Clinical Outcomes Associated with a Remote Postpartum Hypertension Monitoring Program.

OBJECTIVE: To evaluate differences in health care utilization and guideline adherence for postpartum individuals with hypertensive disorders of pregnancy (HDP) who are engaged in a remote monitoring program, compared with usual care. METHODS: This was a retrospective cohort study of postpartum individuals with HDP who delivered between March 2019 and June 2023 at a single institution. The primary exposure was enrollment in a remote hypertension management program that relies on patient home blood pressure (BP) measurement and centralized nursing team management. Patients enrolled in the program were compared with those receiving usual care. Outcomes included postpartum readmission, office visit within 6 weeks postpartum, BP measurement within 10 days, and initiation of antihypertensive medication. We performed multivariable logistic and conditional regression in a propensity score matched cohort. Propensity scores, generated by modeling likelihood of program participation, were assessed for even distribution by group, ensuring standardized bias of less than 10% after matching. RESULTS: Overall, 12,038 eligible individuals (6,556 participants, 5,482 in the control group) were included. Program participants were more likely to be White, commercially insured, be diagnosed with preeclampsia, and have higher prenatal and inpatient postpartum BPs. Differences in baseline factors were well-balanced after implementation of propensity score. Program enrollment was associated with lower 6-week postpartum readmission rates, demonstrating 1 fewer readmission for every 100 individuals in the program (propensity score-matched adjusted risk difference [aRD] -1.5, 95% CI, -2.6 to -0.46; adjusted risk ratio [aRR] 0.78, 95% CI, 0.65-0.93). For every 100 individuals enrolled in the program, 85 more had a BP recorded within 10 days (propensity score-matched aRD 85.4, 95% CI, 84.3-86.6), and six more had a 6-week postpartum office visit (propensity score-matched aRD 5.7, 95% CI, 3.9-7.6). Program enrollment was also associated with increased initiation of an antihypertensive medication postpartum (propensity score-matched aRR 4.44, 95% CI, 3.88-5.07). CONCLUSION: Participation in a postpartum remote BP monitoring program was associated with fewer postpartum hospital readmissions, higher attendance at postpartum visits, improved guideline adherence, and higher rates of antihypertensive use.

Objectively assessed sleep-disordered breathing during pregnancy and infant birthweight.

BACKGROUND: Sleep-disordered breathing (SDB) in pregnancy is associated with adverse maternal outcomes. The relationship between SDB and infant birthweight is unclear. This study's primary aim is to determine if objectively measured SDB in pregnancy is associated with infant birthweight. METHODS: We measured SDB objectively in early (6-15 weeks' gestation) and mid (22-31 weeks' gestation) pregnancy in a large cohort of nulliparous women. SDB was defined as an Apnea-Hypopnea Index ≥5 and in secondary analyses we also examined measures of nocturnal hypoxemia. We used a modified Poisson regression approach to estimate relative risks (RR) of large-for-gestational-age (LGA: >90th percentile for gestational age) and small-for-gestational-age (SGA: <10th percentile for gestational age) birthweights. RESULTS: The prevalence of early-pregnancy SDB was nearly 4%. The incidence of mid-pregnancy SDB was nearly 6.0%. The prevalence of LGA and SGA was 7.4% and 11.9%, respectively. Early-pregnancy SDB was associated with a higher risk of LGA in unadjusted models (RR 2.2, 95% CI 1.3-3.5) but not BMI-adjusted models (aRR 1.0, 95% CI 0.6-1.8). Mid-pregnancy SDB was not associated with SGA or LGA. Mid-pregnancy nocturnal hypoxemia (% of sleep time <90% oxygen saturation) and increasing nocturnal hypoxemia from early to mid-pregnancy were associated with a higher risk of LGA in BMI-adjusted models. SDB and nocturnal hypoxemia were not associated with SGA. CONCLUSIONS: SDB in pregnancy was not associated with an increased risk of LGA or SGA birthweight, independent of BMI. Some measures nocturnal hypoxemia were associated with an increase in LGA risk, independent of BMI. ClinicalTrials.gov Registration number NCT02231398.

Customized versus Population Growth Standards for Morbidity and Mortality Risk Stratification Using Ultrasonographic Fetal Growth Assessment at 22 to 29 Weeks' Gestation.

OBJECTIVE: 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.

Management of Anesthesia and Delivery in Women With Chiari I Malformations.

OBJECTIVE: To estimate whether vaginal delivery or neuraxial anesthesia poses a risk of neurologic deterioration in women with uncorrected Chiari I malformation. METHODS: To assemble this case series, electronic record databases were used to identify women with Chiari I malformation who delivered on two busy tertiary care obstetric services over a 5-year period from January 2010 through December 2015. Women who had undergone surgical decompression were not included in the study. The size of the Chiari malformation, neurologic symptoms before delivery, mode of delivery, anesthetic method used, and neurologic complications were recorded. RESULTS: Ninety-five deliveries in 63 patients were identified. The size of the Chiari malformation was 9.3±4.3 mm (mean±SD). In 58 pregnancies, women reported no headaches; in 36 they did. There was no association between the size of the Chiari malformation and the incidence of headache. Forty-four neonates were delivered by cesarean delivery and 51 were delivered vaginally. No neurologic deterioration occurred in either group. Neuraxial anesthesia was administered before 62 deliveries. No neurologic complications occurred. None of the women who delivered vaginally or received neuraxial anesthesia had signs of increased intracranial pressure. The upper limit of the 95% CI for the risk of neurologic complications from our study of 95 deliveries was 3.1%. CONCLUSION: This case series support that in patients with Chiari I malformation who have no signs of increased intracranial pressure, the mode of delivery should be based on obstetric rather than neurologic considerations. The absence of complications in patients who received epidural or spinal anesthesia suggests that these procedures should be made available to women with Chiari I malformation.

Impairment of trophoblast survival and differentiation by LXR ligands is prevented by cholesterol but not ABCA1 silencing.

INTRODUCTION: The Liver X Receptors (LXRs) drive the transcriptional response to excess intracellular cholesterol. Oxysterols, the products of cholesterol oxidation, are activating ligands for LXR that can accumulate under conditions of oxidative stress and disrupt cholesterol homeostasis. While activation of LXR inhibits trophoblast differentiation, the impact of LXR on trophoblast physiology or cholesterol homeostasis is incompletely understood. We sought to determine if the effects of LXR activation can be ameliorated through modification of cholesterol bioavailability or inhibition of LXR-driven cholesterol efflux in trophoblasts. METHODS: We measured the effect of oxysterol exposure on BeWo cells and primary human trophoblasts (PHT cells) cultured in lipoprotein-deficient medium. We also measured the effect of the synthetic, LXR-specific ligand T0901317 on PHT cell differentiation and survival. Finally, we silenced the ATP-binding cassette transporter A1 (ABCA1), a transcriptional target of LXR that drives cholesterol efflux, to determine if inhibition of cholesterol efflux could block the effects of T0901317. RESULTS: Oxysterols inhibited BeWo survival and PHT cell differentiation, and these effects were blocked by cholesterol supplementation. T0901317 also inhibited PHT cell differentiation, and this effect was similarly blocked by cholesterol. Unlike cholesterol however, ABCA1 silencing did not modify the effect of T0901317 on PHT cell differentiation. DISCUSSION: Oxysterols and LXR inhibit trophoblast survival and differentiation exclusively in conditions of cholesterol scarcity. These findings underscore the importance of cholesterol homeostasis in the maintenance of placental function and suggest that pathways regulating cholesterol homeostasis may represent therapeutic targets to mitigate harmful sequelae of placental injury.

Machine Learning for Fetal Growth Prediction.

Birthweight is often used as a proxy for fetal weight. Problems with this practice have recently been brought to light. We explore whether data available at birth can be used to predict estimated fetal weight using linear and quantile regression, random forests, Bayesian additive regression trees, and generalized boosted models. We train and validate each approach using 18,517 pregnancies (31,948 ultrasound visits) from the Magee-Womens Obstetric Maternal and Infant data and 240 pregnancies in a separate dataset of high-risk pregnancies. We also quantify the relation between smoking and small-for-gestational-age birth, defined as a birthweight in the lower 10th percentile of a population birthweight standard and estimated and predicted fetal weight standard. Using mean squared error and median absolute deviation criteria, quantile regression performed best among the regression-based approaches, but generalized boosted models performed best overall. Using the birthweight standard, smoking during pregnancy increased the risk of small-for-gestational-age 3.84-fold (95% CI: 2.70, 5.47). This ratio dropped to 1.65 (95% CI: 1.50, 1.81) when using the correct fetal weight standard, which was no different from the machine learning-based predicted standards, but higher than the regression-based predicted standards. Machine learning algorithms show promise in recovering missing fetal weight information. See video abstract at, http://links.lww.com/EDE/B314.

Effect of Population-Specific Birthweight Curves on Disparities in Perinatal Mortality in Small-for-Gestational Age Pregnancies.

OBJECTIVE: To determine the effect of adopting sex or race/ethnicity-specific birthweight curves on small-for-gestational age (SGA)-associated mortality rates for specific populations. MATERIALS AND METHODS: Analyzing 20,095,735 singleton pregnancies, we compared rates of perinatal death associated with SGA in distinct sex and racial/ethnic groups when SGA was defined using nonspecific, sex-specific, and race/ethnicity-specific birthweight curves. RESULTS: With use of a nonspecific birthweight curve, the rate of perinatal death was higher for SGA males (20.4/1,000 [95% confidence interval (CI), 20.1, 20.7]) than SGA females [14.6/1,000 (95% CI, 14.4, 14.8)]. With a sex-specific curve, this disparity was reduced, measuring 17.7/1,000 (95% CI, 17.4, 17.9) for SGA males and 16.3/1,000 (95% CI, 16.1, 16.6) for females. Using a nonspecific birthweight curve, perinatal death rates were higher for non-Hispanic blacks (20.4/1,000 [95% CI, 20.0, 20.8]) than for all other racial/ethnic groups (15.9/1,000 [95% CI, 15.7, 16.1]). This difference increased with use of a race-specific birthweight curve: perinatal mortality was 29.7/1,000 (95% CI, 29.0, 30.3) for SGA blacks and 14.7/1,000 (95% CI, 14.6, 14.9) for all other racial/ethnic groups. CONCLUSION: Population-based differences in SGA-associated mortality are reduced with adoption of a sex-specific birthweight curve, but widen with use of a race/ethnicity-specific curve. These findings highlight the importance of outcomes analysis in the selection of diagnostic criteria for SGA.

The expression level of C19MC miRNAs in early pregnancy and in response to viral infection.

INTRODUCTION: We have previously shown that miRNAs produced from the Chromosome 19 MiRNA Cluster (C19MC), which are expressed almost exclusively in primate trophoblasts and are released into the maternal circulation, reduce viral replication in non-placental cells and can modulate migratory behavior of extravillous trophoblast. We sought to define the expression pattern of C19MC miRNA in early pregnancy and in response to viral infection in vitro and in vivo. METHODS: We prospectively followed women undergoing in vitro fertilization (IVF) and determined their blood level of C19MC miRNA using RT-qPCR. To examine the effect of viral exposure on C19MC miRNAs expression, we used three systems: (1) a transgenic mouse overexpressing the C19MC cluster and exposed to Togaviridae during pregnancy, (2) cultured primary human trophoblasts exposed to Vesicular Stomatitis Virus in vitro, and (3) amniotic fluid from women exposed to cytomegalovirus during pregnancy. RESULTS: In 27 IVF pregnancies, C19MC miRNAs were detected as early as 2 weeks after implantation, and their levels increased thereafter. There was no change in C19MC miRNA expression levels in the mouse placenta in response to viral exposure. Similarly, Vesicular Stomatitis Virus infection of primary human trophoblast did not selectively increase C19MC miRNA expression. C19MC miRNA expression in the amniotic fluid was not affected by vertical transmission of cytomegalovirus. DISCUSSION: The expression of C19MC miRNAs in maternal circulation very early in pregnancy suggests a role in the establishment of the maternal-fetal interface. The levels of C19MC miRNA are not influenced by diverse types of viral infection.

Small for Gestational Age: The Differential Mortality When Detected versus Undetected Antenatally.

Background Antenatal detection of fetal growth restriction (FGR) prompts antepartum surveillance to reduce perinatal mortality, yet most cases of FGR are undetected. Objective This study aims to compare rates of adverse neonatal outcomes when FGR is detected versus undetected. Study Design Small-for-gestational-age (SGA) newborns (birth weight < 10% for gestational age) delivered at the Magee-Women's Hospital in Pittsburgh, PA from 2003 to 2010 were divided into three groups: those whom did not undergo third-trimester fetal growth ultrasound (SGA-no US), were appropriate for gestational age (AGA) by ultrasound (SGA-undetected), or were FGR by ultrasound (SGA-detected). We then compared rates of 5-minute Apgar < 4 and neonatal death (ND), with AGA newborns as the referent. Results Out of 29,885 neonates, 2,475 (8.3%) were SGA. Out of the 826 (33%) SGA neonates who underwent growth ultrasound, 185 (22%) were considered FGR. In the SGA-no US group, the adjusted odds ratio (aOR) for Apgar < 4 was 2.84 (95% confidence interval (CI): 1.28-6.29) and 3.87 (95% CI: 2.09-7.18) for ND. The risk of Apgar < 4 (aOR: 3.10, 95% CI: 0.93-10.28) and ND (aOR: 2.16, 95% CI: 0.66-7.14) were not significantly elevated for SGA-undetected neonates, while SGA-detected neonates were most at risk, with an aOR of 18.20 (95% CI: 6.82-48.60) for Apgar < 4 and 18.24 (95% CI: 7.90-42.13) for ND. Conclusion Fetal growth ultrasound effectively stratifies risk amongst SGA neonates.

An Evidence-Based Approach to Defining Fetal Macrosomia.

OBJECTIVE: This study aims to determine the risk of adverse outcomes associated with the current diagnostic criteria for fetal macrosomia. Study DESIGN: We evaluated three techniques for characterizing birth weight as a predictor of shoulder dystocia or third- or fourth-degree laceration in 79,879 vaginal deliveries. First, we compared deliveries with birth weights above or below 4,500 g. We then performed logistic regression using birth weight as a continuous predictor, both with and without fractional polynomial transformation. Finally, we calculated the number of cesarean sections required to prevent one incident of the interrogated outcomes (number needed to treat [NNT]). RESULTS: Rates of adverse intrapartum outcomes increase incrementally with increasing birth weight and are predicted most accurately with logistic regression following fractional polynomial transformation. The NNT for third- or fourth-degree laceration dropped from 14.3 (95% confidence interval [CI], 13.9-14.7) at a birth weight of 3,500 g to 6.4 (95% CI, 6.1-6.8) at 4,500 g and, for shoulder dystocia, from 54.9 (95% CI, 51.5-58.6) at 3,500 g to 5.6 (95% CI, 5.2-6.0) at 4,500 g. CONCLUSION: The conventional distinction between "normal" and "macrosomic" does not reflect the incremental effect of increasing birth weight on the risk of obstetric morbidity. Outcomes analysis can inform fetal growth standards to better reflect relevant thresholds of risk.

Perinatal outcomes and unconventional natural gas operations in Southwest Pennsylvania.

Unconventional gas drilling (UGD) has enabled extraordinarily rapid growth in the extraction of natural gas. Despite frequently expressed public concern, human health studies have not kept pace. We investigated the association of proximity to UGD in the Marcellus Shale formation and perinatal outcomes in a retrospective cohort study of 15,451 live births in Southwest Pennsylvania from 2007-2010. Mothers were categorized into exposure quartiles based on inverse distance weighted (IDW) well count; least exposed mothers (first quartile) had an IDW well count less than 0.87 wells per mile, while the most exposed (fourth quartile) had 6.00 wells or greater per mile. Multivariate linear (birth weight) or logistical (small for gestational age (SGA) and prematurity) regression analyses, accounting for differences in maternal and child risk factors, were performed. There was no significant association of proximity and density of UGD with prematurity. Comparison of the most to least exposed, however, revealed lower birth weight (3323 ± 558 vs 3344 ± 544 g) and a higher incidence of SGA (6.5 vs 4.8%, respectively; odds ratio: 1.34; 95% confidence interval: 1.10-1.63). While the clinical significance of the differences in birth weight among the exposure groups is unclear, the present findings further emphasize the need for larger studies, in regio-specific fashion, with more precise characterization of exposure over an extended period of time to evaluate the potential public health significance of UGD.

The expression and localization of N-myc downstream-regulated gene 1 in human trophoblasts.

The protein N-Myc downstream-regulated gene 1 (NDRG1) is implicated in the regulation of cell proliferation, differentiation, and cellular stress response. NDRG1 is expressed in primary human trophoblasts, where it promotes cell viability and resistance to hypoxic injury. The mechanism of action of NDRG1 remains unknown. To gain further insight into the intracellular action of NDRG1, we analyzed the expression pattern and cellular localization of endogenous NDRG1 and transfected Myc-tagged NDRG1 in human trophoblasts exposed to diverse injuries. In standard conditions, NDRG1 was diffusely expressed in the cytoplasm at a low level. Hypoxia or the hypoxia mimetic cobalt chloride, but not serum deprivation, ultraviolet (UV) light, or ionizing radiation, induced the expression of NDRG1 in human trophoblasts and the redistribution of NDRG1 into the nucleus and cytoplasmic membranes associated with the endoplasmic reticulum (ER) and microtubules. Mutation of the phosphopantetheine attachment site (PPAS) within NDRG1 abrogated this pattern of redistribution. Our results shed new light on the impact of cell injury on NDRG1 expression patterns, and suggest that the PPAS domain plays a key role in NDRG1's subcellular distribution.

Risk of morbid perinatal outcomes in small-for-gestational-age pregnancies: customized compared with conventional standards of fetal growth.

OBJECTIVE: To estimate and compare the risk of morbid perinatal outcomes in pregnancies identified as small for gestational age (SGA) with customized compared with conventional standards of fetal growth. METHODS: Ultrasound-derived estimates of fetal weight were used to generate a fetal growth trajectory (N=7,510). The gestational age at delivery and pathologic and physiologic variables from 5,072 pregnancies were used to calculate a customized threshold for SGA. In a separate analysis of 32,070 pregnancies, rates of morbid outcomes were compared in participants classified as SGA according to a population-based birth weight standard only (SGApop only), a customized standard only (SGAcust only), and both methods (SGAboth). RESULTS: Eight-hundred seventy-five (2.7%) participants were SGApop only, 1,970 (6.1%) participants were SGAboth, and 609 (1.9%) participants were SGAcust only. The odds ratios of neonatal death in SGApop only and SGAcust only pregnancies were 1.78 (95% confidence interval [CI] 0.2-13.1) and 54.6 (95% CI 29.0-102.8), respectively. Rates of prematurity in the SGApop only and SGAcust only cohorts were 4.8% and 64.5%, respectively. After adjustment for the effect of prematurity, odds ratios of neonatal death in the SGApop only and SGAcust only cohorts were 4.8 (95% CI 0.6-37.0) and 2.9 (95% CI 1.4-6.1), respectively. CONCLUSION: After adjustment for confounding stemming from premature delivery, there is little difference in the risk of adverse outcomes between SGAcust only and SGApop only participants. Adoption of customized fetal growth standards into clinical practice may not improve the ability to identify pregnancies with increased risk of perinatal morbidity.

A customized standard of large size for gestational age to predict intrapartum morbidity.

OBJECTIVE: The purpose of this study was to determine whether a customized standard of large-for-gestational age (LGA) identifies pregnancies with increased perinatal risk. STUDY DESIGN: We evaluated 7510 estimates of fetal weight to generate a fetal growth curve. Next, we analyzed the gestational age at delivery, physiologic and pathological variables from 5072 pregnancies to predict birthweight, and calculated a customized ideal birthweight and cutoff for LGA. In a separate analysis of 32,271 pregnancies, rates of macrosomia-related adverse outcomes were compared in pregnancies that had been identified as LGA by a customized standard (LGA(cust)) and those pregnancies that had been identified as LGA or macrosomic by conventional standards. RESULTS: LGA(cust) pregnancies carried increased risk of shoulder dystocia, third- or fourth-degree laceration, and cephalopelvic disproportion. LGA(cust) pregnancies that did not meet conventional criteria for LGA/macrosomia were at increased risk of all measured outcomes. CONCLUSION: A customized standard of LGA identifies a previously unrecognized population that is at increased risk of perinatal morbidity.