Concurrent progestogen and cerclage to reduce preterm birth: a multicenter international retrospective cohort.

BACKGROUND: Both progestogens and cerclage are individually effective in preterm birth prevention in high risk pregnancies. However, national and international guidelines cite a lack of data available to comment on the potential benefit of concurrent progestogen therapy after cerclage has been placed. Studies to date have been small with mixed results regarding benefit of concurrent progestogen with cerclage leaving uncertainty regarding best clinical practice. OBJECTIVE: This study aimed to evaluate whether cerclage with progestogen therapy was superior to cerclage alone in the prevention of spontaneous preterm birth in singleton pregnancies. METHODS: This is an international retrospective cohort study of singleton pregnancies, without major anomaly or aneuploidy, and with cerclage placed at 10 different institutions in the United States and Colombia from June 2016 to June 2020. Exclusion criteria were lack of documentation regarding whether progestogen was prescribed, unavailable delivery outcome, and pregnancy termination (spontaneous or induced) before 16 weeks' gestation. The exposure of interest was progestogen use with cerclage placement, which included those who continued to use progestogen or who started progestogen after cerclage. The comparison group consisted of those without progestogen use after cerclage placement, which included those who had no progestogen use during the entire pregnancy or who initiated progestogen and then stopped it after cerclage placement. Progestogen type, cerclage indication, maternal baseline characteristics, and maternal/neonatal outcomes were collected. The primary outcome was spontaneous preterm birth at <37 weeks. The secondary outcomes were spontaneous preterm birth at <34 weeks, gestational age at delivery, and a composite neonatal outcome including ≥1 of the following: perinatal mortality, confirmed sepsis, grade III or IV intraventricular hemorrhage, retinopathy of prematurity, respiratory distress syndrome, and bronchopulmonary dysplasia. There were planned subgroup analyses by cerclage indication, progestogen type (vaginal progesterone vs 17-hydroxyprogesterone caproate), preterm birth history, and site. Continuous variables were compared in adjusted analyses with analysis of covariance, and categorical variables were compared with multivariable logistic regression, adjusting for potential confounders with adjusted odds ratio. A Cox regression survival curve was generated to compare latency to spontaneous delivery, censored after 37 weeks. RESULTS: During the study period, a total of 699 singletons met the inclusion criteria: 561 in the progestogen with cerclage group and 138 with cerclage alone. Baseline characteristics were similar, except the higher likelihood of previous spontaneous preterm birth in the progestogen group (61% vs 41%; P<.001). Within the progestogen group, 52% were on 17-hydroxyprogesterone caproate weekly, 44% on vaginal progesterone daily, and 3% on oral progesterone daily. Progestogen with cerclage was associated with a significantly lower frequency of spontaneous preterm birth <37 weeks (31% vs 39%; adjusted odds ratio, 0.59 [0.39-0.89]; P=.01) and <34 weeks (19% vs 27%; adjusted odds ratio, 0.55 [0.35-0.87]; P=.01), increased latency to spontaneous delivery (hazard ratio for spontaneous preterm birth <37 weeks, 0.66 [0.49-0.90]; P=.009), and lower frequency of perinatal death (7% vs 16%; adjusted odds ratio, 0.37 [0.20-0.67]; P=.001). In planned subgroup analyses, association with reduced odds of preterm birth <37 weeks persisted in those on vaginal progesterone, those without a previous preterm birth, those with ultrasound- or examination-indicated cerclage, those who started progestogen therapy before cerclage, and in sites restricted to the United States. CONCLUSION: Use of progestogen with cerclage was associated with reduced rates of spontaneous preterm birth and early spontaneous preterm birth compared with cerclage alone. Although this study was not sufficiently powered for subgroup analysis, the strength of evidence for benefit appeared greatest for those with ultrasound- or examination-indicated cerclage, and with vaginal progesterone.

Pregnancy as an Opportunity for Hepatitis C Virus Elimination and Eradication.

Since the development of highly effective direct-acting antivirals, the WHO has set a goal of hepatitis C virus (HCV) elimination by 2030. Key to this strategy is increased screening and treatment. Pregnancy and the postpartum period represent a unique time when underserved populations have increased contact with the healthcare system. We propose using antenatal care to maximize case identification, treatment, and prevention. Pregnant individuals are an ideal sentinel population for HCV surveillance. Universal screening in pregnancy can provide population-level data. Once cases are identified, pregnancy presents an opportunity for intervention. Although not currently WHO approved, clinical trials are examining treatment during pregnancy. In the interim, identification of infection during pregnancy allows for optimization of the treatment cascade postpartum. Pregnancy can be used as a time for prevention. Taking advantage of patient engagement and existing infrastructure, pregnancy presents an opportunity to intervene in the fight for HCV eradication.

Aspirin pharmacokinetics and pharmacodynamics through gestation.

BACKGROUND: Low dose aspirin is recommended for prevention of preeclampsia, however there is not consensus on the appropriate dose. Pregnancy specific changes have the potential to impact the pharmacology of aspirin in pregnancy, however there are very limited studies on aspirin pharmacokinetics in pregnancy and none linking pharmacokinetics (PK, drug dose and drug level) to pharmacodynamics (PD, drug dose and physiologic response) in pregnancy. As a result, we do not have a good understanding of the pharmacologic response to aspirin in pregnancy, which has important implications for clinical efficacy. We sought to describe the PK and PD of aspirin through pregnancy and to identify individual covariates that impacted aspirin PK/PD. OBJECTIVE: We sought to describe the PK and PD of aspirin through pregnancy (first and third trimester), to identify covariates that significantly impact aspirin PK and to identify the relationship between aspirin PK and PD. STUDY DESIGN: This is a prospective study of patients at high risk for preeclampsia recommended to take 81 mg aspirin daily. This study involved 3 visits as follows: (1) baseline, first trimester (10-16 weeks of gestation) 6-hour PK visit, done before initiation of aspirin; (2) follow-up 1: 2 to 4 weeks after aspirin initiation; and (3) follow-up 2: third trimester 6-hour PK visit (28-32 weeks of gestation). The following were assessed at each visit: weight or body mass index, platelet function analysis-100 (Siemens), urinary thromboxane B2, serum thromboxane B2, and plasma salicylic acid. The PK visits consisted of blood work done at baseline (predose), administration of 81 mg nonenteric coated aspirin, and then plasma blood level of salicylic acid assessed at 30 minutes and then hourly 1 to 6 hours after dose. Pearson correlation and multivariable regression were used to identify associations between parameters and identify relevant covariates. Log-adjusted values were used for regression analysis. P<.05 was considered statistically significant. RESULTS: Nineteen participants were included with first trimester data, and 16 with third trimester data. There was no statistically significant change in mean PK parameters between the first and third trimester, although there was a trend to lower peak concentration in the third than in the first trimester (P=.08). In multivariable regression, baseline obesity and current body mass index as a continuous measures were negatively associated with log-adjusted peak salicylic acid concentration (-0.28 [-0.46 to -0.11], P=.003 and -0.02 [-0.03 to -0.009], P=.001, respectively) and log-adjusted plasma salicylic acid area under the curve 0 to 6 hours postdose (-0.25 [-0.45 to 0.05], P=.02, -0.04 [-0.07 to -0.01], P=.008 respectively). There was a significant decrease in urinary thromboxane 2 to 4 weeks after aspirin initiation compared with baseline, which correlated with a concomitant increase in platelet function analysis-100 closure time. In multivariable regression model, there was a strong association between plasma salicylic acid concentration (area under the curve 0-6 hours postdose) and urinary thromboxane (B=-3.12 [-5.38 to -1.04], P=.006), and with urinary thromboxane suppression and platelet inhibition, platelet function analysis-100 (-0.23 [-0.31 to -0.14], P<.001). With progressive thromboxane suppression, platelet inhibition (platelet function analysis-100 closure time) increased. Individual comorbidities, including weight, hypertension, and pregestational diabetes (Type I or II), also impacted aspirin response. CONCLUSION: We have demonstrated the relationship between individual factors, plasma concentrations of salicylic acid, thromboxane suppression, and platelet inhibition at a single dose (81 mg) of aspirin taken through pregnancy. Our findings suggest that dose modification of aspirin in pregnancy may help to achieve the optimal response. Our results may be used to facilitate computational modeling to identify optimal dosing, taking into consideration individual factors.

Reduced maternal immunity and vertical transfer of immunity against SARS-CoV-2 variants of concern with COVID-19 exposure or initial vaccination in pregnancy.

Introduction: As the SARS-CoV-2 pandemic continues to evolve, we face new variants of concern with a concurrent decline in vaccine booster uptake. We aimed to evaluate the difference in immunity gained from the original SARS-CoV-2 mRNA vaccine series in pregnancy versus SARS-CoV-2 exposure during pregnancy against recent variants of concern. Study Design: This is a retrospective analysis of previously collected samples from 192 patients who delivered between February 2021 and August 2021. Participants were categorized as 1) COVID vaccine: mRNA vaccine in pregnancy, 2) COVID-exposed, and 3) controls. The primary outcome was neutralizing capacity against wild-type, Delta, and Omicron-B1 between cohorts. Secondary outcomes include a comparison of cord-blood ID50 as well as the efficiency of vertical transfer, measured by cord-blood:maternal blood ID50 for each variant. Results: Pregnant women with COVID-19 vaccination had a greater spike in IgG titers compared to both those with COVID-19 disease exposure and controls. Both COVID exposure and vaccination resulted in immunity against Delta, but only COVID vaccination resulted in significantly greater Omicron ID-50 versus controls. The neutralizing capacity of serum from newborns was lower than that of their mothers, with COVID-vaccination demonstrating higher cord-blood ID50 vs wildtype and Delta variants compared to control or COVID-exposed, but neither COVID-exposure nor vaccination demonstrated significantly higher Omicron ID50 in cord-blood compared to controls. There was a 0.20 (0.07-0.33, p=0.004) and 0.12 (0.0-0.24, p=0.05) increase in cord-blood:maternal blood ID50 with COVID vaccination compared to COVID-19 exposure for wild-type and Delta respectively. In pair-wise comparison, vertical transfer of neutralization capacity (cord-blood:maternal blood ID50) was greatest for wild-type and progressively reduced for Delta and Omicron ID50. Conclusion: Pregnant patients with either an initial mRNA vaccination series or COVID-exposure demonstrated reduced immunity against newer variants compared to wild-type as has been reported for non-pregnant individuals; however, the COVID-vaccination series afforded greater cross-variant immunity to pregnant women, specifically against Omicron, than COVID-disease. Vertical transfer of immunity is greater in those with COVID vaccination vs COVID disease exposure but is reduced with progressive variants. Our results reinforce the importance of bivalent booster vaccination in pregnancy for both maternal and infant protection and also provide a rationale for receiving updated vaccines as they become available.

Vaginal progesterone for the prevention of recurrent spontaneous preterm birth.

After the United States Food and Drug Administration pulled 17-alpha hydroxyprogesterone caproate from the market for its use in prevention of recurrent spontaneous preterm birth, national societies have had mixed recommendations regarding the management of patients with a singleton pregnancy and previous spontaneous preterm birth. Herein we highlight the randomized trial data and translational evidence supporting the use of vaginal progesterone for prevention of recurrent spontaneous preterm birth in singleton pregnancies. Prophylactic vaginal progesterone starting at 16 weeks and 0 days every night should be offered to patients with singletons and previous singleton spontaneous preterm birth regardless of cervical length, and continued along with placement of cerclage if a transvaginal ultrasound cervical length ≤25 mm is detected at <24 weeks.

SARS-CoV-2 Covid-19 Infection During Pregnancy and Differential DNA Methylation in Human Cord Blood Cells From Term Neonates.

Background: The global pandemic of coronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). About 18.4% of total Covid-19 cases were reported in children. Even though vertical transmission from mother to infant is likely to occur at a low rate, exposure to COVID-19 during fetal life may alter DNA methylation patterns with potential long-term effects. Objective: To determine if COVID-19 infection during pregnancy alters the DNA methylation patterns in umbilical cord blood cells from term infants and to identify potential pathways and genes affected by exposure to COVID-19 infection. Methods: Umbilical cord blood was collected from 8 infants exposed to COVID-19 during pregnancy and 8 control infants with no COVID-19 exposure. Genomic DNA was isolated from umbilical cord blood cells and genome-wide DNA methylation was performed using Illumina Methylation EPIC Array. Results: 119 differentially methylated loci were identified at the FDR level of 0.20 (64 hypermethylated loci and 55 hypomethylated loci) in umbilical cord blood cells of COVID-19 exposed neonates compared to the control group. Important canonical pathways identified by Ingenuity Pathway Analysis (IPA) were related to stress response (corticotropin releasing hormone signaling, glucocorticoid receptor signaling, and oxytocin in brain signaling pathway), and cardiovascular disease and development (nitric oxide signaling in the cardiovascular system, apelin cardiomyocyte signaling pathways, factors promoting cardiogenesis, and renin-angiotensin signaling). The genes affected by the differential methylations were associated with cardiac, renal, hepatic, neurological diseases, developmental and immunological disorders. Conclusions: COVID-19 induces differential DNA methylation in umbilical cord blood cells. The differentially methylated genes may contribute to hepatic, renal, cardiac, developmental and immunological disorders in offspring born to mothers with COVID-19 infection during pregnancy, and their developmental regulation.

Impact of telehealth implementation on diagnosis of hypertensive disorders of pregnancy.

BACKGROUND: COVID-19 caused a rapid integration of telehealth into prenatal care. This raises questions about the ability to screen for hypertensive disorders of pregnancy when caring for patients remotely. OBJECTIVE: This study aimed to assess the effect of telehealth adaptation on the timing and severity of diagnosis of hypertensive disorders of pregnancy. STUDY DESIGN: This was a retrospective study of patients with hypertensive disorders of pregnancy who delivered from April 2019 to October 2019 (before the pandemic) and April 2020 to October 2020 (during the pandemic) at 1 urban tertiary care center. The primary outcome was mean gestational age at diagnosis of a hypertensive disorder of pregnancy. The secondary outcomes included severity of diagnosis, both initially and at the time of delivery. The results were adjusted for baseline characteristic difference at P<.10, using multivariable logistic regression and analysis of covariance, as appropriate. The sample size was calculated based on a previous cohort study of patients who developed preeclampsia, with a mean gestational age at delivery of 36.3 weeks and a standard deviation of 2.8 weeks. A sample size of 124 patients would be needed per group to detect a gestational age difference of 1 week with 80% power and a 95% confidence interval. RESULTS: Overall, 498 patients were included, with 231 from 2019 and 267 from 2020. Of note, 17.1% of patients had preeclampsia with severe features initially, and 29.3% of patients met the criteria at delivery. In 2020, 80.5% of patients used telehealth (vs 0.9% of patients in 2019), doing so for a mean of 29.0% of prenatal appointments. Unadjusted and adjusted analyses showed no significant difference in gestational age at diagnosis or diagnosis severity between cohorts. In the adjusted analysis, cohort year was not significantly associated with severity of initial diagnosis (adjusted odds ratio, 0.86; 95% confidence interval, 0.53-1.39; P=.53) or severity of diagnosis at delivery (adjusted odds ratio, 0.97; 95% confidence interval, 0.64-1.46; P=.87). However, Black race was significantly associated with increased risk of having severe preeclampsia at initial diagnosis (adjusted odds ratio, 1.70; 95% confidence interval, 1.01-2.85; P=.046). In addition, Black race (adjusted odds ratio, 2.62; 95% confidence interval, 1.60-4.28; P<.001), Hispanic ethnicity (adjusted odds ratio for non-Hispanic, 0.40; 95% confidence interval, 0.19-0.82; P=.01), and initial body mass index (adjusted odds ratio, 1.04; 95% confidence interval, 1.01-1.06; P=.005) were significantly associated with a diagnosis of severe preeclampsia at delivery. CONCLUSION: The adaptation of telehealth was not associated with delays in the diagnosis of hypertensive disorders of pregnancy or with increased severity of diagnoses.

Obstetric Indications for Progestin Therapy.

Specifically, meta-analyses of randomized trials demonstrate that vaginal progesterone reduces the risk of preterm birth in selected high-risk singleton pregnancies. 17-OHPC may also reduce the risk of recurrent preterm birth in singletons. Finally, one trial suggests that vaginal progesterone may also be beneficial in improving live birth rates in singletons with prior miscarriages and early pregnancy bleeding.

Eligibility, Utilization, and Effectiveness of 17-Alpha Hydroxyprogesterone Caproate in a Statewide Population-Based Cohort of Medicaid Enrollees.

OBJECTIVE: The primary objective was to estimate the initiation and adherence rates of 17 α-hydroxyprogesterone caproate (17OHPC) among eligible mothers in a statewide population-based cohort of Medicaid enrollees. The secondary objectives were to (1) determine the association of maternal sociodemographic and clinical characteristics with 17OHPC utilization and (2) assess the real-world effectiveness of 17OHPC on recurrent preterm birth prevention and admission to neonatal intensive care unit (NICU). STUDY DESIGN: This is a retrospective cohort study using a linked, longitudinal administrative dataset of birth certificates and medical assistance claims. Medicaid-enrolled mothers in Pennsylvania were included in this study if they had at least one singleton live birth from 2014 to 2016 following at least one spontaneous preterm birth. Maternal Medicaid claims were used to ascertain the use of 17OHPC from various manufacturers, including compounded formulations. Propensity score matching was used to create a covariate balance between 17OHPC treatment and comparison groups. RESULTS: We identified 4,781 Medicaid-covered 17OHPC-eligible pregnancies from 2014 to 2016 in Pennsylvania, 3.4% of all Medicaid-covered singleton live births. The population-based initiation rate was 28.5% among eligible pregnancies. Among initiators, 50% received ≥16 doses as recommended, while 10% received a single dose only. The severity of previous spontaneous preterm birth was the strongest predictor for the initiation and adherence of 17OHPC. In the matched treatment (n = 1,210) and comparison groups (n = 1,210), we found no evidence of 17OHPC effectiveness. The risks of recurrent preterm birth (relative risk [RR] 1.10, 95% confidence interval [CI] 0.97-1.24) and births admitted to NICU (RR 1.00, 95% CI 0.84-1.18) were similar in treated and comparison mothers. CONCLUSION: The 17OHPC-eligible population represented 3.4% of singleton live births. Less than one-third of eligible mothers initiated treatment. Among initiators, 50% were treatment adherent. We found no difference in the risk of recurrent preterm birth or admission to NICU between treatment and comparison groups. KEY POINTS: · About 3.4% of singleton live births were eligible for 17OHPC.. · About 30% of eligible mothers initiated treatment.. · We found no association of 17OHPC with recurrent preterm birth..

Proposed staging criteria for sonographic and physical exam for cervical changes at <24 weeks gestation to predict preterm birth.

Asymptomatic cervical changes, such as cervical length shortening and dilation, which often occur before spontaneous preterm birth, have been described well in singleton pregnancies with or without history of preterm birth. The current screening strategies available to identify patients at increased risk of spontaneous preterm birth include use of transvaginal ultrasound for cervical length assessment and for detection of a short cervical length (≤25 mm) before 24 weeks of gestation. Whether an additional evaluation of the cervix (ie, via speculum or manual exam) is indicated is often pondered by clinicians and may depend on how short the cervical length is and if there is a history of preterm birth. Based on expert opinion, we developed a novel staging system of asymptomatic cervical changes including the following: cervical length measurement, cervical and membrane appearance on speculum exam, and cervical dilation by manual exam. This staging system, if proven accurate, may aid in standardizing definitions for purposes of patient prognosis, evaluation of intervention efficacy, and clinical management.

Platelet protease activated receptor 4 (PAR 4) receptor genotype is associated with an increased risk of preterm birth.

BACKGROUND: Platelet protease activated receptor-4 (PAR4) Thr120 is a common genetic variant associated with increased platelet activity. Increased platelet activity is implicated in the pathogenesis of preeclampsia and preterm birth. OBJECTIVE: Compare the rate of preeclampsia and preterm birth in pregnant individuals homozygous for PAR4 Thr120 variant vs not. STUDY DESIGN: This is a prospective cohort study of patients who delivered November 2020-July 2021. Maternal blood collected on admission for PAR4 genotyping. The primary outcome was the rate of preeclampsia/gestational hypertension in those with Thr/Thr genotype compared with Ala/Thr or Ala/Ala. Secondary outcomes included rates of preterm birth and placental pathology. RESULTS: Three hundred and twenty singletons were included and 52 (16.3%) were PAR4 Thr/Thr. Those PAR4 Thr/Thr were more likely to be Black (67.3% vs 29.5%, p < .001), younger (28 ± 6 vs 31 ± 6, p = .004), and have higher body mass index (35.2 ± 6.8 vs 33.1 ± 7.4, p = .047). There was no difference in preeclampsia/gestational hypertension (19.2% vs 22.8%, p = .705). Those Thr/Thr had a significantly higher rate of preterm birth (15.4% vs 3.7%, adjusted odds ratio [aOR] 4.04 [1.47-11.10], p = .007), indicated preterm birth because of fetal growth restriction or preeclampsia (5.8% vs 0.4%, aOR 10.03 [1.48-67.87], p = .02), spontaneous preterm birth (7.7% vs 2.2%, aOR 4.81 [1.27-18.27], p = .02), and placental intervillous thrombosis (18.5% vs 7.9%, aOR 4.12 [1.14-14.92], p = .03). CONCLUSION: Platelet receptor PAR4 Thr120 is a common variant associated with an increased risk of placental vascular pathology and preterm birth in homozygous individuals. Although a cohort study cannot establish causation, this strong association warrants further exploration.

Cervical Length Ultrasound for the Evaluation of Preterm Labor: A Survey of National Use and Review of Evidence.

OBJECTIVE: The objective of this study was to survey national utilization of cervical length (CL) ultrasound on labor and delivery (L&D) for the evaluation of preterm labor (PTL) and identify provider attitudes and barriers to utilization. STUDY DESIGN: Survey was emailed to Obstetrics and Gynecology Residency and Maternal-Fetal Medicine Fellowship program and advertised via links on obstetric-related Facebook interest groups. The survey was open from August 4, 2020 to January 4, 2021. Characteristics between respondents who did and did not report the use of CL ultrasound for PTL evaluation were compared with chi-square analysis. RESULTS: There were 214 respondents across 42 states. One hundred and thirty-four respondents (63%) reported any use of CL in the evaluation of PTL and eighty (37%) denied it. There was a significant difference in practice location, practice type, delivery volume, and region between those who did and did not utilize CL ultrasound on L&D. Those who did use CL ultrasound were more likely to report no barriers to use (40 vs. 4%, p < 0.001). The most common barriers involved the availability of transvaginal ultrasound (31%), sterilization of transvaginal ultrasound probe (32%), limited availability of persons able to perform/interpret CL imaging (38%). Nineteen percent believed CL ultrasound had little/no utility in clinical practice. Those who did not use CL ultrasound in the evaluation of PTL were significantly more likely to report the feeling that there was little/no utility of CL ultrasound in clinical practice (37 vs. 7%, p < 0.001) and to report transvaginal ultrasound availability as barriers to use (63 vs. 12%, p < 0.001). CONCLUSION: CL ultrasound is used nationally in PTL evaluation. However, significant barriers limit widespread adoption. These barriers can be addressed through the dissemination of information and practice guidelines, addition of CL ultrasound education in residency training and through CME opportunities after training, and providing support/resources/access for those looking to add this tool to their practice environment. KEY POINTS: · In a national survey, 63% of obstetricians endorsed any use of cervical length (CL) ultrasound for preterm labor evaluation on labor and delivery.. · The most common barriers involved the availability of transvaginal ultrasound (31%), sterilization of transvaginal ultrasound probe (32%), limited availability of persons able to perform/interpret CL imaging (38%).. · Those who did not use CL ultrasound in the evaluation of PTL were significantly more likely to report the feeling that there was little/no utility of CL ultrasound in clinical practice and to report transvaginal ultrasound availability as barriers to utilization.. · Barriers to utilization of CL ultrasound for preterm labor evaluation can be addressed through practice guidelines, ultrasound education, and support for equipment/training necessary for use..

COVID-19 Infection During Pregnancy Induces Differential Gene Expression in Human Cord Blood Cells From Term Neonates.

Background: The COVID-19 pandemic continues worldwide with fluctuating case numbers in the United States. This pandemic has affected every segment of the population with more recent hospitalizations in the pediatric population. Vertical transmission of COVID-19 is uncommon, but reports show that there are thrombotic, vascular, and inflammatory changes in the placenta to which neonates are prenatally exposed. Individuals exposed in utero to influenza during the 1918 pandemic had increased risk for heart disease, kidney disease, diabetes, stomach disease and hypertension. Early exposure of COVID-19 during fetal life may lead to altered gene expression with potential long-term consequences. Objective: To determine if gene expression is altered in cord blood cells from term neonates who were exposed to COVID-19 during pregnancy and to identify potential gene pathways impacted by maternal COVID-19. Methods: Cord blood was collected from 16 term neonates (8 exposed to COVID-19 during pregnancy and 8 controls without exposure to COVID-19). Genome-wide gene expression screening was performed using Human Clariom S gene chips on total RNA extracted from cord blood cells. Results: We identified 510 differentially expressed genes (374 genes up-regulated, 136 genes down-regulated, fold change ≥1.5, p-value ≤ 0.05) in cord blood cells associated with exposure to COVID-19 during pregnancy. Ingenuity Pathway Analysis identified important canonical pathways associated with diseases such as cardiovascular disease, hematological disease, embryonic cancer and cellular development. Tox functions related to cardiotoxicity, hepatotoxicity and nephrotoxicity were also altered after exposure to COVID-19 during pregnancy. Conclusions: Exposure to COVID-19 during pregnancy induces differential gene expression in cord blood cells. The differentially expressed genes may potentially contribute to cardiac, hepatic, renal and immunological disorders in offspring exposed to COVID-19 during pregnancy. These findings lead to a further understanding of the effects of COVID-19 exposure at an early stage of life and its potential long-term consequences as well as therapeutic targets.

Vaginal progesterone compared with intramuscular 17-alpha-hydroxyprogesterone caproate for prevention of recurrent preterm birth in singleton gestations: a systematic review and meta-analysis.

OBJECTIVE: Randomized trials have found benefits of both vaginal progesterone and 17-alpha-hydroxyprogesterone caproate in the prevention of recurrent preterm birth. A previous meta-analysis directly comparing the two was limited by low-quality evidence, and national and international society guidelines remain conflicting regarding progestin formulation recommended for prevention of recurrent preterm birth. The aim of this updated systematic review with meta-analysis was to evaluate the efficacy of vaginal progesterone compared with 17-alpha-hydroxyprogesterone caproate in the prevention of spontaneous preterm birth in patients with singleton gestations and previous spontaneous preterm birth. DATA SOURCES: Searches were performed in MEDLINE, Ovid, Scopus, ClinicalTrials.gov, the International Prospective Register of Systematic Reviews (PROSPERO), SciELO, Embase, and the Cochrane Central Register of Controlled Trials (CENTRAL) with the use of a combination of keywords and text words related to "preterm birth," "preterm delivery," "singleton," "cervical length," "progesterone," "progestogens," "vaginal," "17-alpha-hydroxy-progesterone caproate," and "intramuscular" from inception of each database to September 2021. No restrictions for language or geographic location were applied. STUDY ELIGIBILITY CRITERIA: We included all randomized controlled trials of asymptomatic singleton gestations with previous spontaneous preterm birth that were randomized to prophylactic treatment with either vaginal progesterone (ie, intervention group) or intramuscular 17-alpha-hydroxyprogesterone caproate (ie, comparison group). Post hoc sensitivity analysis was performed for studies with low risk of bias and studies with protocol registration. METHODS: The primary outcome was preterm birth <34 weeks' gestation. The summary measures were reported as relative risks with 95% confidence intervals. RESULTS: Seven randomized controlled trials including 1910 patients were included in the meta-analysis. Patients who received vaginal progesterone had a significantly lower rate of preterm birth at <34 weeks (14.7% vs 19.9%; relative risk, 0.74; 95% confidence interval, 0.57-0.96), preterm birth at <37 weeks (36.0% vs 46.6%; relative risk, 0.76; 95% confidence interval, 0.69-0.85), and preterm birth at <32 weeks of gestation (7.9% vs 13.6%; relative risk, 0.58; 95% confidence interval, 0.39-0.86), compared with women who received intramuscular 17-alpha-hydroxyprogesterone caproate. There were no significant differences in the rate of preterm birth at <28 weeks' gestation. Adverse drug reactions were significantly lower in the vaginal progesterone group than in the 17-alpha-hydroxyprogesterone caproate group (15.6% vs 22.2%; relative risk, 0.71; 95% confidence interval, 0.54-0.92). Perinatal mortality was lower in the vaginal progesterone group than in the 17-alpha-hydroxyprogesterone caproate group (2.2% vs 4.4%; relative risk, 0.51; 95% confidence interval, 0.25-1.01). In sensitivity analysis including trials rated with at least 4 Cochrane tools as of "low risk of bias," 4 trials were included (N=575), and there was no longer a significant difference in preterm birth at <34 weeks' gestation between vaginal progesterone and 17-alpha-hydroxyprogesterone caproate (12.2% vs 13.9%; relative risk, 0.87; 95% confidence interval, 0.57-1.32). CONCLUSION: Overall, vaginal progesterone was superior to 17-alpha-hydroxyprogesterone caproate in the prevention of preterm birth at <34 weeks' gestation in singleton pregnancies with previous spontaneous preterm birth. Although sensitivity analysis of high-fidelity studies showed the same trend, findings were no longer statistically significant.

Vaginal progesterone vs intramuscular 17-hydroxyprogesterone caproate for prevention of recurrent preterm birth: a randomized controlled trial.

BACKGROUND: Preterm birth is the leading cause of neonatal morbidity and mortality, and previous preterm birth is one of the strongest risk factors for preterm birth. National and international obstetrical societies have different recommendations regarding progesterone formulation for the prevention of recurrent preterm birth. OBJECTIVE: This study aimed to determine whether vaginal progesterone is superior to 17-hydroxyprogesterone caproate in the prevention of recurrent preterm birth in patients with singleton pregnancies who had a previous spontaneous preterm birth. STUDY DESIGN: This was an open-label multicenter pragmatic randomized controlled trial at 5 US centers of patients with singleton pregnancies at <24 weeks of gestation who had a previous spontaneous preterm birth randomized 1:1 to either 200 mg vaginal progesterone suppository nightly or 250 mg intramuscular 17-hydroxyprogesterone caproate weekly from 16 to 36 weeks of gestation. Based on the estimated recurrent preterm birth rate of 36% with 17-hydroxyprogesterone caproate, 95 participants were needed in each arm to detect a 50% reduction in preterm birth rate with vaginal progesterone, with 80% power and 2-sided alpha of 0.05. The primary outcome was preterm birth at <37 weeks of gestation. Prespecified secondary outcomes included preterm birth at <34 and <28 weeks of gestation, mean gestational age at delivery, neonatal morbidity and mortality, and measures of adherence. Analysis was by intention to treat. The chi-square test and Student t test were used as appropriate. P<.05 was considered significant. RESULTS: Overall, 205 participants were randomized; 94 participants in the vaginal progesterone group and 94 participants in 17-hydroxyprogesterone caproate group were included. Although gestational age at enrollment was similar, those assigned to vaginal progesterone initiated therapy earlier (16.9±1.4 vs 17.8±2.5 weeks; P=.001). Overall continuation of assigned formulation until delivery was similar (73% vs 69%; P=.61). There was no significant difference in preterm birth at <37 (31% vs 38%; P=.28; relative risk, 0.81 [95% confidence interval, 0.54-1.20]), <34 (9.6% vs 14.9%; P=.26; relative risk, 0.64 [95% confidence interval, 0.29-1.41]), or <28 (1.1% vs 4.3%; P=.37; relative risk, 0.25 [95% confidence interval, 0.03-2.20]) weeks of gestation. Participants in the vaginal progesterone group had a later mean gestational age at delivery than participants in the 17-hydroxyprogesterone caproate group (37.36±2.72 vs 36.34±4.10 weeks; mean difference, 1.02 [95% confidence interval, 0.01-2.01]; P=.047). CONCLUSION: Vaginal progesterone did not reduce the risk of recurrent preterm birth by 50% compared with 17-OHPC; however, vaginal progesterone may lead to increased latency to delivery. This trial was underpowered to detect a smaller, but still clinically significant, difference in the efficacy of preterm birth prevention. Patient factors that impact adherence and ability to obtain medication in a timely fashion should be included in counseling on progesterone selection.

Is Maternal Methadone Dose Associated with the Severity of Neonatal Abstinence Syndrome?

OBJECTIVE: The aim of the study is to assess the correlation between maternal methadone dose and severity of neonatal abstinence syndrome (NAS) in infants that required pharmacological treatment for NAS. STUDY DESIGN: This is a retrospective analysis of 574 infants ≥35 weeks' gestation exposed to methadone in utero, born between August 2006 and May 2018, and who required pharmacological therapy for NAS. Indicators of NAS severity (duration of morphine treatment, maximum morphine dose, use of phenobarbital, and length of hospitalization) were compared between infants exposed to high (≥200 mg), intermediate (100-199 mg), and low doses (<100 mg) of methadone. Logistic and linear regression models were used to adjust for the covariates. RESULTS: Median (interquartile range) duration of medical treatment with morphine was higher in infants exposed to higher doses of methadone (low dose 23 [14-37] days, intermediate dose 31 [18-45] days, and high dose 35 [20-48] days, p < 0.001). Higher methadone doses were also predictive of longer duration of hospitalization, higher maximum morphine dose, and increased likelihood of treatment with phenobarbital. The association between maternal methadone dose and the severity of NAS persisted in multivariable regression models. CONCLUSION: Infants exposed to higher methadone doses displayed more severe NAS, as indicated by longer durations of treatment, higher maximum morphine dose, longer duration of hospitalization, and increased likelihood of phenobarbital use. KEY POINTS: · Methadone maintenance therapy is used during pregnancy to control maternal withdrawal symptoms.. · Relationship between maternal methadone dose and severity of NAS is not adequately investigated.. · Increased doses of methadone during pregnancy correlate with increased severity of NAS..