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Item Antenatal Fetal Adrenal Measurements at 22 to 30 Weeks' Gestation, Fetal Growth Restriction, and Perinatal Morbidity(Thieme, 2021) Blue, Nathan R.; Hoffman, Matthew; Allshouse, Amanda A.; Grobman, William A.; Simhan, Hyagriv N.; Turan, Ozhan M.; Parry, Samuel; Chung, Judith H.; Reddy, Uma; Haas, David M.; Myers, Stephen; Mercer, Brian; Saade, George R.; Silver, Robert M.; Obstetrics and Gynecology, School of MedicineObjective: Our objective was to test the association of fetal adrenal size with perinatal morbidity among fetuses with fetal growth restriction (FGR; estimated fetal weight [EFW] < 10th percentile). Study design: This was a secondary analysis of the Nulliparous Pregnancy Outcomes Study: Monitoring Mothers-to-be (nuMoM2b) adrenal study, which measured fetal adrenal gland size at 22 to 30 weeks' gestation. We analyzed the transverse adrenal area (TAA) and fetal zone area (absolute measurements and corrected for fetal size) and the ratio of the fetal zone area to the total transverse area using a composite perinatal outcome of stillbirth, neonatal intensive care unit admission, respiratory distress syndrome, necrotizing enterocolitis, retinopathy of prematurity, sepsis, mechanical ventilation, seizure, or death. Among fetuses with FGR, adrenal measurements were compared between those that did and did not experience the composite perinatal outcome. Results: There were 1,709 eligible neonates. Seven percent (n = 120) were diagnosed with FGR at the time of adrenal measurement, and 14.7% (n = 251) experienced perinatal morbidity. EFW-corrected and absolute adrenal measurements were similar among fetuses with and without FGR as well as among those who did and did not experience morbidity. The area under the curve for corrected TAA was 0.52 (95% confidence interval 0.38-0.67). Conclusion: In our cohort, adrenal size was not associated with risk of morbidity among fetuses with FGR.Item Customized versus Population Growth Standards for Morbidity and Mortality Risk Stratification Using Ultrasonographic Fetal Growth Assessment at 22 to 29 Weeks' Gestation(Thieme, 2021) Blue, Nathan R.; Grobman, William A.; Larkin, Jacob C.; Scifres, Christina M.; Simhan, Hyagriv N.; Chung, Judith H.; Saade, George R.; Haas, David M.; Wapner, Ronald; Reddy, Uma M.; Mercer, Brian; Parry, Samuel I.; Silver, Robert M.; Obstetrics and Gynecology, School of MedicineObjective: The aim of study is to compare the performance of ultrasonographic customized and population fetal growth standards for prediction adverse perinatal outcomes. Study design: This was a secondary analysis of the Nulliparous Pregnancy Outcomes Study: Monitoring Mothers-to-Be, in which l data were collected at visits throughout pregnancy and after delivery. Percentiles were assigned to estimated fetal weights (EFWs) measured at 22 to 29 weeks using the Hadlock population standard and a customized standard (www.gestation.net). Areas under the curve were compared for the prediction of composite and severe composite perinatal morbidity using EFW percentile. Results: Among 8,701 eligible study participants, the population standard diagnosed more fetuses with fetal growth restriction (FGR) than the customized standard (5.5 vs. 3.5%, p < 0.001). Neither standard performed better than chance to predict composite perinatal morbidity. Although the customized performed better than the population standard to predict severe perinatal morbidity (areas under the curve: 0.56 vs. 0.54, p = 0.003), both were poor. Fetuses considered FGR by the population standard but normal by the customized standard had morbidity rates similar to fetuses considered normally grown by both standards.The population standard diagnosed FGR among black women and Hispanic women at nearly double the rate it did among white women (p < 0.001 for both comparisons), even though morbidity was not different across racial/ethnic groups. The customized standard diagnosed FGR at similar rates across groups. Using the population standard, 77% of FGR cases were diagnosed among female fetuses even though morbidity among females was lower (p < 0.001). The customized model diagnosed FGR at similar rates in male and female fetuses. Conclusion: At 22 to 29 weeks' gestation, EFW percentile alone poorly predicts perinatal morbidity whether using customized or population fetal growth standards. The population standard diagnoses FGR at increased rates in subgroups not at increased risk of morbidity and at lower rates in subgroups at increased risk of morbidity, whereas the customized standard does not.Item Developing a predictive model for perinatal morbidity among small for gestational age infants(Taylor & Francis, 2022) Blue, Nathan R.; Allhouse, Amanda A.; Grobman, William A.; Day, Robert C.; Haas, David M.; Simhan, Hyagriv N.; Parry, Samuel; Saade, George R.; Silver, Robert M.; Obstetrics and Gynecology, School of MedicineBackground: While neonates with birth weight <10th percentile are at increased risk of morbidity and mortality, most of these are constitutionally small and not at increased risk. There are no current strategies that reliably distinguish constitutionally small neonates from small neonates at the highest risk of morbidity, so additional tools for risk stratification are needed. Objective: Our objectives were to identify factors that are independently associated with perinatal morbidity among neonates with birth weight <10th percentile (small for gestational age, SGA) and to create predictive models of perinatal morbidity among SGA neonates based on the timing of information availability. Study design: This secondary analysis of the Nulliparous Pregnancy Outcomes Study: Monitoring Mothers-to-Be, was a nested case-control study. Participants were prospectively enrolled at eight U.S. centers, with data collection occurring at three standard time points during pregnancy and again after delivery. Our analysis included neonates with birth weights <10th percentile and excluded those with major congenital malformations or suspected or confirmed aneuploidy. The primary outcome was a composite of perinatal morbidity, defined as NICU admission >48 h, NEC, sepsis, RDS, mechanical ventilation, retinopathy of prematurity, seizures, grade 3 or 4 IVH, stillbirth, or death before discharge. Cases were SGA neonates that experienced the primary outcome, and controls were SGA neonates that did not. Maternal factors for potential inclusion in predictive modeling were drawn from a broad list of variables collected as part of the NuMoM2B study, including demographic, anthropometric, clinical, ultrasound, social/behavioral, dietary, and psychological variables. Characteristics that were different in bivariate analysis between cases and controls then underwent further evaluation and refinement. Continuous and multi-category variables were assessed using multiple approaches, including as continuous variables, using standard categories (such as for BMI) as well as empirically-derived cut-points identified by receiver-operating characteristics methodology. The approach for each variable that resulted in the best performance was selected for use in modeling. After variable optimization, multivariable analysis was used to derive prediction models using factors known at mid-pregnancy (Model 1) and delivery (Model 2). Results: Of the original cohort, 865 were eligible and analyzed, with 134 (15.5%) experiencing the primary outcome. After bivariable and multivariable analysis, these variables were included in Model 1: BMI, stress level, diastolic blood pressure, narcotic use (all in 1st trimester), and uterine artery pulsatility index at 16-21 weeks. Model 2 added the following variables to Model 1: preterm delivery, preeclampsia, and suspected fetal growth restriction. When models 1 and 2 were empirically tested and compared to predicted performance to demonstrate calibration, observed morbidity rates approximately followed expected rates within deciles. Models 1 and 2 had respective areas under the receiver-operating characteristic curve of 0.72 (95% CI 0.67-0.76) and 0.84 (0.80-0.88), to predict the composite morbidity. Conclusion: Using a deeply phenotyped cohort of nulliparous women, we created two models with the moderate-good prediction of perinatal morbidity among SGA neonates.Item Glyphosate exposure in early pregnancy and reduced fetal growth: a prospective observational study of high-risk pregnancies(BMC, 2022-10-11) Gerona, Roy R.; Reiter, Jill L.; Zakharevich, Igor; Proctor, Cathy; Ying, Jun; Mesnage, Robin; Antoniou, Michael; Winchester, Paul D.; Medical and Molecular Genetics, School of MedicineBackground: Prenatal glyphosate (GLY) exposure is associated with adverse reproductive outcomes in animal studies. Little is known about the effects of GLY exposure during pregnancy in the human population. This study aims to establish baseline urine GLY levels in a high-risk and racially diverse pregnancy cohort and to assess the relationship between prenatal GLY exposure and fetal development and birth outcomes. Methods: Random first trimester urine specimens were collected from high risk pregnant women between 2013 and 2016 as part of the Indiana Pregnancy Environmental Exposures Study (PEES). Demographic and clinical data were abstracted from mother and infant medical records. Urine glyphosate levels were measured as a proxy for GLY exposure and quantified using liquid chromatography-tandem mass spectrometry. Primary outcome variables included gestation-adjusted birth weight percentile (BWT%ile) and neonatal intensive care unit (NICU) admission. Relationships between primary outcome variables and GLY exposure were assessed using univariate and multivariate linear and logistic regression models. Results: Urine GLY levels above the limit of detection (0.1 ng/mL) were found in 186 of 187 (99%) pregnant women. Further analyses were limited to 155 pregnant women with singleton live births. The mean age of participants was 29 years, and the majority were non-Hispanic white (70%) or non-Hispanic Black (21%). The mean (± SD) urine GLY level was 3.33 ± 1.67 ng/mL. Newborn BWT%iles were negatively related to GLY (adjusted slope ± SE = -0.032 + 0.014, p = 0.023). Infants born to women living outside of Indiana's large central metropolitan area were more likely to have a lower BWT%ile associated with mother's first trimester GLY levels (slope ± SE = -0.064 ± 0.024, p = 0.007). The adjusted odds ratio for NICU admission and maternal GLY levels was 1.16 (95% CI: 0.90, 1.67, p = 0.233). Conclusion: GLY was found in 99% of pregnant women in this Midwestern cohort. Higher maternal GLY levels in the first trimester were associated with lower BWT%iles and higher NICU admission risk. The results warrant further investigation on the effects of GLY exposure in human pregnancies in larger population studies.Item The value of introducing cerebroplacental ratio (CPR) versus umbilical artery (UA) Doppler alone for the prediction of neonatal small for gestational age (SGA) and short-term adverse outcomes(Taylor & Francis, 2021) Leavitt, Karla; Odibo, Linda; Nwabuobi, Chinedu; Tuuli, Methodius G.; Odibo, Anthony; Obstetrics and Gynecology, School of MedicineObjective: To compare the role of umbilical artery (UA) Doppler versus CPR in the prediction of neonatal SGA and short-term adverse neonatal outcome in a high-risk population. Study design: We conducted a prospective study on women referred for fetal growth ultrasounds between 26 and 36 weeks of gestation and with an EFW <20th percentile by Hadlock standard. UA and middle cerebral artery (MCA) Doppler assessments were performed. Abnormal UA Doppler was defined as: pulsatility index (PI) above the 95th percentile and absent or reverse end-diastolic flow. The CPR, calculated as a ratio of the MCA PI by the UA PI, was defined as low if <1.08. The primary outcome was the sensitivity and specificity of the two Doppler assessments to predict neonatal SGA, defined as birthweight <10th percentile by using Alexander curves. The secondary outcomes included umbilical cord arterial pH <7.10, Apgars at 5 minutes <7, NICU admission, respiratory distress syndrome (RDS), hypoglycemia or a composite including any of these secondary outcomes. Chi-square was performed for statistical analysis. Results: Of the 199 women meeting inclusion criteria, 94 (47.2%) had SGA and 68 (34.2%) had a composite adverse outcome. A total of seven pregnancies with FGR had a low CPR. Abnormal UA Doppler showed a better sensitivity for predicting SGA and adverse neonatal outcomes with comparable specificity to low CPR. The area under the ROC curve (AUC) using abnormal UA Doppler for predicting SGA was 0.54, 95% CI 0.50-0.58; and 0.51, 95% CI 0.48-0.53 for low CPR. The AUC for predicting a composite adverse neonatal outcome are: 0.60, 95% CI 0.51-0.68 for abnormal UA Doppler; and 0.54, 95% CI 0.47-0.84 for low CPR. Conclusion: The CPR did not improve our ability to predict neonatal SGA or other short-term adverse outcomes.