Guideline No. 441: Antenatal Fetal Health Surveillance.

OBJECTIVE: To summarize the current evidence and to make recommendations for antenatal fetal health surveillance (FHS) to detect perinatal risk factors and potential fetal decompensation in the antenatal period and to allow for timely intervention to prevent perinatal morbidity and/or mortality. TARGET POPULATION: Pregnant individuals with or without maternal, fetal, or pregnancy-associated perinatal risk factors for antenatal fetal decompensation. OPTIONS: To use basic and/or advanced antenatal testing modalities, based on risk factors for potential fetal decompensation. OUTCOMES: Early identification of potential fetal decompensation allows for interventions that may support fetal adaptation to maintain well-being or expedite delivery. BENEFITS, HARMS, AND COSTS: Antenatal FHS in pregnant individuals with identified perinatal risk factors may reduce the chance of adverse outcomes. Given the high false-positive rate, FHS may increase unnecessary interventions, which may result in harm, including parental anxiety, premature or operative birth, and increased use of health care resources. Optimization of surveillance protocols based on evidence-informed practice may improve perinatal outcomes and reduce harm. EVIDENCE: Medline, PubMed, Embase, and the Cochrane Library were searched from inception to January 2022, using medical subject headings (MeSH) and key words related to pregnancy, fetal monitoring, fetal movement, stillbirth, pregnancy complications, and fetal sonography. This document represents an abstraction of the evidence rather than a methodological review. VALIDATION METHODS: The authors rated the quality of evidence and strength of recommendations using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. See online Appendix A (Tables A1 for definitions and A2 for interpretations of strong and weak recommendations). INTENDED AUDIENCE: All health care team members who provide care for or education to obstetrical patients, including maternal fetal medicine specialists, obstetricians, family physicians, midwives, nurses, nurse practitioners, and radiologists. SUMMARY STATEMENTS: RECOMMENDATIONS.

Directive clinique no 441 : Surveillance prénatale du bien-être fœtal.

OBJECTIF: Résumer les données probantes actuelles et formuler des recommandations pour la surveillance prénatale du bien-être fœtal afin de détecter les facteurs de risque périnatal et toute potentielle décompensation fœtale et de permettre une intervention rapide en prévention de la morbidité et la mortalité périnatales. POPULATION CIBLE: Personnes enceintes avec ou sans facteurs maternels, fœtaux ou gravidiques associés à des risques périnataux et à la décompensation fœtale. OPTIONS: Utiliser des examens prénataux par technologie de base et/ou avancée en fonction des facteurs de risque de décompensation fœtale. RéSULTATS: La reconnaissance précoce de toute décompensation fœtale potentielle permet d'intervenir de façon à favoriser l'adaptation fœtale pour maintenir le bien-être ou à accélérer l'accouchement. BéNéFICES, RISQUES ET COûTS: Chez les personnes enceintes ayant des facteurs de risque périnatal confirmés, la surveillance du bien-être fœtal contribue à réduire le risque d'issue défavorable. Compte tenu du taux élevé de faux positifs, la surveillance du bien-être fœtal peut augmenter le risque d'interventions inutiles, ce qui peut avoir des effets nuisibles, dont l'anxiété parentale, l'accouchement prématuré ou assisté et l'utilisation accrue des ressources de soins de santé. L'optimisation des protocoles de surveillance d'après des pratiques fondées sur des données probantes peut améliorer les issues périnatales et réduire les effets nuisibles. DONNéES PROBANTES: Des recherches ont été effectuées dans les bases de données Medline, PubMed, Embase et Cochrane Library, de leur création jusqu'à janvier 2022, à partir de termes MeSH et de mots clés liés à la grossesse, à la surveillance fœtale, aux mouvements fœtaux, à la mortinaissance, aux complications de grossesse et à l'échographie fœtale. Le présent document est un résumé des données probantes et non pas une revue méthodologique. MéTHODES DE VALIDATION: Les auteurs ont évalué la qualité des données probantes et la force des recommandations en utilisant le cadre méthodologique GRADE (Grading of Recommendations Assessment, Development and Evaluation). Voir l'annexe A en ligne (tableau A1 pour les définitions et tableau A2 pour l'interprétation des recommandations fortes et faibles). PROFESSIONNELS CONCERNéS: Tous les membres de l'équipe de soins qui prodiguent des soins ou donnent de l'information aux patientes en obstétrique, notamment les spécialistes en médecine fœto-maternelle, les obstétriciens, les médecins de famille, les sages-femmes, les infirmières, les infirmières praticiennes et les radiologistes. DÉCLARATIONS SOMMAIRES: RECOMMANDATIONS.

Technical Update No. 436: Classification of Cesarean Deliveries in Canada: The Modified Robson Criteria.

OBJECTIVE: To describe and advocate for the use of a common classification system for cesarean delivery in Canada. TARGET POPULATION: Pregnant individuals undergoing cesarean delivery. BENEFITS, HARMS, COSTS: Use of a standardized classification system for cesarean delivery allows for local, regional, national, and international comparison of cesarean delivery rates and trends. The system is inclusive and simple to implement, based on existing databases. EVIDENCE: A comprehensive literature review was updated to April 2022 with medical subject headings (MeSH) and keywords (cesarean section, classification, taxonomy, nomenclature, terminology) in MEDLINE/PubMed and Embase databases. Results were restricted to systematic reviews, randomized controlled trials and clinical trials, and observational studies. Additional literature was identified by backward citation tracking using relevant full-text articles. The grey literature was reviewed by searching websites of health agencies. VALIDATION METHODS: The authors rated the quality of evidence and strength of recommendation using the Grade of Recommendations, Assessment, Development and Evaluation (GRADE) approach. See online Appendix A (Tables A1 for definitions and A2 for interpretation of strong and conditional [weak] recommendations).The Board of the SOGC approved the final draft for publication. INTENDED AUDIENCE: Obstetric care providers, health care administrators, epidemiologists.

Mise à jour technique N° 436 : Classification des césariennes au Canada : Critères de Robson modifiés.

OBJECTIF: Décrire et promouvoir l'utilisation d'un système de classification universel de la césarienne au Canada. POPULATION CIBLE: Les femmes enceintes devant subir une césarienne. BéNéFICES, RISQUES ET COûTS: L'utilisation d'un système de classification normalisé de la césarienne permet de comparer les taux de césariennes et tendances aux échelles locale, régionale, nationale et internationale. Le système inclusif et simple à mettre en œuvre repose sur des bases de données existantes. DONNéES PROBANTES: La revue exhaustive de la littérature a été mise à jour pour tenir compte des articles publiés jusqu'en avril 2022; les articles ont été répertoriés à partir de mots clés et de termes MeSH (cesarean section, classification, taxonomy, nomenclature, terminology) dans les bases de données PubMed-Medline et Embase. Seuls les résultats de revues systématiques, d'essais cliniques randomisés, d'essais cliniques et d'études observationnelles ont été retenus. D'autres publications ont été répertoriées par consultation des références d'articles intégraux pertinents. La littérature grise a été examinée en recherchant sur les sites Web d'organismes de santé. MéTHODES DE VALIDATION: Les auteures ont évalué la qualité des données probantes et la force des recommandations en utilisant le cadre méthodologique GRADE (Grading of Recommendations, Assessment, Development, and Evaluation). Voir l'annexe A en ligne (tableau A1 pour les définitions et tableau A2 pour l'interprétation des recommandations fortes et conditionnelles [faibles]). Le conseil d'administration de la SOGC a approuvé la version définitive aux fins de publication. PROFESSIONNELS CONCERNéS: Fournisseurs de soins obstétricaux, administrateurs des services de santé, épidémiologistes.

Myasthenia gravis in pregnancy: Systematic review and case series.

Background: Myasthenia gravis is an autoimmune disease which can impact pregnancy. Methods: Six databases were systematically searched for studies with at least five subjects reporting pregnancy outcomes for women with myasthenia gravis in pregnancy. Assessment of bias was performed for all included studies. Forty-eight cases from our own centre were also included in the analysis. Results: In total, 32 publications met inclusion criteria for systematic review, for a total of 33 unique data sets including 48 cases from our institution. Outcome data was available for 824 pregnancies. Spontaneous vaginal delivery occurred in 56.3% of pregnancies. Overall risk of myasthenia gravis exacerbation was 33.8% with a 6.4% risk of myasthenic crisis in pregnancy and 8.2% postpartum. The incidence risk of transient neonatal myasthenia gravis was 13.0%. Conclusions: The current systematic review provides the best estimates of risk currently available to aid in counselling women with myasthenia gravis in pregnancy.

Homozygous GLUL deletion is embryonically viable and leads to glutamine synthetase deficiency.

Glutamine synthetase (GS) is the enzyme responsible for the biosynthesis of glutamine, providing the only source of endogenous glutamine necessary for several critical metabolic and developmental pathways. GS deficiency, caused by pathogenic variants in the glutamate-ammonia ligase (GLUL) gene, is a rare autosomal recessive inborn error of metabolism characterized by systemic glutamine deficiency, persistent moderate hyperammonemia, and clinically devastating seizures and multi-organ failure shortly after birth. The four cases reported thus far were caused by homozygous GLUL missense variants. We report a case of GS deficiency caused by homozygous GLUL gene deletion, diagnosed prenatally and likely representing the most severe end of the spectrum. We expand the known phenotype of this rare condition with novel dysmorphic, radiographic and neuropathologic features identified on post-mortem examination. The biallelic deletion identified in this case also included the RNASEL gene and was associated with immune dysfunction in the fetus. This case demonstrates that total absence of the GLUL gene in humans is viable beyond the embryonic period, despite the early embryonic lethality found in GLUL animal models.

Fetal arthrogryposis multiplex congenita/fetal akinesia deformation sequence (FADS)-Aetiology, diagnosis, and management.

Arthrogryposis multiplex congenita (AMC) refers to an aetiologically heterogenous condition, which consists of joint contractures affecting two or more joints starting prenatally. The incidence is approximately one in 3000 live births; however, the prenatal incidence is higher, indicating a high intrauterine mortality. Over 320 genes have been implicated showing the genetic heterogeneity of the condition. AMC can be of extrinsic aetiology resulting from intrauterine crowding secondary to congenital structural uterine abnormalities (eg, bicornuate or septate uterus), uterine tumors (eg, fibroid), or multifetal pregnancy or intrinsic/primary/fetal aetiology, due to functional abnormalities in the brain, spinal cord, peripheral nerves, neuromuscular junction, muscles, bones, restrictive dermopathies, tendons and joints. Unlike many of the intrinsic/primary/fetal causes which are difficult to treat, secondary AMC can be treated by physiotherapy with good response. Primary cases may present prenatally with fetal akinesia associated with joint contractures and occasionally brain abnormalities, decreased muscle bulk, polyhydramnios, and nonvertex presentation while the secondary cases usually present with isolated contractures. Complete prenatal and postnatal investigations are needed to identify an underlying aetiology and provide information regarding its prognosis and inheritance, which is critical for the obstetrical care providers and families to optimize the pregnancy management and address future reproductive plans.

Comparison of cesarean versus vaginal delivery of extremely preterm gestations in breech presentation: retrospective cohort study.

Objective: As survival increases at earlier gestational ages, the optimal mode of delivery, especially in cases of breech presentation, is of increasing importance. The objective of this study was to compare outcomes of vaginal delivery (VD) and cesarean section (CS) births for infants in breech presentation at borderline viability. Study design: A retrospective chart review of live breech births between 23 + 0 and 25 + 6 weeks gestation at a tertiary university center from 2003 to 2013 was conducted. Those delivered vaginally were compared with those delivered by CS. Stillbirths and deliveries where no resuscitation was intended were removed from the analysis. Variables were compared using a Student t-test (continuous), Mann-Whitney U test (categorical), or a Chi-squared test (count). Logistic regression analysis was performed to further evaluate the results. Results with p < .05 were considered significant. Results: One hundred seventy-six births were included, 36 VD and 140 CS. Baseline characteristics were similar between groups. Gestational age at delivery was significantly higher in CS deliveries (24.9 ± 0.6 versus 24.5 ± 0.7, p = .0007). The rate of neonatal death (23.6% versus 44.4%, p = .0127) was significantly lower in those born by CS. All other neonatal outcomes including Apgar scores at one and 5 min, cord gases, birth weight, length of stay in NICU, incidence of respiratory complications, and incidence of high-grade IVH demonstrated no significant differences. Logistic regression suggested that male sex, lower birth weight, and earlier gestational age are significantly associated with neonatal mortality. Thirty percent of uterine incisions were of the classical, high transverse or inverted-T types. The estimated blood loss was significantly higher in CS births (706.6 ± 226.4 versus 327.4 ± 174.1 mL, p < .0001), but there was no difference in the rate of blood transfusion. Conclusion: CS delivery of breech infants at borderline viability had a protective effect on neonatal mortality compared to VD depending on the regression model utilized. Infant sex, birth weight, and gestational age also contribute significantly to neonatal mortality. A prospective study of planned method of delivery is recommended to further explore this finding.

Surgical Management Algorithm for Caesarean Scar Pregnancy.

OBJECTIVES: To report our experience with the management of Caesarean scar pregnancy (CSP) in the first trimester and to develop a unique treatment algorithm allowing physicians to customize their management based on clinical patient characteristics. METHODS: A retrospective review of 12 patients diagnosed with CSP between December 2012 and June 2016 was conducted in a tertiary care hospital in Toronto. All patients were diagnosed with CSP by transvaginal ultrasound using radiologic criteria. Patients were initially treated with an ultrasound-guided embryocidal injection when fetal heart activity was present. Next, patients underwent medical management with systemic multidose methotrexate (MTX) or surgical management using a laparoscopic or transcervical approach depending on CSP characteristics. RESULTS: The mean age at diagnosis was 35.6 years. The median number of previous CSs was one. The mean serum human chorionic gonadotropin level was 59 938 IU/L. The mean GA at presentation was 8+1 weeks. Two-thirds of patients received medical management with systemic multidose methotrexate. Of these, 50% required additional surgical treatment for the resolution of their CSP. One-third of patients underwent primary surgical treatment, resulting in complete resolution of CSP with no complications. Given the improved outcomes of surgical management in our series, we suggest a treatment algorithm that tailors the surgical approach, either laparoscopic or transcervical, to the characteristics of the CSP. CONCLUSION: This constitutes the largest case series of CSP in Canada. Based on our results, CSP can be safely and effectively managed using the suggested surgical algorithm, which accounts for individual patient characteristics.

Modulation of imprinted gene expression following superovulation.

Although assisted reproductive technologies increase the risk of low birth weight and genomic imprinting disorders, the precise underlying causes remain unclear. Using a mouse model, we previously showed that superovulation alters the expression of imprinted genes in the placenta at 9.5days (E9.5) of gestation. Here, we investigate whether effects of superovulation on genomic imprinting persisted at later stages of development and assess the surviving fetuses for growth and morphological abnormalities. Superovulation, followed by embryo transfer at E3.5, as compared to spontaneous ovulation (controls), resulted in embryos of normal size and weight at 14.5 and 18.5days of gestation. The normal monoallelic expression of the imprinted genes H19, Snrpn and Kcnq1ot1 was unaffected in either the placentae or the embryos from the superovulated females at E14.5 or E18.5. However, for the paternally expressed imprinted gene Igf2, superovulation generated placentae with reduced production of the mature protein at E9.5 and significantly more variable mRNA levels at E14.5. We propose that superovulation results in the ovulation of abnormal oocytes with altered expression of imprinted genes, but that the coregulated genes of the imprinted gene network result in modulated expression.

Stability of DNA methylation patterns in mouse spermatogonia under conditions of MTHFR deficiency and methionine supplementation.

Little is known about the conditions contributing to the stability of DNA methylation patterns in male germ cells. Altered folate pathway enzyme activity and methyl donor supply are two clinically significant factors that can affect the methylation of DNA. 5,10-Methylenetetrahydrofolate reductase (MTHFR) is a key folate pathway enzyme involved in providing methyl groups from dietary folate for DNA methylation. Mice heterozygous for a targeted mutation in the Mthfr gene (Mthfr(+/-)) are a good model for humans homozygous for the MTHFR 677C>T polymorphism, which is found in 10% of the population and is associated with decreased MTHFR activity and infertility. High-dose folic acid is administered as an empirical treatment for male infertility. Here, we examined MTHFR expression in developing male germ cells and evaluated DNA methylation patterns and effects of a range of methionine concentrations in spermatogonia from Mthfr(+/-) as compared to wild-type, Mthfr(+/+) mice. MTHFR was expressed in prospermatogonia and spermatogonia at times of DNA methylation acquisition in the male germline; its expression was also found in early spermatocytes and Sertoli cells. DNA methylation patterns were similar at imprinted genes and intergenic sites across chromosome 9 in neonatal Mthfr(+/+) and Mthfr(+/-) spermatogonia. Using spermatogonia from Mthfr(+/+) and Mthfr(+/-) mice in the spermatogonial stem cell (SSC) culture system, we examined the stability of DNA methylation patterns and determined effects of low or high methionine concentrations. No differences were detected between early and late passages, suggesting that DNA methylation patterns are generally stable in culture. Twenty-fold normal concentrations of methionine resulted in an overall increase in the levels of DNA methylation across chromosome 9, suggesting that DNA methylation can be perturbed in culture. Mthfr(+/-) cells showed a significantly increased variance of DNA methylation at multiple loci across chromosome 9 compared to Mthfr(+/+) cells when cultured with 0.25- to 2-fold normal methionine concentrations. Taken together, our results indicate that DNA methylation patterns in undifferentiated spermatogonia, including SSCs, are relatively stable in culture over time under conditions of altered methionine and MTHFR levels.

Critical period of nonpromoter DNA methylation acquisition during prenatal male germ cell development.

The prenatal period of germ cell development is a key time of epigenetic programming in the male, a window of development that has been shown to be influenced by maternal factors such as dietary methyl donor supply. DNA methylation occurring outside of promoter regions differs significantly between sperm and somatic tissues and has recently been linked with the regulation of gene expression during development as well as successful germline development. We examined DNA methylation at nonpromoter, intergenic sequences in purified prenatal and postnatal germ cells isolated from wildtype mice and mice deficient in the DNA methyltransferase cofactor DNMT3L. Erasure of the parental DNA methylation pattern occurred by 13.5 days post coitum (dpc) with the exception of approximately 8% of loci demonstrating incomplete erasure. For most loci, DNA methylation acquisition occurred between embryonic day 13.5 to 16.5 indicating that the key phase of epigenetic pattern establishment for intergenic sequences in male germ cells occurs prior to birth. In DNMT3L-deficient germ cells at 16.5 dpc, average DNA methylation levels were low, about 30% of wildtype levels; however, by postnatal day 6, about half of the DNMT3L deficiency-specific hypomethylated loci had acquired normal methylation levels. Those loci normally methylated earliest in the prenatal period were the least affected in the DNMT3L-deficient mice, suggesting that some loci may be more susceptible than others to perturbations occurring prenatally. These results indicate that the critical period of DNA methylation programming of nonpromoter, intergenic sequences occurs in male germline progenitor cells in the prenatal period, a time when external perturbations of epigenetic patterns could result in diminished fertility.

Epigenetic modification of the gene for the vitamin B(12) chaperone MMACHC can result in increased tumorigenicity and methionine dependence.

Methionine dependence, the inability of cells to grow when the amino acid methionine is replaced in culture medium by its metabolic precursor homocysteine, is characteristic of many cancer cell lines and some tumors in situ. Most cell lines proliferate normally under these conditions. The methionine dependent tumorigenic human melanoma cell line MeWo-LC1 was derived from the methionine independent non-tumorigenic line, MeWo. MeWo-LC1 has a cellular phenotype identical to that of cells from patients with the cblC inborn error of cobalamin metabolism, with decreased synthesis of cobalamin coenzymes and decreased activity of the cobalamin-dependent enzymes methionine synthase and methylmalonylCoA mutase. Inability of cblC cells to complement the defect in MeWo-LC1 suggested that it was caused by decreased activity of the MMACHC gene. However, no potentially disease causing mutations were detected in the coding sequence of MMACHC in MeWo-LC1. No MMACHC expression was detected in MeWo-LC1 by quantitative or non-quantitative PCR. There was virtually complete methylation of a CpG island at the 5'-end of the MMACHC gene in MeWo-LC1, consistent with inactivation of the gene by methylation. The CpG island was partially methylated (30-45%) in MeWo and only lightly methylated (2-11%) in control fibroblasts. Infection of MeWo-LC1 with wild type MMACHC resulted in correction of the defect in cobalamin metabolism and restoration of the ability of cells to grow in medium containing homocysteine. We conclude that epigenetic inactivation of the MMACHC gene is responsible for methionine dependence in MeWo-LC1.