Faculty Bibliography

OBJECTIVE:Evaluate rates of vaccination against infectious diseases (Tdap and influenza) in pregnancy during the COVID-19 pandemic compared to contemporary historical controls. STUDY DESIGN/METHODS:This was a retrospective cohort study comparing rates of Tdap and influenza vaccination in pregnant people who received care at NYU Langone Health and delivered from 9/1/2020 to 1/1/2021 ("COVID cohort") to the same period the prior year ("2019 cohort"). Demographic information, trimester of initiation of prenatal care, insurance status, and medical comorbidities were evaluated. Outcomes were analyzed using Chi- squared, Fisher's exact test, and multivariable logistic regression, with significance of p<0.05. RESULTS:1713 pregnant people were included. Compared to historical controls, the COVID cohort differed in age, race, timing of initiation of prenatal care, insurance status, and medical comorbidities. After adjusting for these covariates, pregnant people were significantly more likely to accept influenza vaccine in the COVID cohort (aOR 1.7, 95% CI 1.27-2.29) and had similar Tdap acceptance (aOR 1.5, 95% CI 0.99 - 2.17). However, this trend was not observed for the entire obstetric population; public insurance status and medical comorbidities were associated with lower vaccine rates during the pandemic. For those who had public insurance, rates of influenza vaccination decreased from 83% in 2019 to 40% during COVID (aOR 0.16, 95% CI 0.10 - 0.24) and for Tdap rates decreased from 93% to 54% (aOR 0.13, 95% CI 0.08 - 0.21). CONCLUSION/CONCLUSIONS:During the COVID-19 pandemic era, pregnant people at large were more likely to accept the influenza vaccine. However, this trend did not apply to Tdap, and did not apply to high-risk groups with public insurance and medical comorbidities. This study highlights potential disparities in vaccination rates, which need to be accounted for when evaluating national vaccine trends. These data support increased efforts in vaccine counseling for high-risk populations.

BACKGROUND:Analysis of cell-free DNA from maternal blood provides effective screening for trisomy 21 in singleton pregnancies. Data on cell-free DNA screening in twin gestations are promising although limited. In previous twin studies, cell-free DNA screening was primarily performed in the second trimester and many studies did not report chorionicity. OBJECTIVE:This study aimed to evaluate the screening performance of cell-free DNA for trisomy 21 in twin pregnancies in a large, diverse cohort. A secondary aim was to evaluate screening performance for trisomy 18 and trisomy 13. STUDY DESIGN/METHODS:This was a retrospective cohort study of twin pregnancies from 17 centers for which cell-free DNA screening was performed from December 2011 to February 2020 by one laboratory using massively parallel sequencing technology. Medical record review was conducted for all newborns and data on the birth outcome, the presence of any congenital abnormalities, phenotypic appearance at birth, and any chromosomal testing that was undertaken in the antenatal or postnatal period were extracted. Cases with a possible fetal chromosomal abnormality with no genetic test results were reviewed by a committee of maternal-fetal medicine geneticists. Cases with a vanishing twin and inadequate follow-up information were excluded. A minimum of 35 confirmed cases of trisomy 21 was required to capture a sensitivity of at least 90% with a prevalence of at least 1.9% with 80% power. Test characteristics were calculated for each outcome. RESULTS:A total of 1764 samples were sent for twin cell-free DNA screening. Of those, 78 cases with a vanishing twin and 239 cases with inadequate follow-up were excluded, leaving a total of 1447 cases for inclusion in the analysis. The median maternal age was 35 years and the median gestational age at cell-free DNA testing was 12.3 weeks. In total, 81% of the twins were dichorionic. The median fetal fraction was 12.4%. Trisomy 21 was detected in 41 of 42 pregnancies, yielding a detection rate of 97.6% (95% confidence interval, 83.8-99.7). There was 1 false negative and no false positive cases. Trisomy 21 was detected in 38 out of 39 dichorionic twin pregnancies, yielding a detection rate of 97.4% (95% confidence interval, 82.6-99.7). Trisomy 18 was detected in 10 of the 10 affected pregnancies. There was 1 false positive case. Trisomy 13 was detected in 4 of the 5 cases, yielding a detection rate of 80% (95% confidence interval, 11.1-99.2). There was one false negative and no false positive cases. The nonreportable rate was low at 3.9 %. CONCLUSION/CONCLUSIONS:Cell-free DNA testing is effective in screening for trisomy 21 in twin gestations from the first trimester of pregnancy. Detection of trisomy 21 was high in dichorionic and monochorionic twins, and the nonreportable result rates were low. This study included high numbers of cases of trisomy 18 and 13 when compared with the current literature. Although screening for these conditions in twins seems to be promising, the numbers were too small to make definitive conclusions regarding the screening efficacy for these conditions. It is possible that cell-free DNA testing performance may differ among laboratories and vary with screening methodologies.

BACKGROUND:The clinical implications of nonreportable cell-free DNA screening results are uncertain, but such results may indicate poor placental implantation in some cases and be associated with adverse obstetrical and perinatal outcomes. OBJECTIVE:This study aimed to assess the outcomes of pregnancies with nonreportable cell-free DNA screening in a cohort of patients with complete genetic and obstetrical outcomes. STUDY DESIGN/METHODS:This was a prespecified secondary analysis of a multicenter prospective observational study of prenatal cell-free DNA screening for fetal aneuploidy and 22q11.2 deletion syndrome. Participants who underwent cell-free DNA screening from April 2015 through January 2019 were offered participation. Obstetrical outcomes and neonatal genetic testing results were collected from 21 primary-care and referral centers in the United States, Europe, and Australia. The primary outcome was risk for adverse obstetrical and perinatal outcomes (aneuploidy, preterm birth at <28, <34, and <37 weeks' gestation, preeclampsia, small for gestational age or birthweight <10th percentile for gestational week, and a composite outcome that included preterm birth at <37 weeks, preeclampsia, small for gestational age, and stillbirth at >20 weeks) after nonreportable cell-free DNA screening because of low fetal fraction or other causes. Multivariable analyses were performed, adjusting for variables known to be associated with obstetrical and perinatal outcomes, nonreportable results, or fetal fraction. RESULTS:In total, 25,199 pregnant individuals were screened, and 20,194 were enrolled. Genetic confirmation was missing in 1165 (5.8%), 1085 (5.4%) were lost to follow-up, and 93 (0.5%) withdrew; the final study cohort included 17,851 (88.4%) participants who had cell-free DNA, fetal or newborn genetic confirmatory testing, and obstetrical and perinatal outcomes collected. Results were nonreportable in 602 (3.4%) participants. A sample was redrawn and testing attempted again in 427; in 112 (26.2%) participants, results were again nonreportable. Nonreportable results were associated with higher body mass index, chronic hypertension, later gestational age, lower fetal fraction, and Black race. Trisomy 13, 18, or 21 was confirmed in 1.6% with nonreportable tests vs 0.7% with reported results (P=.013). Rates of preterm birth at <28, 34, and 37 weeks, preeclampsia, and the composite outcome were higher among participants with nonreportable results, and further increased among those with a second nonreportable test, whereas the rate of small for gestational age infants was not increased. After adjustment for confounders, the adjusted odds ratios were 2.2 (95% confidence interval, 1.1-4.4) and 2.6 (95% confidence interval, 0.6-10.8) for aneuploidy, and 1.5 (95% confidence interval, 1.2-1.8) and 2.1 (95% confidence interval, 1.4-3.2) for the composite outcome after a first and second nonreportable test, respectively. Of the patients with nonreportable tests, 94.9% had a live birth, as opposed to 98.8% of those with reported test results (adjusted odds ratio for livebirth, 0.20 [95% confidence interval, 0.13-0.30]). CONCLUSION/CONCLUSIONS:Patients with nonreportable cell-free DNA results are at increased risk for a number of adverse outcomes, including aneuploidy, preeclampsia, and preterm birth. They should be offered diagnostic genetic testing, and clinicians should be aware of the increased risk of pregnancy complications.

PURPOSE/OBJECTIVE:To assess the performance of cell-free DNA (cfDNA) screening to detect sex chromosome aneuploidies (SCA) in an unselected obstetrical population with genetic confirmation. METHODS:This was a planned secondary analysis of the multicenter, prospective SMART study. Patients receiving cfDNA results for autosomal aneuploidies and who had confirmatory genetic results for the relevant sex chromosomal aneuploidies were included. Screening performance for SCAs, including monosomy X (MX) and the sex chromosome trisomies (SCTs; 47,XXX; 47,XXY; 47,XYY) was determined. Fetal sex concordance between cfDNA and genetic screening was also evaluated in euploid pregnancies. RESULTS:17,538 cases met inclusion criteria. Performance of cfDNA for MX, SCTs and fetal sex was determined in 17,297, 10,333 and 14,486 pregnancies, respectively. Sensitivity, specificity, and PPV of cfDNA were 83.3%, 99.9%, and 22.7% for MX, and 70.4%, 99.9%, and 82.6% for the combined SCTs. The accuracy of fetal sex prediction by cfDNA was 100%. CONCLUSION/CONCLUSIONS:Screening performance of cfDNA for SCAs is comparable to that reported in other studies. The PPV for the SCTs was similar to the autosomal trisomies, while the PPV for MX was substantially lower. No discordance in fetal sex was observed between cfDNA and postnatal genetic screening in euploid pregnancies. These data will assist interpretation and counseling for cfDNA results for sex chromosomes.

Background: Crown-rump length discordance, defined as ≥10% discordance, has been investigated as an early sonographic marker of subsequent growth abnormalities and is associated with an increased risk of fetal loss in twin pregnancies. Previous studies have not investigated the prevalence of fetal aneuploidy or structural anomalies in twins with discordance or the independent association of crown-rump length discordance with adverse perinatal outcomes. Moreover, data are limited on cell-free DNA screening for aneuploidy in dichorionic twins with discordance. Objective: This study aimed to evaluate whether crown-rump length discordance in dichorionic twins between 11 and 14 weeks of gestation is associated with a higher risk of aneuploidy, structural anomalies, or adverse perinatal outcomes and to assess the performance of cell-free DNA screening in dichorionic twin pregnancies with crown-rump length discordance. Study Design: This was a secondary analysis of a multicenter retrospective cohort study that evaluated the performance of cell-free DNA screening for the common trisomies in twin pregnancies from December 2011 to February 2020. For this secondary analysis, we included live dichorionic pregnancies with crown-rump length measurements between 11 and 14 weeks of gestation. First, we compared twin pregnancies with discordant crown-rump lengths with twin pregnancies with concordant crown-rump lengths and analyzed the prevalence of aneuploidy and fetal structural anomalies in either twin. Second, we compared the prevalence of a composite adverse perinatal outcome, which included preterm birth at <34 weeks of gestation, hypertensive disorders of pregnancy, stillbirth or miscarriage, small-for-gestational-age birthweight, and birthweight discordance. Moreover, we assessed the performance of cell-free DNA screening in pregnancies with and without crown-rump length discordance. Outcomes were compared with multivariable regression to adjust for confounders. Results: Of 987 dichorionic twins, 142 (14%) had crown-rump length discordance. The prevalence of aneuploidy was higher in twins with crown-rump length discordance than in twins with concordance (9.9% vs 3.9%, respectively; adjusted relative risk, 2.7; 95% confidence interval, 1.4"“4.9). Similarly, structural anomalies (adjusted relative risk, 2.5; 95% confidence interval, 1.4"“4.4]) and composite adverse perinatal outcomes (adjusted relative risk, 1.2; 95% confidence interval, 1.04"“1.3) were significantly higher in twins with discordance. A stratified analysis demonstrated that even without other ultrasound markers, there were increased risks of aneuploidy (adjusted relative risk, 3.5; 95% confidence interval, 1.5"“8.4) and structural anomalies (adjusted relative risk, 2.7; 95% confidence interval, 1.5"“4.8) in twins with CRL discordance. Cell-free DNA screening had high negative predictive values for trisomy 21, trisomy 18, and trisomy 13, regardless of crown-rump length discordance, with 1 false-negative for trisomy 21 in a twin pregnancy with discordance. Conclusion: Crown-rump length discordance in dichorionic twins is associated with an increased risk of aneuploidy, structural anomalies, and adverse perinatal outcomes, even without other sonographic abnormalities. Cell-free DNA screening demonstrated high sensitivity and negative predictive values irrespective of crown-rump length discordance; however, 1 false-negative result illustrated that there is a role for diagnostic testing. These data may prove useful in identifying twin pregnancies that may benefit from increased screening and surveillance and are not ascertained by other early sonographic markers.

Objective: To determine whether a machine learning model can predict patients at risk for shoulder dystocia (SD) better than estimations of birthweight (BW) alone.
Study Design: This was a retrospective analysis of 17,731 pregnant individuals from 7/2013 to 10/2018. Utilizing a machine learning model, a total of 122 binary and continuous variables were included. Baseline models were built with different sets of variables during 3 time periods: 57 in antepartum period, 96 in stage 1 and 119 in stage 2 of labor. BW was used as a proxy for estimated fetal weight (EFW) because documented assessment of EFW was not available in all cases. Two decision tree-based models, Random Forest and XGBoost, were used as predictive models and performance was evaluated with 5-fold cross validation. Area under the receiver operating characteristic curve (AUROC) and area under precision/recall curve (AUPR) were used as metrics for evaluating model performance. Mean and standard error of performance metrics were calculated.
Result(s): The cohort included 21,232 vaginal deliveries. There were 415 (1.95%) vaginal deliveries complicated by SD that occurred in 406 patients. An AUROC of 0.73 +/- 0.01 (mean +/- standard error) was achieved for RandomForest model and 0.78 +/- 0.01 for XGBoost model for BW. BW was then added as a variable to variable sets from the antepartum period and each labor stage to assess performance change. The RandomForest model predicted patients at risk for SD better than BW alone, but only the AUROC was statistically significant at all stages (p < 0.05). (Figure 1) This finding was not demonstrated in the XGBoost model.
Conclusion(s): Our machine learning model performed better in predicting SD than EFW alone (using BW as a proxy) at each time period evaluated - the antepartum period, 1st stage and 2nd stage of labor. While our results indicate that our model may enhance the prediction of SD, these findings should be validated using a more robust data set that includes documented EFW to account for the margin of error between BW and EFW. [Formula presented] [Formula presented]
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Objective: Iron deficiency is the most common cause of anemia in pregnancy, which is associated with maternal and neonatal complications. The objective of this study was to identify the frequency and risk factors for isolated iron deficiency (iID) in the 1^st trimester.
Study Design: This was a secondary analysis of a prospective cohort study to identify risk factors for iID of non-anemic pregnant individuals presenting for prenatal care in the 1^st trimester from February 2022 to June 2022 at NYU Langone Health. iID was defined as serum ferritin level of <= 29 ng/mL. Inclusion criteria included pregnant individuals ages 18-60 years with a singleton gestation enrolled in the 1^st trimester (prior to 14 weeks 0 days gestation) and were non-anemic (hemoglobin >=11.0 g/dl). Patients were excluded if they had 1^st trimester anemia or history of blood transfusion 3 months prior to pregnancy. Univariate analyses were followed by multiple logistic regression (OR [95% CI]) with statistical significance defined at p< 0.05.
Result(s): Of 600 patients enrolled in the study, 89 (14.8%) had 1^st trimester iID. Black/African American patients (19.1% vs. 8.2%, p=0.003), those with uterine fibroids (20.2% vs. 9.4%, p=0.003), and those with higher median BMI (25.2 kg/m² (IQR 22.7-29.6) vs. 23.6 kg/m² (IQR 21.4-27.3), p=0.01) were more likely have to 1^st trimester iID. White patients (41.6% vs. 56.6%, p=0.01) and those with a normal BMI (44.9% vs. 57.3%, p=0.04) were less likely to have 1^st trimester iID. After adjusting for confounders in regression models, Black/African American patients had the strongest association with 1^st trimester iID (aOR 2.18 [1.12-4.11], p=0.02), followed by uterine fibroids (aOR 2.02 [1.05-3.72], p=0.03). Overweight or obese BMIs were not identified as risk factors for 1^st trimester iID.
Conclusion(s): Based on our findings, Black/African American pregnant individuals and those with uterine fibroids are at highest risk for 1^st trimester iID. Future studies should investigate perinatal outcomes for pregnant individuals with 1^st trimester iID. [Formula presented]
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Objective: Reticulocyte hemoglobin (RetHb) is used for early detection of iron deficiency (ID) in the nonpregnant patient population. It provides an indication of iron availability in the bone marrow and is an early marker of iron deficiency (ID) erythropoiesis before anemia is present. Due to the paucity of data regarding RetHb use in pregnancy, the study objective was to establish normal values and trend for RetHb during the 1^st and 2^nd trimester of pregnancy by correlating it with ferritin and Hb.
Study Design: This is a secondary analysis of an observational, prospective cohort study evaluating ID parameters in singleton gestations presenting for prenatal care in the first trimester from 2/2022 to 6/2022. ID was defined as serum ferritin level of <= 29 ng/mL. For this analysis, patients were excluded if they had 1^st trimester anemia (Hb< 11.0 g/dL) or history of blood transfusion 3 months prior to pregnancy. Data were analyzed using student's t-test and linear regression modeling with statistical significance defined at p< 0.05.
Result(s): 209 patients met inclusion criteria. In table 1, demographics of the study cohort are shown. There was a prevalence of 16.3% of ID in the 1^st trimester and 69.9% in the 2^nd trimester. Distribution of RetHb values throughout the first 2 trimesters are demonstrated in figure 1. In the 1^st trimester, the mean RetHb in women with ID was 34.01 pg +/- SD 1.64 compared to 34.68 pg +/- 1.65 in women without iron deficiency (p=0.03). In the second trimester, the mean RetHb in women with ID was 33.02 pg +/- 2.34 compared to 34.20 pg +/- SD 1.94 in women without ID (p< 0.001).
Conclusion(s): A statistically significant physiologic decrease was observed among pregnant individuals both with and without iron deficiency in the first and second trimester of pregnancy. Future studies should evaluate the utility of RetHb use in pregnancy to predict ID and iron deficiency anemia throughout pregnancy. [Formula presented] [Formula presented]
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Objective: To compare pregnancy latency achieved with oral labetalol versus extended-release nifedipine during expectant management of preterm preeclampsia with severe features (PEC-SF).
Study Design: This is a retrospective cohort study of patients initiated on antihypertensive therapy with oral labetalol or extended-release nifedipine during admission for expectant management of PEC-SF < 34 weeks between 1/2013 and 4/2022. Those on antihypertensive therapy prior to admission or with another indication for delivery < 34 weeks were excluded (monochorionic-monoamniotic twins, higher order multiples, absent or reversed umbilical artery Dopplers). Pregnancy latency (from oral agent initiation to delivery decision) was compared between groups. Secondary outcomes included need for initial agent dose uptitration, addition of second oral agent, acute antihypertensive therapy, and delivery for refractory hypertension. Linear and modified Poisson regression models were used to estimate adjusted mean differences (AMD) with 95% confidence intervals.
Result(s): The cohort included 78 patients (Table 1). Comparing those initiated on labetalol versus extended-release nifedipine (Table 2), there was no difference in latency (6.2 (7.5) vs 5.4 (7.4) days, AMD 1.1 days, 95% CI [-2.1, 4.4]), nor in the proportion of patients achieving 1 week latency (25.0% vs 23.8%, respectively, AMD 2.9%, 95% CI [-16.5, 22.3]). Those initiated on labetalol were less likely to require a second agent (16.7% vs 38.1% for nifedipine, AMD -18.4, 95% CI [-37.3, 0.5]). There were no differences in need for initial agent uptitration, acute antihypertensive therapy, or delivery for refractory hypertension.
Conclusion(s): There was no difference in pregnancy latency among patients with PEC-SF initiated on oral labetalol versus extended-release nifedipine. Patients on labetalol may be less likely to require a second antihypertensive agent, but comparative outcome estimates may be limited by small cohort size. Further investigations with a larger cohort should be performed to evaluate for any relative advantages of the two oral agents. [Formula presented] [Formula presented]
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