Maternal outcomes following postpartum autotransfusion of blood lost during vaginal obstetric hemorrhage.

BACKGROUND: Autotransfusion following vaginal delivery has not been as widely adopted and existing data on this topic are limited to small case series. METHODS: This is a single-center retrospective matched cohort study. Deliveries exposed to autotransfusion during obstetric hemorrhage were matched to unexposed controls with obstetric hemorrhage who did not receive autotransfusion. The primary outcome was allogeneic transfusion of packed red blood cells. Planned secondary analyses included change in hemoglobin following delivery, composite maternal safety outcomes, and unplanned postpartum health care utilization. RESULTS: Thirty-six deliveries exposed to autotransfusion were matched to 144 unexposed controls. There was no significant difference in allogenic transfusion of packed red blood cells in the patients exposed to autotransfusion red with unexposed controls (adjusted OR 1.1; 95% CI 0.5-2.4). Deliveries that received autotransfusion had a less severe pre- to post-delivery decline in hemoglobin compared with unexposed controls across all values of QBL (p = .003). There were no significant differences in maternal morbidity outcomes evaluated in exposed versus unexposed deliveries. CONCLUSION: Autotransfusion in cases of vaginal obstetric hemorrhage did not attenuate rates of allogenic packed red blood cell transfusion but did result in a less severe pre- to postdelivery decline in hemoglobin at discharge. Autotransfusion cases did not have any markers of increased maternal morbidity when compared with a control group. These findings support emerging evidence indicating that autotransfusion of blood lost during vaginal obstetric hemorrhage is a safe and potentially effective tool for use in the management of obstetric hemorrhage.

Factors associated with postpartum initiation of anti-hypertensive medication after hospital discharge among individuals with hypertensive disorders of pregnancy in a remote monitoring program.

Importance: Following a hypertensive disorder of pregnancy, hypertension can worsen in the postpartum period following hospital discharge. Risk factors for hypertension exacerbation and associated outcomes have not been well characterized. Objective: We sought to identify risk factors and characterize outcomes for individuals requiring initiation of anti-hypertensive medication following hospital discharge postpartum through our hospital system's remote blood pressure management program. Design: We performed a cohort study of individuals delivered between 9/2019-6/2021 and enrolled in our remote blood pressure monitoring program, which utilizes standardized protocols for anti-hypertensive medication initiation postpartum. Setting: Postpartum unit at a referral hospital. Participants: Population-based sample of individuals with a hypertensive disorder of pregnancy (HDP, preeclampsia or gestational hypertension) and no pre-pregnancy hypertension. Exposure: Anti-hypertensive medication initiation timing: no anti-hypertensive medications, initiation prior to hospital discharge postpartum, and initiation after hospital discharge postpartum. Main outcomes: Postpartum readmission and emergency room visits. Results: Of 2,705 individuals in our cohort, 1,458 (54%) required no anti-hypertensive medications postpartum, 637 individuals (24%) were discharged on anti-hypertensive medications, and 610 (23%) required initiation of anti-hypertensive agents after discharge. Utilizing an inpatient threshold of ≥ 150/100 mmHg in line with current obstetric guidelines for medication initiation postpartum fails to identify 385 (63%) of individuals who required medication initiation after discharge. These individuals had higher home blood pressures, increased odds of Emergency Room visits [aOR 2.22 (95%CI 1.65-2.98)] and hospital readmissions postpartum [aOR 5.73 (95%CI 3.72-8.82)] compared with individuals discharged on no medications. Conclusions and Relevance: Over 20% of individuals with hypertensive disorders of pregnancy required initiation of anti-hypertensive medications after hospital discharge. Current blood pressure guidelines for medication initiation fail to identify the majority of these individuals during delivery hospitalization. These data support the critical role of remote blood pressure monitoring programs and highlight the need for improved tools for risk strati cation and liberalization of thresholds for medication initiation postpartum.

Autotransfusion of vaginally shed blood as a novel therapy in obstetric hemorrhage: A case series.

OBJECTIVE: To report maternal outcomes in a cohort of women who received autotransfusion of vaginally shed blood and to describe the feasibility of blood collection and cell salvage processing at the time of vaginal hemorrhage. STUDY DESIGN AND METHODS: We conducted a retrospective case series of patients who received autotransfusion of vaginally shed blood at the time of obstetric hemorrhage from January 2014 to August 2020. Maternal data and cell salvage utilization characteristics were abstracted from the electronic medical record. RESULTS: Sixty-four cases were identified in which autotransfusion of vaginally shed blood occurred during an obstetric hemorrhage. Median quantitative blood loss was 2175 ml (interquartile range 1500-2250 ml) with 89% of cases having a blood loss greater than 1000 ml. Patients on average received approximately 1.3 units of autologous blood product (384 ml, interquartile range 244-520 ml) and no direct adverse events were observed during transfusion. We observed heterogeneity in autologous blood volume across all values of quantitative blood loss. The need for allogenic blood transfusion was common and occurred in 72% of all cases (N = 46). There were no documented cases of maternal sepsis or severe infectious morbidity. CONCLUSION: In 64 cases where autotransfusion of vaginally shed blood occurred, autotransfusion was well tolerated. Heterogeneity in autologous blood volume collection likely represents the lack of standardized protocols for blood collection in the delivery room. Autotransfusion of vaginally shed blood is a feasible and reasonable technique to employ during severe obstetric hemorrhage.

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.

Racial Differences in Postpartum Blood Pressure Trajectories Among Women After a Hypertensive Disorder of Pregnancy.

Importance: Maternal morbidity and mortality are increasing in the United States, most of which occur post partum, with significant racial disparities, particularly associated with hypertensive disorders of pregnancy. Blood pressure trajectory after a hypertensive disorder of pregnancy has not been previously described. Objectives: To describe the blood pressure trajectory in the first 6 weeks post partum after a hypertensive disorder of pregnancy and to evaluate whether blood pressure trajectories differ by self-reported race. Design, Setting, and Participants: This prospective cohort study included deliveries between January 1, 2018, and December 31, 2019. Women with a clinical diagnosis of a hypertensive disorder of pregnancy were enrolled in a postpartum remote blood pressure monitoring program at the time of delivery and were followed up for 6 weeks. Statistical analysis was performed from April 6 to 17, 2020. Main Outcomes and Measures: Mixed-effects regression models were used to display blood pressure trajectories in the first 6 weeks post partum. Results: A total of 1077 women were included (mean [SD] age, 30.2 [5.6] years; 804 of 1017 White [79.1%] and 213 of 1017 Black [20.9%]). Systolic and diastolic blood pressures were found to decrease rapidly in the first 3 weeks post partum, with subsequent stabilization (at 6 days post partum: mean [SD] peak systolic blood pressure, 146 [13] mm Hg; mean [SD] peak diastolic blood pressure, 95 [10] mm Hg; and at 3 weeks post partum: mean [SD] peak systolic blood pressure, 130 [12] mm Hg; mean [SD] peak diastolic blood pressure, 85 [9] mm Hg). A significant difference was seen in blood pressure trajectory by race, with both systolic and diastolic blood pressure decreasing more slowly among Black women compared with White women (mean [SD] peak systolic blood pressure at 1 week post partum: White women, 143 [14] mm Hg vs Black women, 146 [13] mm Hg; P = .01; mean [SD] peak diastolic blood pressure at 1 week post partum: White women, 92 [9] mm Hg vs Black women, 94 [9] mm Hg; P = .02; and mean [SD] peak systolic blood pressure at 3 weeks post partum: White women, 129 [11] mm Hg vs Black women, 136 [15] mm Hg; P < .001; mean [SD] peak diastolic blood pressure at 3 weeks post partum: White women, 84 [8] mm Hg vs Black women, 91 [13] mm Hg; P < .001). At the conclusion of the program, 126 of 185 Black women (68.1%) compared with 393 of 764 White women (51.4%) met the criteria for stage 1 or stage 2 hypertension (P < .001). Conclusions and Relevance: This study found that, in the postpartum period, blood pressure decreased rapidly in the first 3 weeks and subsequently stabilized. The study also found that, compared with White women, Black women had a less rapid decrease in blood pressure, resulting in higher blood pressure by the end of a 6-week program. Given the number of women with persistent hypertension at the conclusion of the program, these findings also appear to support the importance of ongoing postpartum care beyond the first 6 weeks after delivery.

A Postpartum Remote Hypertension Monitoring Protocol Implemented at the Hospital Level.

OBJECTIVE: To evaluate the feasibility, acceptability, and compliance of a remote blood pressure monitoring protocol implemented as a quality improvement measure at the hospital level for management of hypertension in postpartum women after hospital discharge. METHODS: This is an ongoing quality improvement project that included women admitted to the postpartum unit of a single tertiary care hospital. We designed nursing call center-driven blood pressure management and treatment algorithms, which were initiated after hospital discharge until 6 weeks postpartum. Women are eligible to participate if they have a diagnosis of chronic hypertension, superimposed preeclampsia, gestational hypertension, preeclampsia, or postpartum hypertension and have access to a text messaging-enabled smartphone device. After identification by an obstetric care provider, women are enrolled into the program, which is automatically indicated in the electronic medical record. Maternal, obstetric, and sociodemographic data were obtained from the electronic medical record. RESULTS: Between February 2018 and January 2019, we enrolled 499 patients. Here we report on the first 409 enrolled patients. Participants include 168 (41%) with gestational hypertension, 179 (44%) with preeclampsia with no history of chronic hypertension, 49 (12%) with chronic hypertension with superimposed preeclampsia, and 13 (3%) with postpartum preeclampsia. One hundred seventy-one (42%) participants had antihypertensives initiated or titrated through the program. Three hundred forty women (83%) continued the program beyond 3 weeks postpartum, and 360 (88%) attended an in-person 6-week postpartum visit. Two hundred thirty-five out of 250 women who completed a postprogram survey (94%) reported satisfaction with the program. CONCLUSION: In this study, we detail results from an ongoing remote blood pressure monitoring program. We demonstrate high compliance, retention, and patient satisfaction with the program. This is a feasible, scalable remote monitoring program connected to the electronic medical record.

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.

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.

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.

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.

Neonatal outcomes following preterm birth classified according to placental features.

BACKGROUND: Preterm birth has staggering health implications, and yet the causes of most cases are still unknown. Placental features have been understudied as an etiology for preterm birth, and the association between placental pathologic lesions and neonatal outcomes are incompletely understood. OBJECTIVE: We sought to characterize births according to placental pathology and relate these to adverse neonatal outcomes. STUDY DESIGN: We studied 20,091 births (15,710 term and 4381 preterm) with placental evaluations. Births were classified according to the presence or absence of placental lesions consistent with malperfusion (vasculopathy, infarct, advanced villous maturation, perivillous fibrin, fibrin deposition) and intrauterine inflammation/infection (chorioamnionitis, funisitis, vasculitis). Outcomes were gestational week of delivery, birthweight z-score, neonatal respiratory distress syndrome, and intraventricular hemorrhage. RESULTS: Among all preterm births, evidence of placental malperfusion was identified more often than inflammation/infection (50.6% vs 27.3%, P < .0001). Placental malperfusion was associated with reduced fetal growth (adjusted birthweight z-score, -0.83, P < .0001) and lesions of inflammation/infection were associated with earlier delivery (adjusted difference -2.08 weeks, P < .0001) than those with no lesions. When both placental lesions were present, earlier delivery (adjusted difference -2.28 weeks, P < .0001) and reduced fetal growth (adjusted birthweight z-score difference, -0.24, P = .001) were observed more often than when neither lesion was present. Findings were similar when restricted to cases of spontaneous preterm birth. Intraventricular hemorrhage was higher in preterm births with malperfusion lesions than cases with no lesions (7.6% vs 3.4%; odds ratio, 1.98; confidence interval, 1.18-3.32), accounting for gestational age and other covariates. CONCLUSION: Placental pathology provides important insight into subtypes of preterm birth with adverse neonatal outcomes. Co-occurrence of malperfusion and inflammation/infection, especially among spontaneous preterm births, may be a novel pattern of placental injury linked to severe adverse outcomes.

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.

NDRG1 deficiency attenuates fetal growth and the intrauterine response to hypoxic injury.

Intrauterine mammalian development depends on the preservation of placental function. The expression of the protein N-myc downstream-regulated gene 1 (NDRG1) is increased in placentas of human pregnancies affected by fetal growth restriction and in hypoxic primary human trophoblasts, where NDRG1 attenuates cell injury. We sought to assess the function of placental NDRG1 in vivo and tested the hypothesis that NDRG1 deficiency in the mouse embryo impairs placental function and consequently intrauterine growth. We found that Ndrg1 knock-out embryos were growth restricted in comparison to wild-type or heterozygous counterparts. Furthermore, hypoxia reduced the survival of female, but not male, knock-out embryos. Ndrg1 deletion caused significant alterations in placental gene expression, with a marked reduction in transcription of several lipoproteins in the placental labyrinth. These transcriptional changes were associated with reduced fetal:maternal serum cholesterol ratio exclusively in hypoxic female embryos. Collectively, our findings indicate that NDRG1 promotes fetal growth and regulates the metabolic response to intrauterine hypoxic injury in a sexually dichotomous manner.

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.