of polyhydramnios. Conclusion Idiopathic polyhydramnios is independently associated with increased risks of morbidity. There appears to be a dose-response relationship for neonatal macrosomia and low 5-minute Apgar score risks.

Outcomes of shared institutional review board compared with multiple individual site institutional review board models in a multisite clinical trial.

BACKGROUND: Institutional review boards play a crucial role in initiating clinical trials. Although many multicenter clinical trials use an individual institutional review board model, where each institution uses their local institutional review board, it is unknown if a shared (single institutional review board) model would reduce the time required to approve a standard institutional review board protocol. OBJECTIVE: This study aimed to compare processing times and other processing characteristics between sites using a single institutional review board model and those using their individual site institutional review board model in a multicenter clinical trial. STUDY DESIGN: This was a retrospective study of sites in an open-label, multicenter randomized control trial from 2014 to 2021. Participating sites in the multicenter Chronic Hypertension and Pregnancy trial were asked to complete a survey collecting data describing their institutional review board approval process. RESULTS: A total of 45 sites participated in the survey (7 used a shared institutional review board model and 38 used their individual institutional review board model). Most sites (86%) using the shared institutional review board model did not require a full-board institutional review board meeting before protocol approval, compared with 1 site (3%) using the individual institutional review board model (P<.001). Median total approval times (41 vs 56 days; P=.42), numbers of submission rounds (1 vs 2; P=.09), and numbers of institutional review board stipulations (1 vs 4; P=.12) were lower for the group using the shared institutional review board model than those using the individual site institutional review board model; however, these differences were not statistically significant. CONCLUSION: The findings supported the hypothesis that the shared institutional review board model for multicenter studies may be more efficient in terms of cumulative time and effort required to obtain approval of an institutional review board protocol than the individual institutional review board model. Given that these data have important implications for multicenter clinical trials, future research should evaluate these findings using larger or multiple multicenter trials.

Circulating Angiogenic Factor Levels in Hypertensive Disorders of Pregnancy.

BACKGROUND: Among women with hypertensive disorders of pregnancy, biomarkers may stratify risk for developing preeclampsia with severe features (sPE). METHODS: Across 18 U.S. centers, we prospectively measured the ratio of serum soluble fms-like tyrosine kinase 1 (sFlt-1) to placental growth factor (PlGF) in pregnant women hospitalized between 23 and 35 weeks of gestation. The primary outcome was predicting sPE, and secondary outcomes included predicting adverse outcomes within 2 weeks. The prognostic performance of the sFlt-1:PlGF ratio was assessed by using a derivation/validation design. RESULTS: A total of 1014 pregnant women were evaluated; 299 were included in the derivation cohort and 715 in the validation cohort. In the derivation cohort, the median sFlt-1:PlGF ratio was 200 (interquartile range, 53 to 458) among women who developed sPE compared with 6 (interquartile range, 3 to 26) in those who did not (P<0.001). The discriminatory ratio of ≥40 was then tested in the validation cohort and yielded a 65% positive (95% confidence interval [CI], 59 to 71) and a 96% negative (95% CI, 93 to 98) predictive value for the primary outcome. The ratio performed better than standard clinical measures (area under the receiver-operating characteristic curve, 0.92 versus <0.75 for standard-of-care tests). Compared with women with a ratio <40, women with a ratio ≥40 were at higher risk for adverse maternal outcomes (16.1% versus 2.8%; relative risk, 5.8; 95% CI, 2.8 to 12.2). CONCLUSIONS: In women with a hypertensive disorder of pregnancy presenting between 23 and 35 weeks of gestation, measurement of serum sFlt-1:PlGF provided stratification of the risk of progressing to sPE within the coming fortnight. (Funded by Cedars-Sinai Medical Center and Thermo Fisher Scientific; ClinicalTrials.gov NCT03815110.)

Neonatal Outcomes After Delivery in Water.

OBJECTIVE: To assess neonatal intensive care unit (NICU) admissions and neonatal outcomes after water birth or land birth in an alternative birthing center. METHODS: We conducted a prospective observational study of preselected low-risk parturients separated into three groups depending on their location for labor and delivery: land-land, water-land, and water-water. Delivery outcomes, labor length, maternal pain assessment, need for newborn resuscitation, and NICU admission and diagnoses were collected. The primary outcome was admission to the NICU. RESULTS: There were 2,077 total deliveries from April 2015 to December 2019, consisting of 458 land-land deliveries, 730 water-land deliveries, and 889 water-water deliveries. The rate of NICU admission was 2.8% (95% CI 1.5-4.8%) for land-land deliveries, 4.1% (2.8-5.8%) for water-land deliveries, and 2.0% (1.2-3.2%) for water-water deliveries. A post hoc power analysis revealed a 70% power to detect a 2.1% difference in NICU admissions between the water-land and water-water groups. CONCLUSION: In this cohort of low-risk pregnant women, births in water and on land were associated with similar rates of admission to the NICU.

Wernicke's encephalopathy complicating pregnancy in a woman with neonatal necrotizing enterocolitis and resultant chronic malabsorption.

Wernicke's encephalopathy (WE) is a metabolic disturbance resulting from severe thiamine deficiency classically described in malnourished alcoholics. Untreated, it can result in stupor, coma, and death. WE has previously been reported as a complication of pregnancy in women with hyperemesis gravidarum. We report a case of WE complicating pregnancy in a woman with chronic malabsorption secondary to premature birth and subsequent necrotizing enterocolitis (NEC). Our patient progressed through classic stages of WE before lapsing into a coma. She made a complete recovery after aggressive intravenous thiamine and nutritional support. This is the first report of WE in pregnancy secondary to NEC-related chronic malabsorption. We report this case to bring attention to a potential pregnancy complication affecting women with malabsorptive conditions.

Naloxone and Metabolites Quantification in Cord Blood of Prenatally Exposed Newborns and Correlations with Maternal Concentrations.

Objective To quantify naloxone and metabolite concentrations in newborns prenatally exposed to sublingual buprenorphine/naloxone and to correlate neonatal and maternal metabolite concentrations. Methods This is a prospective observational cohort study. Eleven pregnant women treated for opioid use disorder with sublingual buprenorphine/naloxone were enrolled. Maternal and newborn blood was collected and analyzed for naloxone, buprenorphine, and metabolites via liquid chromatography tandem mass spectrometry. Descriptive statistics and correlation coefficients were utilized to analyze data. Results Maternal daily naloxone and buprenorphine doses were 1 to 5 mg and 4 to 20 mg, respectively; the mean (standard deviation) time from medication until delivery was 9.9 (4.3) hours. Naloxone was below the limits of quantification (LOQ) in five infants and six mothers with a range of less than LOQ to 0.3 µg/L. There was a strong positive correlation between maternal and newborn naloxone concentrations: Spearman's ρ = 0.89 (p < 0.01). There were strong positive correlations between maternal and neonatal assays for the buprenorphine analyte concentrations: buprenorphine ρ = 0.88 (p < 0.01), norbuprenorphine ρ = 0.71 (p = 0.01), and norbuprenorphine-glucuronide ρ = 0.98 (p < 0.01), but not for buprenorphine-glucuronide, ρ = 0.53 (p = 0.10). Conclusion Naloxone and buprenorphine are transferred to the fetus during prenatal exposure to maternal sublingual buprenorphine/naloxone. The quantity of naloxone transferred from maternal circulation is minimal and highly correlated with maternal concentrations.

Buprenorphine and naloxone compared with methadone treatment in pregnancy.

OBJECTIVE: To compare neonatal abstinence syndrome prevalence and characteristics among neonates born to women prescribed buprenorphine and naloxone compared with methadone during pregnancy. METHODS: Retrospective cohort analysis of mother-neonate dyads treated with either buprenorphine and naloxone or methadone during pregnancy. Primary neonatal outcomes included diagnosis of neonatal abstinence syndrome, neonatal abstinence syndrome peak scores, total amount of morphine used to treat neonatal abstinence syndrome (mg), and duration of treatment for neonatal abstinence syndrome (days). Secondary outcomes included head circumference, birth weight, length, preterm birth, neonatal intensive care unit admission, Apgar scores, and overall length of hospitalization. RESULTS: From January 1, 2011, to November 30, 2013, we identified 62 mother-neonate dyads, 31 treated with methadone and 31 treated with buprenorphine and naloxone. Sixteen neonates (51.6%) in the methadone group were diagnosed with neonatal abstinence syndrome compared with eight (25.1%) in the buprenorphine and naloxone group (adjusted odds ratio 2.55, 95% confidence interval [CI] 1.31-4.98, P = .01). The buprenorphine and naloxone-exposed neonates had lower peak neonatal abstinence syndrome scores (9.0 ± 4.4 compared with 10.7 ± 3.7, multivariate-adjusted mean difference = -2.77, 95% CI -4.99 to -0.56, P = .02) and shorter overall hospitalization (5.6 ± 5.0 compared with 9.8 ± 7.4 days, multivariate-adjusted mean difference = -3.90, 95% CI, -7.13 to -0.67, P = .02). We found no other differences in primary or secondary outcomes. CONCLUSION: In a cohort of pregnant patients treated with either methadone or buprenorphine and naloxone in pregnancy, newborns exposed to maternal buprenorphine and naloxone had less frequent neonatal abstinence syndrome. Additionally, neonates exposed to buprenorphine and naloxone had shorter overall hospitalization lengths.

Serial sonographic growth assessment in pregnancies complicated by an isolated single umbilical artery.

Pregnancies complicated by an isolated single umbilical artery (SUA) are thought to be at increased risk for intrauterine growth restriction (IUGR). The management of these pregnancies often includes serial sonographic assessments of fetal growth. The goal of our study was to test the validity of this assertion. We conducted a longitudinal sonographic assessment of intrauterine fetal growth in pregnancies complicated by a SUA. We included pregnancies where fetal growth was assessed three or more times, and the presence of SUA was repeatedly demonstrated. Pregnancies with fetal anomalies and multiple gestations were excluded. IUGR was defined as an estimated fetal weight (EFW) < or = 10th percentile of the normal ranges established by Hadlock. Between January 1999 and December 2005, we identified 273 pregnancies with SUA, for an overall incidence of 0.48% within the total population of patients examined at our institution. One hundred and thirty-five pregnancies did not meet our inclusion criteria. Of the 138 we analyzed, four pregnancies (2.9%) were found to have EFW < or = 10th percentile. We concluded that the occurrence of IUGR in pregnancies complicated by an isolated SUA is not increased. Serial sonographic assessments of fetal growth do not appear to be indicated in the management of such pregnancies.