The Effect of Fetal Trisomy 21 on Adverse Perinatal Obstetrical Outcomes in Nova Scotia, 2000-2019.

OBJECTIVE: To understand the risks associated with trisomy 21 in pregnancy in order to inform obstetrical care and improve outcomes. METHODS: A population-based retrospective cohort study was undertaken of all pregnancies involving a fetus with trisomy 21 in Nova Scotia, Canada, from 2000 to 2019. Cases were identified from the provincial laboratory genetics database, linked to the Nova Scotia Atlee Perinatal Database for pregnancy outcomes, and compared with the general obstetrical population. RESULTS: A total of 350 pregnancies were identified, of which 23% were ongoing pregnancies in which trisomy 21 was diagnosed prenatally and 24% involved diagnoses made after delivery. Compared with the general obstetrical population, women with ongoing pregnancies affected by trisomy 21 were more likely to be older (mean age 34 vs. 29 y), multiparous (67% vs. 55%), and in a relationship (79% vs. 68%). Trisomy 21 was associated with a significantly increased risk of preterm birth (<37 weeks; 24.1% vs. 8.3%); small for gestational age (<10th percentile; 21.7% vs. 8.2%); cesarean delivery (31.5% vs. 27.1%); and combined perinatal/neonatal mortality (8.0% vs. 0.8%) (P < 0.001 for all). CONCLUSION: Trisomy 21 is associated with significant adverse perinatal and neonatal risks. Population screening to identify trisomy 21 can be used to optimize perinatal outcomes with appropriate fetal surveillance in these pregnancies.

Incidence and Carrier Frequency of CFTR Gene Mutations in Pregnancies With Echogenic Bowel in Nova Scotia and Prince Edward Island.

OBJECTIVE: Fetal echogenic bowel (echogenic bowel) is associated with cystic fibrosis (CF), with a reported incidence ranging from 1% to 13%. Prenatal testing for CF in the setting of echogenic bowel can be done by screening parental or fetal samples for pathogenic CFTR variants. If only one pathogenic variant is identified, sequencing of the CFTR gene can be undertaken, to identify a second pathogenic variant not covered in the standard screening panel. Full gene sequencing, however, also introduces the potential to identify variants of uncertain significance (VUSs) that can create counselling challenges and cause parental anxiety. To provide accurate counselling for families in the study population, the incidence of CF associated with echogenic bowel and the carrier frequency of CFTR variants were investigated. METHODS: All pregnancies for which CF testing was undertaken for the indication of echogenic bowel (from Nova Scotia and Prince Edward Island) were identified (January 2007-July 2017). The CFTR screening and sequencing results were reviewed, and fetal outcomes related to CF were assessed. RESULTS: A total of 463 pregnancies with echogenic bowel were tested. Four were confirmed to be affected with CF, giving an incidence of 0.9% in this cohort. The carrier frequency of CF among all parents in the cohort was 5.0% (1 in 20); however, when excluding parents of affected fetuses, the carrier frequency for the population was estimated at 4.1% (1 in 25). CFTR gene sequencing identified an additional VUS in two samples. CONCLUSION: The incidence of CF in pregnancies with echogenic bowel in Nova Scotia and Prince Edward Island is 0.9%, with an estimated population carrier frequency of 4.1%. These results provide the basis for improved counselling to assess the risk of CF in the pregnancy, after parental carrier screening, using Bayesian probability. Counselling regarding VUSs should be undertaken before gene sequencing.

Factors Associated with Trial of Labour and Mode of Delivery in Robson Group 5: A Select Group of Women With Previous Caesarean Section.

OBJECTIVE: To determine the proportion of women in Robson group 5 (RG5) who were eligible for a trial of labour after Caesarean (TOLAC) and, among eligible candidates, identify determinants of having a TOLAC and subsequent vaginal delivery (VD). METHODS: This population-based cohort study used data derived from the Nova Scotia Atlee Perinatal Database. Deliveries from 1998-2014 to women in RG5 (≥1 previous CS with a singleton term cephalic fetus) were included. Eligibility for a TOLAC was based on SOGC criteria. Multivariable logistic regression was used to identify characteristics independently associated with TOLAC and VD. The characteristics associated with VD were used in a logistic model to predict the theoretical probability of VD in women who did not have a TOLAC. RESULTS: Of the 15 111 deliveries in RG5, 75.3% were by CS. Of the 14 763 eligible women, 5488 (37.2%) had a TOLAC, of which 3739 (68.1%) resulted in VD. Predictors of VD included high area-level income and either a CS without labour or a spontaneous VD in the preceding pregnancy. While mode of previous delivery also predicted TOLAC among eligible women, high area-level income was associated with reduced odds of TOLAC. The probability of VD in women who did not undergo TOLAC was estimated to be 47.1%, and the lowest CS rate attainable in RG5 was estimated at 46.3%. CONCLUSIONS: Sociodemographic factors such as income and previous mode of delivery were associated with the rates of TOLAC and subsequent VD in eligible women, and suggest that the Caesarean section rate in RG5 could be safely reduced.

Adverse Perinatal Conditions Associated With Prenatally Detected Fetal Echogenic Bowel in Nova Scotia.

OBJECTIVE: This study sought to estimate the association of adverse perinatal outcomes with pregnancies complicated by fetal echogenic bowel. METHODS: Data for pregnancies complicated with echogenic bowel identified in the second trimester were derived from the tertiary referral IWK Health Centre (Halifax, NS) Viewpoint Ultrasound Database augmented by medical chart review. The study was undertaken between 2003 and 2014. Rates of positive cytomegalovirus and toxoplasmosis infection were determined using maternal serology and amniocentesis results. Rates of intrauterine growth restriction, abnormal karyotype, cystic fibrosis, antenatal bleeding, and bowel abnormalities were also determined. Neonatal information included newborn urine culture results and postnatal genetic testing. Univariate analyses compared rates of infection with isolated echogenic bowel and echogenic bowel with other ultrasound findings, with statistical significance set at P <0.05. RESULTS: There were 422 pregnancies identified prenatally with echogenic bowel (82% had isolated echogenic bowel). Of these, 92 (22%) had at least one of the foregoing associated abnormalities. Three percent of women had serologic test results positive for cytomegalovirus or toxoplasmosis, with <1% documented newborn infections. Cystic fibrosis and other genetic diagnoses were observed in 8%, intrauterine growth restriction in 14%, antenatal bleeding in 19%, and bowel abnormalities in 3% of the cases of echogenic bowel. Pregnancies with isolated echogenic bowel had an 80% reduction in risk for these significant outcomes, in contrast to a four- to 11-fold increased risk of specific outcomes when additional ultrasound findings were present. CONCLUSION: An overall rate of adverse conditions of 22% with prenatally detected echogenic bowel serves to inform women and health care providers and emphasizes the importance of careful screening fetal ultrasound studies and timely referral for comprehensive assessment with findings of echogenic bowel for evaluation for associated findings.

Association Between Factor V Leiden Mutation, Small for Gestational Age, and Preterm Birth: A Systematic Review and Meta-Analysis.

OBJECTIVE: To estimate the association of a maternal factor V Leiden (FVL) mutation with SGA and preterm birth. DATA SOURCES: We performed a search of PubMed, Embase, Scopus, CINAHL, and the Cochrane Library from inception to April 2016 for cohort and case-control studies of women with FVL mutation and associated outcomes of SGA and preterm birth that included a reference group without FVL mutation. Additional studies were identified from reference lists of relevant research and review articles. STUDY SELECTION: Two authors (JKB, AMO) independently examined the abstracts of the potentially eligible studies, and full texts of eligible studies were retrieved for further evaluation. Disagreements were resolved by consensus. We identified 42 studies suitable for inclusion in the meta-analysis. DATA EXTRACTION: Thirty-two studies evaluated SGA, and 18 studies assessed preterm birth. Study quality was assessed using the Newcastle Ottawa Scale. A random effects model with inverse variance weighting was used to calculate pooled ORs and 95% CIs. Subgroup analyses were performed by study design. DATA SYNTHESIS: The overall OR associating FVL mutation with SGA was significant (OR 1.40, 95% CI 1.18 to 1.67). Analysis of 13 cohort studies resulted in an OR of 1.20 (95% CI 1.03 to 1.41), and data from 19 case-control studies yielded an OR of 1.86 (95% CI 1.35 to 2.56). There was no significant association between FVL mutation and preterm birth (OR 1.17, 95% CI 1.00 to 1.37) when all groups were studied, but the association was significant for case-control studies alone (OR 1.40, 95% CI 1.05 to 1.86). CONCLUSION: There is an increased risk for SGA in pregnancies complicated by FVL mutation in both cohort and case-control study designs. The risk of preterm birth with FVL mutation is less clear, although there is conflicting evidence from cohort and case-control studies regarding the risk of preterm birth associated with FVL mutation.

Mosaic tetrasomy 5p resulting from an isochromosome 5p marker chromosome: case report and review of literature.

We report on the fifth case, and oldest reported patient, of an individual affected with mosaic tetrasomy 5p resulting from an isochromosome 5p [i(5)(p10)] marker chromosome. A syndrome of mosaic tetrasomy 5p is defined, and includes the following features seen in the reported cases: developmental delay, seizures, ventriculomegaly (other brain anomalies), small stature/growth delay and mosaic pigmentary skin changes. Other findings include various dysmorphic facial features as well as hand and foot anomalies. This syndrome is likely more common than suggested in the literature, as the clinical presentation can be variable, and the chromosome anomaly is unlikely to be found on routine karyotype of peripheral blood lymphocytes. The i(5)(p10) marker chromosome is found only as a mosaic anomaly, with levels ranging from 0% to 10% in cultured lymphocytes to 12-85% in cultured skin fibroblasts. Microarray analysis performed on unstimulated lymphocytes from the patient in this report did not detect any evidence of the chromosome abnormality, indicating that this methodology may not be useful as a diagnostic tool in this disorder. Diagnosis of the mosaic tetrasomy 5p syndrome will rely on good clinical assessment, and appropriate cytogenetic studies, including analysis of skin fibroblasts. A child with unexplained developmental delay, seizures, hypotonia, and ventriculomegaly with or without dysmorphic features should be assessed carefully for pigmentary changes of the skin. If a diagnosis of mosaic 5p tetrasomy is suspected, karyotype of cultured fibroblasts in addition to routine cytogenetic analysis, to look for this marker chromosome is warranted.

Family history screening: use of the three generation pedigree in clinical practice.

With a growing understanding of genetic disorders in the scientific and lay literature, it is becoming increasingly important to consider risk factors based on family history and ethnicity for identifying individuals for whom genetic testing is indicated and will be most beneficial. A pedigree helps to identify patients and families who have an increased risk for genetic disorders, to optimize counselling, screening, and diagnostic testing, with the goal of disease prevention or early diagnosis and management of the disease. Information should be updated periodically as new information regarding family history is acquired. This review was designed to provide a rationale for and an approach to obtaining a three-generation pedigree for patients who are seen as new assessments or those under ongoing care by primary care or specialist physicians, as well to summarize some resources available for constructing a useful pedigree.

Successful outcome in pregnancy with arterial tortuosity syndrome.

BACKGROUND: Arterial tortuosity syndrome is a rare, autosomal recessive, severe, connective tissue disorder caused by a mutation in the SLC2A10 gene. We describe the pregnancy and delivery with this high-risk connective tissue disorder involving generalized abnormalities of the vasculature. CASE: A woman with an undefined connective tissue disorder was referred for tertiary prenatal care. Diagnostic imaging demonstrated multiple pulmonary artery aneurysms and arterial tortuosity, consistent with a clinical diagnosis of arterial tortuosity syndrome. With a team considering all potential complications, a delivery plan was undertaken involving cesarean delivery and intensive perioperative and postpartum monitoring. The outcome was optimal for mother and neonate. Concurrent molecular testing demonstrated homozygosity for the SLC2A10 gene. CONCLUSION: Optimal maternal, fetal and neonatal outcomes were obtained with comprehensive multidisciplinary care and close maternal and fetal surveillance.