Lethal multiple pterygium syndrome, large cystic hygroma, and cleft palate: Rare and severe fetal presentations of RYR1- and NEB-related congenital myopathies.

Congenital myopathies are a genetically heterogeneous group of neuromuscular disorders that commonly present with congenital hypotonia and weakness but can also present broadly. The most severe presentation is neonatal with arthrogryposis and, rarely, fetal akinesia and pterygia, features also seen in lethal multiple pterygium syndrome (LMPS). We describe two fetuses with similar phenotype, including hydrops fetalis, large cystic hygromas, bilateral talipes, and fetal akinesia in the second trimester. Genetic diagnoses were made using exome sequencing. Both fetuses had a severe form of congenital myopathy. In the first fetus, we identified two novel compound heterozygous likely pathogenic variants consistent with autosomal recessive RYR1-related congenital myopathy (congenital myopathy 1B). In the second fetus, we identified two likely pathogenic variants, one of which is novel, likely in trans consistent with a diagnosis of autosomal recessive NEB-related congenital myopathy. Reaching a genetic diagnosis for these fetuses allowed the families to receive accurate genetic counseling for future pregnancies. These fetuses highlight the genetic and phenotypic heterogeneity of LMPS, and support a broad approach to genetic testing.

Absence of Ductus Venosus: A Comparison of 2 Distinctive Fetal Autopsy Cases and Embryologic Perspectives.

In fetal circulation, oxygenated blood from the placenta flows through the umbilical vein into the ductus venosus (DV), then enters the inferior vena cava, and subsequently reaches the right atrium of the heart. The DV serves as a shunt, allowing this oxygen-rich blood to bypass the liver. The absence of the DV (ADV), also known as agenesis of the DV, is a rare congenital anomaly. Without a DV, blood from the umbilical vein must follow alternative routes to the heart. In ADV cases, blood from the umbilical vein must follow 1 of 2 primary drainage patterns: either an extrahepatic shunt or an intrahepatic shunt. This report details the antenatal ultrasound and postmortem findings of 2 fetuses diagnosed with ADV by prenatal imaging studies. The first case involved a fetus with a persistent right umbilical vein connected directly to the suprahepatic IVC, accompanied by early obliteration of the left umbilical vein and true agenesis of the DV. This fetus also had additional congenital anomalies. In contrast, the second case involved a fetus with a normal left umbilical vein that entered the liver. However, despite an ultrasound diagnosis of "absence" of the DV, a DV was present, though markedly hypoplastic and probably minimally functional or non-functional. In this case, blood from the umbilical vein likely followed an alternate intrahepatic route through the portal and hepatic veins, before reaching the heart (intrahepatic shunt). These contrasting cases emphasize the heterogeneity of vascular anomalies and embryologic origins captured by the term "ADV." Additionally, the terminology of "absence" or "agenesis" may be misleading in some purported ADV cases. Specifically, in the second case, the DV was not absent; it was markedly hypoplastic instead. This also appears to be the first reported case of a hypoplastic DV in a fetus. Both cases underscore the importance of effective collaboration and clear communication between maternal-fetal medicine specialists and pathologists.

Thiopurine Exposure During Pregnancy is Not Associated With Anemia in Infants Born to Mothers With IBD.

Background: Thiopurines are commonly used to treat inflammatory bowel disease (IBD). Thiopurines are considered safe throughout pregnancy. However, a published study suggested the risk of neonatal anemia was increased if exposed to thiopurines in utero. This prospective cohort study aimed to determine if there is an increased risk of cytopenia among infants born to pregnant people with IBD, exposed or unexposed to thiopurines, compared to infants born to those without IBD. Methods: Pregnant IBD patients, with and without thiopurine exposure, and one cohort of control individuals were recruited over a 5-year period. Consenting individuals completed a questionnaire and infants had a complete blood cell count at the newborn heel prick. Anemia was defined as hemoglobin (Hb) < 140g/L. Descriptive statistics were used to characterize the study population. Fisher exact tests were used to examine differences in outcomes between groups, a P-value of < 0.05 was deemed significant. Results: Three cohorts were recruited: 19 IBD patients on thiopurines, 50 IBD patients not on thiopurines, and 37 controls (total of 106). Neonatal median Hb was not different with 177g/L (IQR 38g/L) for the IBD thiopurine group, 180.5g/L (IQR 40g/L) for the IBD non-thiopurine group, and 181g/L (IQR 37g/L) for the controls. Nineteen infants (18%) were cytopenic with 12 (11%) anemic, 6 (5.6%) thrombocytopenic, and 1 (0.94%) lymphopenic. Thiopurine exposure was only in one, mildly anemic, infant. Conclusions: These findings further support physicians and IBD patients contemplating pregnancy that current guidelines recommending thiopurine adherence do not lead to increased perinatal risk of anemia or cytopenia.

Congenital SARS-CoV-2 Infection in Two Neonates with Confirmation by Viral Culture of the Placenta in One Case.

Congenital infections with SARS-CoV-2 are uncommon. We describe two confirmed congenital SARS-CoV-2 infections using descriptive, epidemiologic and standard laboratory methods and in one case, viral culture. Clinical data were obtained from health records. Nasopharyngeal (NP) specimens, cord blood and placentas when available were tested by reverse transcriptase real-time PCR (RT-PCR). Electron microscopy and histopathological examination with immunostaining for SARS-CoV-2 was conducted on the placentas. For Case 1, placenta, umbilical cord, and cord blood were cultured for SARS-CoV-2 on Vero cells. This neonate was born at 30 weeks, 2 days gestation by vaginal delivery. RT-PCR tests were positive for SARS-CoV-2 from NP swabs and cord blood; NP swab from the mother and placental tissue were positive for SARS-CoV-2. Placental tissue yielded viral plaques with typical morphology for SARS-CoV-2 at 2.8 × 102 pfu/mL confirmed by anti-spike protein immunostaining. Placental examination revealed chronic histiocytic intervillositis with trophoblast necrosis and perivillous fibrin deposition in a subchorionic distribution. Case 2 was born at 36 weeks, 4 days gestation. RT-PCR tests from the mother and infant were all positive for SARS-CoV-2, but placental pathology was normal. Case 1 may be the first described congenital case with SARS-CoV-2 cultivated directly from placental tissue.

The Implementation of Preeclampsia Screening and Prevention (IMPRESS) Study.

BACKGROUND: Preeclampsia affects between 2% and 5% of pregnancies and is one of the leading causes of perinatal morbidity and mortality worldwide. Despite strong evidence that the combination of systematic preeclampsia screening based on the Fetal Medicine Foundation preeclampsia risk calculation algorithm with treatment of high-risk patients with low-dose aspirin reduces the incidence of preterm preeclampsia more than currently used risk-factor-based screening, real-world implementation studies have not yet been done in Canada. OBJECTIVE: This study aimed to assess the operational feasibility of implementing first-trimester screening and prevention of preterm preeclampsia (<37 weeks) alongside a publicly funded first-trimester combined screening program for aneuploidies. STUDY DESIGN: This was a prospective implementation study. Consecutive pregnant patients referred for first-trimester combined screening (11-13+6 weeks) were offered screening for preeclampsia based on the Fetal Medicine Foundation algorithm concomitantly with their aneuploidy screen. Consenting participants were screened using maternal risk factors, mean arterial pressure, uterine artery Doppler pulsatility index, pregnancy-associated plasma protein-A, and placental growth factor. Risk for preterm preeclampsia (<37 weeks) was calculated using the Fetal Medicine Foundation algorithm, and individuals with a risk score ≥1 per 100 were recommended to use aspirin (162 mg once daily at bedtime, <16-36 weeks). Implementation metrics assessed included: acceptability, operational impact, proportion of aspirin initiation, quality and safety measures, and screen performance. RESULTS: Between December 1, 2020 and April 23, 2021, 1124 patients consented to preeclampsia screening (98.3% uptake), and 92 (8.2%) screened positive. Appointments for patients receiving first-trimester combined screening aneuploidy and preeclampsia screening averaged 6 minutes longer than first-trimester combined screening alone, and adding uterine artery Doppler pulsatility index averaged 2 minutes. Of the 92 patients who screened as high-risk for preeclampsia, 72 (78.3%) were successfully contacted before 16 weeks' gestation. Of these, 62 (86.1%) initiated aspirin, and 10 (13.9%) did not. Performance audit identified a consistent negative bias with mean arterial pressure measurements (median multiple of the median <1 in 10%); other variables were satisfactory. There were 7 cases of preterm preeclampsia (0.69%): 5 and 2 in the high- and low-risk groups, respectively. Screening detected 5 of 7 (71.4 %) preterm preeclampsia cases, with improved performance after adjustment for aspirin treatment effect. CONCLUSION: This study confirms the operational feasibility of implementing an evidence-based preeclampsia screening and prevention program in a publicly funded Canadian setting. This will facilitate implementation into clinical service and the scaling up of this program at a regional and provincial level.

Comparing adverse neonatal and maternal outcomes of chlamydia, gonorrhoea, and syphilis infections and co-infections in pregnancy.

BACKGROUND: While maternal sexually transmitted infections (STIs) during pregnancy have been extensively studied, fewer studies have directly compared the associations of different infections and co-infections or investigated the association between STIs in pregnancy and maternal outcomes. OBJECTIVES: We examine associations between STIs and co-infections in pregnancy on risks of adverse neonatal and maternal outcomes. METHODS: Data from the 2019 US natality files (n = 3,747,882) were used to assess the associations between STIs in pregnancy on adverse pregnancy outcomes. Five mutually exclusive STI groups were examined: a single chlamydia, syphilis, or gonorrhoeal infection, chlamydia and gonorrhoea co-infection, and syphilis co-infection (with chlamydia, gonorrhoea, or both). Demographic and obstetric characteristics among each STI group were compared to those of an uninfected comparison group. Prevalence ratios (PR) of adverse neonatal outcomes (preterm birth, small for gestational age [SGA] births, and 5-min APGAR (Appearance, Pulse, Grimace, Activity, and Respiration) score < 7) and maternal outcomes (gestational hypertension) by STI status were examined using log-binomial regression. RESULTS: Increased prevalence of preterm birth was apparent, especially among those with a syphilis infection (PR 1.19, 95% confidence intreval [CI] 1.10, 1.30 for single infections and PR 1.31, 95% CI 1.10, 1.57 for co-infections). All STI groups, except gonorrhoea and chlamydia co-infections, were associated with an increased prevalence of gestational hypertension, with the strongest association among those with syphilis co-infections (PR 1.41, 95% CI 1.13, 1.76). CONCLUSIONS: An increased prevalence was of preterm birth and low APGAR scores were associated with syphilis infection. Increased prevalence of GH among those with STIs warrants further investigation into the relationships and corresponding mechanisms of STIs in pregnancy on adverse maternal outcomes.

Association of SARS-CoV-2 Infection During Pregnancy With Maternal and Perinatal Outcomes.

Importance: There are limited high-quality, population-level data about the effect of SARS-CoV-2 infection on pregnancy using contemporaneous comparator cohorts. Objectives: To describe maternal and perinatal outcomes associated with SARS-CoV-2 infection in pregnancy and to assess variables associated with severe disease in the pregnant population. Design, Setting, and Participants: CANCOVID-Preg is an observational surveillance program for SARS-CoV-2-affected pregnancies in Canada. This analysis presents exploratory, population-level data from 6 Canadian provinces for the period of March 1, 2020, to October 31, 2021. A total of 6012 pregnant persons with a positive SARS-CoV-2 polymerase chain reaction test result at any time in pregnancy (primarily due to symptomatic presentation) were included and compared with 2 contemporaneous groups including age-matched female individuals with SARS-CoV-2 and unaffected pregnant persons from the pandemic time period. Exposure: SARS-CoV-2 infection during pregnancy. Incident infections in pregnancy were reported to CANCOVID-Preg by participating provinces/territories. Main Outcomes and Measures: Maternal and perinatal outcomes associated with SARS-CoV-2 infection as well as risk factors for severe disease (ie, disease requiring hospitalization, admission to an intensive care unit/critical care unit, and/or oxygen therapy). Results: Among 6012 pregnant individuals with SARS-CoV-2 in Canada (median age, 31 [IQR, 28-35] years), the greatest proportion of cases were diagnosed at 28 to 37 weeks' gestation (35.7%). Non-White individuals were disproportionately represented. Being pregnant was associated with a significantly increased risk of SARS-CoV-2-related hospitalization compared with SARS-CoV-2 cases among all women aged 20 to 49 years in the general population of Canada (7.75% vs 2.93%; relative risk, 2.65 [95% CI, 2.41-2.88]) as well as an increased risk of intensive care unit/critical care unit admission (2.01% vs 0.37%; relative risk, 5.46 [95% CI, 4.50-6.53]). Increasing age, preexisting hypertension, and greater gestational age at diagnosis were significantly associated with worse maternal outcomes. The risk of preterm birth was significantly elevated among SARS-CoV-2-affected pregnancies (11.05% vs 6.76%; relative risk, 1.63 [95% CI, 1.52-1.76]), even in cases of milder disease not requiring hospitalization, compared with unaffected pregnancies during the same time period. Conclusions and Relevance: In this exploratory surveillance study conducted in Canada from March 2020 to October 2021, SARS-CoV-2 infection during pregnancy was significantly associated with increased risk of adverse maternal outcomes and preterm birth.

Arterial flow patterns in healthy transitioning near-term neonates.

OBJECTIVE: Significant haemodynamic changes occur at delivery impacting organ blood flow distribution. We aimed to characterise Doppler indices patterns over time in three different organs (brain, gut and kidney) and test them as measures of vascular resistance. DESIGN: Observational cohort study. Serial Doppler interrogations of the anterior cerebral, superior mesenteric and renal arteries within 2 hours, 2-6, and 24 hours of life, in combination with central haemodynamic data. PATIENTS: Healthy, near-term (>36 weeks of gestation) neonates. OUTCOME MEASURES: Pulsatility (PI) and Resistance Indices (RI) patterns and organ-specific conductances, detailed echocardiographic haemodynamic measures. RESULTS: Twenty-one babies were studied. Doppler morphology and adaptation patterns were distinctly different between the organs (brain, gut and kidney) supporting autonomous vascular regulatory effects. The PI differentiated especially between kidney and other organ flow consistently over time. PI and RI for all three organs decreased. The variance in organ conductance did not explain the variance in 1/PI, indicating that PI is not a measure of resistance. Superior mesenteric artery had the highest velocity with 72 cm/s. Non-invasively acquired pilot serial values in a normal population are given. Patent ductus arteriosus flow remained open at discharge for 36%. CONCLUSIONS: Haemodynamic transitioning patterns assessed by serial Dopplers in healthy near-term neonates differ in brain, gut and kidney: Doppler waveform morphology differs, and PI differentiates renal Doppler morphology, compared with the other organs. While PI and RI decline for all organs, they do not measure resistance. Brain artery velocity increases, mesenteric perfusion is variable and renal Vmax decreases.

Antenatal predictors of outcome in prenatally diagnosed congenital diaphragmatic hernia (CDH).

BACKGROUND: Pulmonary hypoplasia is the main cause of mortality in isolated congenital diaphragmatic hernia (CDH) and its prediction is paramount when counseling parents. We sought to identify antenatal parameters that predicted neonatal mortality in CDH. METHOD: Search was conducted in MEDLINE, EMBASE, Cochrane Database of Systematic reviews, PubMed, Scopus, and Web of Science on the ability of lung-to-head ratio (LHR), observed-to-expected LHR (o/e LHR), total fetal lung volume (TFLV), o/e TFLV, percentage predicted lung volume (PPLV) and degree of liver herniation to predict neonatal morbidity and mortality in fetuses with CDH. Primary outcome was perinatal survival and secondary was the use of extracorporeal membrane oxygenation (ECMO). RESULTS: Until April 2016, 1067 articles were found, of which 22 were included in our meta-analysis. This showed that the odds of survival with LHR <1.0 and liver herniation on ultrasound were 0.14 (CI 0.10-0.27) and 0.21 (CI 0.13-0.35) respectively. Mean LHR, o/e LHR, absolute TFLV, o/e TFLV, PPLV and liver herniation all predicted survival, however o/e LHR and o/e TFLV performed best in this prediction. When the longest diameter measurement method was used, the o/e TFLV (summary area under curve (AUC) 0.8) was slightly superior to o/e LHR (summary AUC 0.78). This difference disappeared when LHR was measured by the trace method. The most discriminatory threshold for O/E LHR and O/E TFLV was 25%. LHR <1 was predictive of extracorporeal life support (ECLS) use. CONCLUSION: O/E LHR, o/e TFLV (thresholds of 25%) and liver herniation are good predictors of mortality in CDH. LEVEL OF EVIDENCE: Level II Type of study: Systematic review and meta-analysis.

Immortal time bias in the study of stillbirth risk factors: the example of gestational diabetes.

BACKGROUND: Current understanding of the increased risk for stillbirth in gestational diabetes mellitus is often based on large cohort studies in which the risk of stillbirth in women with this disease is compared with the risk in women without. However, such studies could be susceptible to immortal time bias because, although many cohorts begin at 20 weeks' gestation, pregnancies must "survive" until 24-28 weeks in order to be screened and diagnosed with gestational diabetes. METHODS: We describe the theoretical potential for immortal time bias in studies of stillbirth and gestational diabetes and then quantify the magnitude of the bias using 2006 United States vital statistics data. RESULTS: Although gestational diabetes was protective against stillbirth when including all births (relative risk = 0.88 [95% confidence interval = 0.79-0.99]), restricting analyses to births at >28 weeks' gestation reversed the effect and diabetes became associated with an increased risk of stillbirth (1.25 [1.11-1.41]). CONCLUSION: Immortal time before diagnosis of gestational diabetes may bias our understanding of the stillbirth risk associated with this condition.