Clinical implications of crown-rump length discordance at 11 to 14 weeks in dichorionic twins.

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.

Cell-free DNA screening for trisomy 21 in twin pregnancy: a large multicenter cohort study.

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: 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: 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.

The Hassan Neonatal Morbidity Composite Scale and Neonatal Length of Stay-A Validation Study.

OBJECTIVE: Obstetric studies often report neonatal morbidity as a composite score. Composite scores can simplify data analysis when multiple outcomes of interest are present and allows researchers to conduct smaller, more manageable trials. The Hassan scale is a neonatal morbidity composite scale that assigns high scores to infants with multiple morbidities and low scores to infants without or with single morbidities. The objective of this study was to validate the association between scores on the Hassan scale and neonatal intensive care unit (NICU) length of stay STUDY DESIGN: We conducted a cohort study of all infants born between 22 and 366/7 weeks' gestation and cared for within 419 neonatal units in the Pediatrix Medical Group between 1997 and 2018. Each infant was assigned a Hassan's score based on the number of neonatal morbidity events that occurred during the delivery hospitalization. The association between Hassan's scores and neonatal length of stay was evaluated using linear regression. Multivariable models were constructed to determine if the Hassan score was independently associated with neonatal length of stay. RESULTS: There were 760,037 infants included. The median (interquartile range [IQR]) gestational age of delivery was 34 (31, 35) weeks and the median (IQR) birth weight at delivery was 2,000 (1,503, 2,430) g. The median length of stay for infants discharged home was 17 (10-33) days. A Hassan's score was able to be assigned to 699,206 (92%) patients. Neonatal morbidities included in the Hassan scale were more common among infants born earlier in gestation. On adjusted analysis, the Hassan scale was found to be independently associated with neonatal length of stay (p < 0.001, coefficient = 10.4 days [95% confidence interval (CI): 10.3, 10.4 days]) with higher scores associated with longer lengths of stay. CONCLUSION: The Hassan scale, more than a binary composite score, is able to differentiate preterm infants with prolonged hospitalizations from those with short hospitalizations. KEY POINTS: · The Hassan scale is an independent predictor of neonatal length of stay.. · Classification of infants based on number of morbidities correlates with neonatal length of stay.. · The Hassan scale provided better discrimination than binary composite morbidity scores.. · The Hassan scale may be an economic predictor of health-related costs..

The Effect of Blood Loss on Cefazolin Levels in Women Undergoing Cesarean Delivery.

OBJECTIVE: To quantify the effects of operative blood loss during cesarean on tissue and plasma cefazolin concentrations. STUDY DESIGN: This was a prospective observational study of singleton pregnancies undergoing scheduled cesarean between 34 and 40 weeks. Cefazolin administered prior to skin incision. Maternal plasma samples were obtained (Time 1[T1]: immediately, T2: 20 minutes, T3: 40 minutes, and T4: 60 minutes after cefazolin infusion). Subcutaneous adipose tissue sampled before and after fascia. Primary outcome was subcutaneous adipose cefazolin level after fascial closure. Formal quantitative blood loss (QBL) performed. Women with higher QBL, those at/above 75% of QBL in this population, were compared with those with lower QBL (QBL below 75%). Data analyzed using bivariable statistics. RESULTS: Ninety-two women were screened, 32 were eligible, and 20 enrolled. Median QBL was 630 mL (interquartile range [IQR]: 473-818) and 1,160 mL (IQR: 1,000-1,560) in the low and high QBL groups, respectively. Demographics and operative characteristics were similar. Median adipose cefazolin level after fascial closure did not differ between the groups (3.5 vs. 3.9 µg/g, p = 0.75). No differences in maternal plasma cefazolin concentrations between the groups at any time point or in pharmacokinetic parameters were seen. CONCLUSION: Intraoperative maternal plasma concentrations and adipose levels of cefazolin are similar between women with high and low blood loss at the time of cesarean delivery.

Uterocervical Angle Measurement Improves Prediction of Preterm Birth in Twin Gestation.

OBJECTIVE: Twin pregnancies are associated with an increased risk of spontaneous preterm birth. Our objective was to compare the performance of uterocervical angle to cervical length as predictors of spontaneous preterm birth in this population. METHODS: We conducted a retrospective cohort study of twin gestations at a single center from May 2008 to 2016 who received a transvaginal ultrasound for the evaluation of the cervix between 16 0/7 and 23 0/7 weeks. The primary outcome was prediction of preterm birth <28 and <32 weeks by uterocervical angle and cervical length. RESULTS: Among 259 women with twin gestation, the mean gestational age at birth was 34.83 ± 3.48 weeks. Receiver operator characteristic curves demonstrated optimal prediction of spontaneous preterm birth prior to 32 weeks at a uterocervical angle >110° (80% sensitivity, 82% specificity) [odds ratio (OR), 15.7 (95% confidence interval (CI), 7.2-34.4)] versus cervical length <20 mm (53% sensitivity, 85% specificity; p < 0.001, OR, 6.4 [95% CI, 2.3-17.8]) and similarly, prior to 28 weeks at a uterocervical angle >114° (OR, 24.3 [95% CI, 6.7-88.5]) compared with cervical length <20 mm (OR, 11.4 [95% CI, 3.5-36.7]). CONCLUSION: Uterocervical angles >110° performed better than cervical length for the prediction of spontaneous preterm birth in twin gestations.

Transplacental Passage of Acetaminophen in Term Pregnancy.

Objective The objective of this study was to determine the maternal and fetal pharmacokinetic (PK) profiles of acetaminophen after administration of a therapeutic oral dose. Study Design After obtaining Institutional Review Board approval and their written informed consent, pregnant women were given a single oral dose (1,000 mg) of acetaminophen upon admission for scheduled cesarean delivery. Maternal venous blood and fetal cord blood were obtained at the time of delivery and acetaminophen levels were measured using gas chromatography-mass spectroscopy. PK parameters were calculated by noncompartmental analysis. Nonparametric correlation of maternal/fetal acetaminophen levels and PK curves were calculated. Results In this study, 34 subjects were enrolled (median, 32 years; range, 25-39 years). The median maternal weight was 82 kg (range, 62-100 kg). All but two subjects were delivered beyond 39 weeks' gestation. The median newborn birth weight was 3,590 g (interquartile range, 3,403-3,848 g). Noncompartmental analysis described similar PK parameters in the maternal (T1/2, 84 minutes; apparent clearance [Cl/F], 28.8 L/h; apparent volume of distribution [Vd/F], 57.5 L) and fetal compartments (T1/2, 82 minutes; Cl/F, 31.2 L/h; Vd/F, 61.2 L). Paired maternal/fetal acetaminophen levels were highly correlated (p < 0.0001). Conclusion Fetal acetaminophen PKs in the fetus parallels that in the mother suggesting that placental transfer is flow limited. Maternal acetaminophen levels can be used as a surrogate for fetal exposure.

Characterization of Maternal and Fetal CYP3A-Mediated Progesterone Metabolism.

INTRODUCTION: Progesterone is critical for maintaining pregnancy and onset of labor. We evaluated CYP450-mediated progesterone meta-bolism, specifically the contribution of CYP3A isoforms. MATERIALS AND METHODS: In vitro progesterone metabolism was characterized in human liver microsomes (HLMs) with and without selective cytochrome P450 inhibitors and in recombinant CYP3A4, CYP3A5, and CYP3A7. 6ß-hydroxyprogesterone (6ß-OHP) and 16α-hydroxyprogesterone (16α-OHP) metabolites were quantified by HPLC/UV and fit to the Michaelis-Menten equation to determine Km and Vmax. The effect of CYP3A5 expression on progesterone clearance was determined by in vitro in vivo extrapolation. RESULTS: Ketoconazole inhibited formation of both 6ß-OHP and 16α-OHP more than 95%. 6ß-OHP and 16α-OHP were both produced by CYP3A4 (2.3 and 1.3 µL/min/pmol, respectively) to a greater extent than by CYP3A5 (0.09 and 0.003 µL/min/pmol) and CYP3A7 (0.004 and 0.003 µL/min/pmol). CONCLUSIONS: Maternal clearance of progesterone by hepatic CYP450's is driven primarily by CYP3A4, with limited contributions from CYP3A5 and CYP3A7.

The Impact of Gestational Age at Delivery on Urologic Outcomes for the Fetus with Hydronephrosis.

OBJECTIVE: Compare short-term urologic outcomes with delivery timing in fetuses with severe hydronephrosis. METHODS: An ultrasound database was queried for severe hydronephrosis. Cases were categorized into late preterm/early term (36 0/7 - 38 6/7 weeks) and full term (39 0/7 weeks or greater) groups. Baseline characteristics were compared using standard statistical methods. Spearman's correlation analysis was performed for grade and severity of hydronephrosis on first postnatal ultrasound with gestational age at delivery. RESULTS: Of 589 cases, 79 (33 late preterm/early term, 46 full term) met criteria. Baseline characteristics were similar between groups. Spearman's correlation coefficients (rs) indicated that increased postnatal Society for Fetal Urology grade, rs= -0.26 (95% CI [-.48, -.002]), and severity of hydronephrosis, rs= -0.39 (95% CI [-.59, -.14]), both correlated with earlier delivery. CONCLUSION: Late preterm/early term delivery resulted in worse short-term postnatal renal outcomes. Unless otherwise indicated, delivery for fetal hydronephrosis should be deferred until 39 weeks.

Pseudomonoamniotic Pregnancy: Case Report and Review of Etiologic Considerations.

Pseudomonoamniotic gestations are increasingly recognized through sonographic surveillance of monochorionic twins, though etiologic factors remain undefined. We present a case of spontaneous pseudomonoamniotic twins and propose umbilical cord insertion proximity as a sonographic marker. Systematic review of the literature was performed and additional cases with similar findings were noted. Approximately 75% of reported cases (28/37) were deemed spontaneous and several included short inter-cord distances. Shunting of blood away from the membranes in the region between the cord insertions may be responsible for membrane rupture. Further investigation is needed into short inter-cord distance as a marker for monochorionic twins at risk to become a pseudomonoamniotic gestation.

Guided outcomes in learned efficiency model in clinical medical education: a randomized controlled trial of self-regulated learning.

OBJECTIVE: The guided outcomes in learned efficiency (GOLE) model emphasizes the use of evidence-based resources to understand the diagnosis, treatment, follow-up, and prevention of disease. We seek to determine whether presentations created using the GOLE model are superior to an unstructured approach in achieving Accreditation Council for Graduate Medical Education (ACGME) Core Competencies. STUDY DESIGN: Consenting medical students were randomized to GOLE or control groups to individually research a self-selected clinical topic. A validated survey instrument was used prepresentation and postpresentation to assess perceived improvement in knowledge. Subjects completed self-evaluations at enrollment and after presentation of their chosen clinical topic. Other students, residents, and a faculty member also completed evaluations after each student presentation. Standard statistical methods (analysis of variance, 2-tailed t test) were used to determine if a statistically significant difference existed between intervention and control groups. RESULTS: Self-assessments were similar in the GOLE and control groups. Externally perceived presentation scores were greater in the GOLE group (ACGME global P < .0001, presentation global P = .07), which demonstrated a significant improvement in 5 core competencies. Time spent preparing the presentation and resources utilized did not differ between groups. CONCLUSION: The presentations prepared using the GOLE model were rated higher by observers than those prepared using traditional techniques.

Health care providers' use of a drug information service for pregnancy-related inquiries.

OBJECTIVES: To characterize pregnancy and lactation-related medication inquiries to a drug information center to identify classes of medications of most concern to providers. A secondary objective was to identify any trends in provider inquiries over the study period. DESIGN: A retrospective descriptive study of pregnancy and lactation-related inquiries to the University of North Carolina Health Care System Drug Information Center database between January 2001 and December 2010. SETTING: University of North Carolina Health Care System Drug Information Center. INTERVENTION: Provider inquiries and responses were extracted and characterized by indication for treatment and reason for inquiry. Comparison of the first and second 5-year periods was performed to delineate trends. Descriptive statistics, Fisher's Exact and χ2 tests were used for analysis. MAIN OUTCOME MEASURES: Inquiry origin, time, and subject. RESULTS: 433 inquiries were retrieved over the study period from physicians (50%), pharmacists (21%), and nurses (18%). Inquiries were most often made during the antepartum period (34%), followed by the postpartum (28%) and preconception (22%) periods. The most frequent indications for inquiry were psychiatry (15%) and infectious diseases (14%), which remained constant throughout the study period. Safety was the most common reason for inquiry (52%). The responses provided to callers were limited due to lack of information availability 37% of the time. CONCLUSION: Psychiatry and infectious disease-related indications are the most frequent subjects of provider inquiry regarding medication use in pregnancy. Rates of inquiry remained constant throughout the past decade in most therapeutic areas. These findings are consistent with previous observations in other developed countries and suggest high-yield areas for pharmacist education.

Systematic review and meta-analysis of COVID-19 maternal and neonatal clinical features and pregnancy outcomes up to June 3, 2021.

OBJECTIVE: COVID-19 is a rapidly changing and developing emergency that requires constant re-evaluation of available data. We report a systematic review and meta-analysis based on all published high-quality data up to and including June 3, 2021 on the maternal and neonatal outcomes in pregnant women infected with COVID-19. DATA SOURCES: PubMed, SCOPUS, MEDLINE, ClinicalTrials.gov, and Web of Science databases were queried from inception up to June 3, 2021. STUDY ELIGIBILITY CRITERIA: We included all clinical studies (prospective and retrospective cohort studies, case-control studies, case series, and rapid communications) that reported data on any maternal and neonatal outcomes of pregnant women with COVID-19. METHODS: The data were analyzed as pooled proportions or odds ratios and 95% confidence intervals in meta-analysis models. RESULTS: We included 111 studies enrolling 42,754 COVID-19-positive pregnant women. From COVID-19-positive pregnant women, the incidence rates were 53.2% (95% confidence interval, 48-58.4) for cesarean delivery, 41.5% (95% confidence interval, 36.3-46.8) for spontaneous vaginal delivery, and 6.4% (95% confidence interval, 4.5-9.2) for operative delivery. The rates of some adverse neonatal events, including premature delivery (16.7%; 95% confidence interval, 12.8-21.5) and low birthweight (16.7%; 95% confidence interval, 12.8-21.5) were relatively high in mothers infected with COVID-19. Vertical transmission (3.5%; 95% confidence interval, 2.7-4.7), neonatal death (3%; 95% confidence interval, 2-4), stillbirth (1.9%; 95% confidence interval, 1.5-2.4), and maternal mortality (0.012%; 95% confidence interval, 0.010-0.014) were rare adverse events. The mean birthweight was 3069.7 g (95% confidence interval, 3009.7-3129.8 g). In the comparative analysis, COVID-19 significantly increased the risk of premature delivery (odds ratio, 1. 48 [95% confidence interval, 1.22-1.8]), preeclampsia (odds ratio, 1.6 [95% confidence interval, 1.2-2.1]), stillbirth (odds ratio, 2.36 [95% confidence interval, 1.24-4.462]), neonatal mortality (odds ratio, 3.35 [95% confidence interval, 1.07-10.5]), and maternal mortality (odds ratio, 3.08 [95% confidence interval, 1.5-6.3]). The pooled analyses were homogenous, with mild heterogeneity in premature delivery and preeclampsia outcomes. CONCLUSION: The data must be interpreted with caution as limited data are available, and no complete assessment of bias is possible at this time. Our data suggest that pregnant women who test positive for COVID-19 seem to be at a higher risk of lower birth weights and premature delivery. There is no evidence at this time of the sharply increased maternal mortality that was seen previously with both the 2003 SARS and 2012 MERS pandemics.

Telehealth multidisciplinary prenatal consultation during the COVID-19 pandemic: enhancing patient care coordination while maintaining high provider satisfaction.

OBJECTIVE: Comprehensive fetal care centers address congenital anomalies by developing pre- and post-natal care plans in a multidisciplinary format. To reduce exposure during the Coronavirus Infectious Disease-2019 (COVID-19) pandemic, the Centers for Medicare & Medicaid Services (CMS) broadened access to telehealth services. We assessed provider satisfaction with the rapid transition from in-person prenatal visits to multidisciplinary consultations via telehealth as an adaptive response to the pandemic. METHODS: Patients referred to an urban academic fetal care center during the first 6 weeks of the COVID-19 pandemic underwent advanced imaging including fetal MRI, focused ultrasound, and fetal echocardiography. Subsequently, multidisciplinary telehealth consultations occurred with all providers attending virtually. Patients were given the option of attending the multidisciplinary telehealth consultation in a conference room in the hospital or from home. During these meetings, relevant images were reviewed with all participants via screen sharing through a secure video platform. Provider satisfaction with the telehealth paradigm was assessed using an electronic survey. RESULTS: Twenty-two surveys were administered with a response rate of 82%. 89% of providers were highly satisfied with the telehealth format. 72% of providers would prefer the multidisciplinary telehealth format to an in-person visit for future visits after COVID-19 restrictions are lifted. 22% of providers would leave the choice to the patient's family. One provider preferred in-person visits. Some providers noted that virtual conferences limited the ability to draw pictures, show educational materials, and provide emotional support. CONCLUSION: Providers were overwhelmingly supportive of continuing multidisciplinary telehealth conferences for complex prenatal consultations, even after restrictions are lifted, which has led to the continuation of this model for the duration of the pandemic. Providers highlighted the convenience and improved care coordination across specialties. Further studies to examine the patient experience with virtual consultations are warranted.

Prediction of neonatal morbidity and very preterm delivery using maternal steroid biomarkers in early gestation.

BACKGROUND: Preterm delivery is a common pregnancy complication that can result in significant neonatal morbidity and mortality. Limited tools exist to predict preterm birth, and none to predict neonatal morbidity, from early in pregnancy. The objective of this study was to determine if the progesterone metabolites 11-deoxycorticosterone (DOC) and 16-alpha hydroxyprogesterone (16α-OHP), when combined with patient demographic and obstetric history known during the pregnancy, are predictive of preterm delivery-associated neonatal morbidity, neonatal length of stay, and risk for spontaneous preterm delivery prior to 32 weeks' gestation. METHODS AND FINDINGS: We conducted a cohort study of pregnant women with plasma samples collected as part of Building Blocks of Pregnancy Biobank at the Indiana University School of Medicine. The progesterone metabolites, DOC and 16α-OHP, were quantified by mass spectroscopy from the plasma of 58 pregnant women collected in the late first trimester/early second trimester. Steroid levels were combined with patient demographic and obstetric history data in multivariable logistic regression models. The primary outcome was composite neonatal morbidity as measured by the Hassan scale. Secondary outcomes included neonatal length of stay and spontaneous preterm delivery prior to 32 weeks' gestation. The final neonatal morbidity model, which incorporated antenatal corticosteroid exposure and fetal sex, was able to predict high morbidity (Hassan score ≥ 2) with an area under the ROC curve (AUROC) of 0.975 (95% CI 0.932, 1.00), while the model without corticosteroid and fetal sex predictors demonstrated an AUROC of 0.927 (95% CI 0.824, 1.00). The Hassan score was highly correlated with neonatal length of stay (p<0.001), allowing the neonatal morbidity model to also predict increased neonatal length of stay (53 [IQR 22, 76] days vs. 4.5 [2, 31] days, above and below the model cut point, respectively; p = 0.0017). Spontaneous preterm delivery prior to 32 weeks' gestation was also predicted with an AUROC of 0.94 (95% CI 0.869, 1.00). CONCLUSIONS: Plasma levels of DOC and 16α-OHP in early gestation can be combined with patient demographic and clinical data to predict significant neonatal morbidity, neonatal length of stay, and risk for very preterm delivery, though validation studies are needed to verify these findings. Early identification of pregnancies at risk for preterm delivery and neonatal morbidity allows for timely implementation of multidisciplinary care to improve perinatal outcomes.

Alterations in endogenous progesterone metabolism associated with spontaneous very preterm delivery.

STUDY QUESTION: Do maternal serum levels of progesterone metabolites early in pregnancy correspond to an increased risk for very preterm delivery prior to 32 weeks? SUMMARY ANSWER: Maternal serum levels of 11-deoxycorticosterone (DOC) measured during the late first trimester or early second trimester correlate with an increased risk for preterm delivery prior to 32 weeks, and the correlation becomes stronger when the ratio of DOC to 16-alpha-hydroxyprogesterone was measured. WHAT IS KNOWN ALREADY: Progesterone is a pro-gestational steroid hormone that has been shown to decrease the risk of preterm birth in some pregnant women. Progesterone is metabolized by the body into various metabolites including members of the mineralocorticoid and glucocorticoid families. Our group has previously demonstrated that some progesterone metabolites enhance myometrial contractility in an ex vivo system, while others result in myometrial relaxation. The current exploratory study was designed to determine if pre-specified metabolites of progesterone measured early in pregnancy were associated with a woman's risk for delivery prior to 32 weeks, which is referred to as a very preterm delivery. STUDY DESIGN SIZE DURATION: The Building Blocks of Pregnancy Biobank (BBPB) is a biorepository at Indiana University (IU) that follows women prospectively through their pregnancy. A variety of biospecimens are collected at various time points during a woman's pregnancy. Women participating in the IU BBPB who were enrolled after 8 weeks' gestation with pregnancy outcome data were eligible for participation. PARTICIPANTS/MATERIALS SETTING METHODS: Women delivering prior to 37 weeks (preterm) and at or after 37 weeks (term) who had blood samples collected during the late first trimester/early second trimester and/or during the early third trimester were identified. These samples were then processed for mass spectroscopy, and the amount of progesterone and progesterone metabolites in the samples were measured. Mean values of each measured steroid metabolite were calculated and compared among women delivering at less than 32 weeks, less than 37 weeks and greater than or equal to 37 weeks. Receiver operating characteristic (ROC) curves were constructed and threshold levels determined for each compound to identify a level above or below which best predicted a woman's risk for delivery prior to 32 and prior to 37 weeks. Mann-Whitney U nonparametric testing with Holm-Bonferroni correction for multiple comparisons was utilized to identify steroid ratios that could differentiate women delivering spontaneously at less than 32 weeks from all other pregnancies. MAIN RESULTS AND THE ROLE OF CHANCE: Steroid hormone levels and pregnancy outcome data were available for 93 women; 28 delivering prior to 32 weeks, 40 delivering between 32 0/7 and 36 6/7 weeks and 25 delivering at or greater than 37 weeks: the mean gestational age at delivery within the three groups was 27.0, 34.4 and 38.8 weeks, respectively. Among women delivering spontaneously at less than 37 weeks, maternal 11-deoxycorticosterone (DOC) levels drawn in the late first trimester/early second trimester were significantly associated with spontaneous preterm delivery prior to 32 weeks; a threshold level of 47.5 pg/ml had 78% sensitivity, 73% specificity and an AUC of 0.77 (P = 0.044). When DOC levels were analyzed as a ratio with other measured steroid hormones, the ratio of DOC to 16-alpha-hydroxyprogesterone among women delivering spontaneously prior to 37 weeks was able to significantly discriminate women delivering prior to 32 weeks from those delivering at or greater than 32 weeks, with a threshold value of 0.2 with 89% sensitivity, 91% specificity and an AUC of 0.92 (P = 0.002). When the entire study cohort population was considered, including women delivering at term and women having an iatrogenic preterm delivery, the ratio of DOC to 16-alpha-hydroxyprogesterone was able to discriminate women delivering spontaneously prior to 32 weeks from the rest of the population at a threshold of 0.18 and 89% sensitivity, 59% specificity and an AUC of 0.81 (P = 0.003). LIMITATIONS REASONS FOR CAUTION: This is a discovery study, and the findings have not been validated on an independent cohort. To mitigate issues with multiple comparisons, we limited our study to pre-specified metabolites that are most representative of the major metabolic pathways for progesterone, and adjustments for multiple comparisons were made. WIDER IMPLICATIONS OF THE FINDINGS: Spontaneous preterm birth is increasingly being recognized to represent a common end pathway for a number of different disease phenotypes that include infection, inflammation, premature rupture of the membranes, uterine over distension, cervical insufficiency, placental dysfunction and genetic predisposition. In addition to these phenotypes, longitudinal changes in the maternal-fetal hypothalamic-pituitary-adrenal (HPA) axis also likely contribute to a significant proportion of the disease burden of spontaneous preterm birth. Here, we demonstrate that differential production of steroid metabolites is associated with very early preterm birth. The identified biomarkers may hint at a pathophysiologic mechanism and changes in the maternal-fetal dyad that result in preterm delivery. The early identification of abnormal changes in HPA axis metabolites may allow for targeted interventions that reverse the aberrant steroid metabolic profile to a more favorable one, thereby decreasing the risk for early delivery. Further research is therefore required to validate and extend the results presented here. STUDY FUNDING/COMPETING INTERESTS: Funding for this study was provided from the Office of the Vice Chancellor for Research at IUPUI, 'Funding Opportunities for Research Commercialization and Economic Success (FORCES) grant'.Both A.S.P. and C.A.G. are affiliated with Nixxi, a biotech startup. The remaining authors report no conflict of interest. TRIAL REGISTRATION NUMBER: Not applicable.

Progesterone Metabolites Inhibit the Human Ether-a-go-go-Related Gene and Predict QT Interval Length.

A decrease in the human ether-a-go-go-related gene (hERG/KCNH2)-related channel has been linked to intrauterine fetal death. The formation of cytochrome P450 (CYP) 3A-mediated progesterone metabolites, 6-beta-hydroxy-progesterone (6ß-OHP) and 16α-hydroxy-progesterone (16α-OHP), is variable among adults and differs from fetal metabolism. The primary objective of this study was to assess the potential for progesterone metabolites to inhibit hERG-related current and predict QTc intervals. Whole-cell voltage-clamp electrophysiology was performed on human embryonic kidney 293 cells stably expressing hERG exposed to progesterone or metabolites. Both 6ß-OHP and 16α-OHP positively shifted the voltage dependence of activation relative to vehicle from -4.0 ± 0.8 to -0.3 ± 0.8 mV, P < .01; and 1.0 ± 0.6 mV, P < .01, respectively. In addition, 6ß-OHP decreased maximal outward tail currents from 49.4 ± 4.9 to 32.5 ± 4.1 pA/pF, P < 0.01, and reduced the expression of fully glycosylated hERG by 42%. Healthy female subjects were administered progesterone 400 mg orally for 7 days, ibutilide 0.003 mg/kg was infused, and serial electrocardiograms and blood samples collected. Relationships between rate-corrected QT intervals (QTcI) with circulating hormones and metabolites were assessed. The 6ß-OHP and 16α-OHP metabolites were independent predictors of QTcI intervals prior to and following ibutilide administration. In conclusion, the progesterone metabolites formed via CYP3A cause inhibitory effects on hERG channels and predict QTcI intervals in healthy women pretreated with progesterone. Further study into maternal and fetal exposure to these metabolites and potential to prolong cardiac repolarization is warranted.

Severity of congenital heart defects associated with assisted reproductive technologies: Case series and review of the literature.

OBJECTIVE: Assisted reproductive technology (ART) has been associated with a higher incidence of congenital anomalies, including a specific increase in the rate of congenital heart defects (CHD). In this study, the rate of CHD in pregnancies resulting from ART at a single high-risk pregnancy referral center are compared to the published literature. METHODS: Pregnancies were screened by fetal echocardiography for the indication of ART over a 2-year period. CHD were classified as either mild or severe based on the need for postnatal surgical intervention. Results were compared to findings from a literature review of studies examining CHD in pregnancies resulting from ART since 1980. RESULTS: Over the course of two years, 363 fetuses in 264 pregnancies from our cohort were screened for CHD. The incidence of mild CHD in fetuses from ART pregnancies was 2.75% (10 out of 363 fetuses). None of the affected fetuses had severe CHD. Review of the literature yielded 20 studies since 1980 that examined CHD in pregnancies resulting from ART. Composite data from the studies was described based on characterization of severity of the CHD anomalies. The incidence of mild CHD in ART pregnancies was 2.2%, compared to 1% in non-ART pregnancies (out of 332,157 infants). The incidence of severe CHD in ART pregnancies and naturally conceived pregnancies was 1.4% and 1.2%, respectively (out of 661,455 infants). The incidence of unspecified CHD in ART pregnancies was 1.8%, compared to 1% in naturally conceived pregnancies (out of 1,593,277 infants). CONCLUSION: The greatest increase in risk appears to be for mild CHD (nonsurgical), which may inform counseling of patients prior to use of assisted reproductive technologies.

Utility of volumetric assessment of cervical funneling to predict cerclage failure.

OBJECTIVE: To assess the utility of cervical funnel volume as a predictor of cerclage failure. METHODS: We performed a retrospective cohort study of pregnant women with a McDonald cerclage and sonographic evidence of cervical funneling between 1/2008 and 2/2014. Funnel volume (FV) was calculated and used as a correction factor for cervical length (CL) or cerclage height (CH). Receiver operating characteristic (ROC) curves were used to compare the predictive value of CL, CL:FV, CH and CH:FV for cerclage failure at <28 or <34 weeks. CL:FV was further stratified to the <5th, <10th and >10th percentiles and analyzed for prediction of preterm delivery. RESULTS: Subjects with cerclage failure (n = 30) delivered at a mean gestational age of 29.8 +/- 5.3 weeks compared to 38.1+/- 1.39 weeks in those without failure (n = 27; p < 0.001). ROC curves demonstrated CL:FV was the best predictor of delivery <28 weeks (AUC 0.80), while CL was the best predictor of delivery <34 weeks (AUC 0.76). Stratification of CL:FV into <5th versus >10th percentile groups was predictive of early preterm delivery (25.1 weeks versus 34 weeks, p = 0.01). CONCLUSIONS: Volumetric assessment of cervical funneling may improve prediction of cerclage failure in the mid-trimester.

Fundamentals of Clinical Pharmacology With Application for Pregnant Women.

Medication use is common in pregnancy, yet for most medications the optimal formulation and dosage have not been described specifically for pregnant women. Often, adverse effects are only discovered anecdotally or after extensive off-label use occurs. Since pharmacologic research that includes pregnant women is sparse and animal studies are often not applicable to the human fetus, providers must use knowledge of drug behavior and normal physiologic changes of pregnancy to personalize treatment for pregnant women. In this review, we present an overview of the basic concepts of clinical pharmacology: pharmacokinetics, pharmacodynamics, and pharmacogenomics. The normal physiologic changes of pregnancy are presented as a framework to understand alterations in drug behavior. A clinical vignette that addresses 4 pregnancy scenarios involving medications-preterm birth, vaccination, herpes simplex virus infection, and codeine toxicity-is provided to illustrate application of core clinical pharmacologic concepts. Discussion of relevant literature illustrates the challenges of offering individualized pharmacologic therapy in pregnancy.