Prospective Validation of First-Trimester Screening for Preterm Preeclampsia in Nulliparous Women (PREDICTION Study).

BACKGROUND: Fetal Medicine Foundation (FMF) studies suggest that preterm preeclampsia can be predicted in the first trimester by combining biophysical, biochemical, and ultrasound markers and prevented using aspirin. We aimed to evaluate the FMF preterm preeclampsia screening test in nulliparous women. METHODS: We conducted a prospective multicenter cohort study of nulliparous women recruited at 11 to 14 weeks. Maternal characteristics, mean arterial blood pressure, PAPP-A (pregnancy-associated plasma protein A), PlGF (placental growth factor) in maternal blood, and uterine artery pulsatility index were collected at recruitment. The risk of preterm preeclampsia was calculated by a third party blinded to pregnancy outcomes. Receiver operating characteristic curves were used to estimate the detection rate (sensitivity) and the false-positive rate (1-specificity) for preterm (<37 weeks) and for early-onset (<34 weeks) preeclampsia according to the FMF screening test and according to the American College of Obstetricians and Gynecologists criteria. RESULTS: We recruited 7554 participants including 7325 (97%) who remained eligible after 20 weeks of which 65 (0.9%) developed preterm preeclampsia, and 22 (0.3%) developed early-onset preeclampsia. Using the FMF algorithm (cutoff of ≥1 in 110 for preterm preeclampsia), the detection rate was 63.1% for preterm preeclampsia and 77.3% for early-onset preeclampsia at a false-positive rate of 15.8%. Using the American College of Obstetricians and Gynecologists criteria, the equivalent detection rates would have been 61.5% and 59.1%, respectively, for a false-positive rate of 34.3%. CONCLUSIONS: The first-trimester FMF preeclampsia screening test predicts two-thirds of preterm preeclampsia and three-quarters of early-onset preeclampsia in nulliparous women, with a false-positive rate of ≈16%. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02189148.

Multimodal Pain Control Utilizing Buprenorphine for Robotic-assisted Laparoscopic Prostatectomy: A Quality Improvement Comparison to Conventional Opioid Management.

INTRODUCTION: This study investigated the effectiveness of buprenorphine as an alternative to the use of conventional opioids perioperatively in an effort to help mitigate the impact of the use of perioperative conventional opioids for patients undergoing robotic-assisted laparoscopic prostatectomy. METHODS: Outcomes of patients with localized prostate cancer undergoing robotic-assisted laparoscopic prostatectomy were examined before and after implementation of novel quality improvement study that included receiving buprenorphine compared to conventional opioids for pain control intraoperatively and postoperatively. The primary end point was adequate pain control with secondary end points being analgesic consumption at home, opioid-related side effects, and patient satisfaction. RESULTS: When analyzing the secondary end point of oral morphine milligram equivalents, the buprenorphine group received significantly less morphine milligram equivalent compared to the conventional opioid group (15.19 vs 47.91, P = .006). The buprenorphine group also had lower reported pain scores at discharge (4.3; scale 1-10) compared to the conventional opioid group (5.4), though this did not reach significance (P = .069). In the buprenorphine group, 76.9% strongly agreed that their pain was adequately controlled in the hospital compared to 57.5% of the conventional opioid group (P = .223). There was no difference in overall satisfaction at postoperative day 5 (P = .358). CONCLUSIONS: Our study demonstrates buprenorphine's analgesic capabilities to maintain adequate pain control and patient satisfaction compared to conventional opioids during robotic-assisted laparoscopic prostatectomy, while decreasing perioperative opioid use.

First-trimester preeclampsia screening and prevention: impact on patient satisfaction and anxiety.

BACKGROUND: Preeclampsia affects between 2% and 5% of pregnant people in North America. First-trimester preeclampsia screening based on the Fetal Medicine Foundation risk calculation algorithm combined with treatment of high-risk patients with aspirin effectively reduces the incidence of preterm preeclampsia more than the currently used risk factor-based screening. However, the impact of such screening on patient satisfaction and maternal anxiety is unknown. OBJECTIVE: This study aimed to assess the impact of first-trimester prediction and prevention of preterm preeclampsia on patient satisfaction and anxiety. STUDY DESIGN: Consenting pregnant patients participating in a local first-trimester (11-13+6 weeks) preterm preeclampsia screening and prevention implementation study1 were contacted 6 weeks postpartum to complete an online patient satisfaction survey, designed to assess their satisfaction with the screening program and their levels of trait anxiety (using an abbreviated version of the State-Trait Anxiety Inventory [STAIT-5]). In addition to assessing overall patient satisfaction, the level of patient satisfaction was stratified and compared according to levels of patient risk for preterm preeclampsia. RESULTS: Between June 2021 and December 2021, surveys were emailed to 765 participants. The response rate was 47.80% (358/765). Overall, 93% of participants reported high levels of satisfaction with preterm preeclampsia screening (70%-100%), and 98% stated that they would recommend the screening to all pregnant patients. With respect to levels of satisfaction with the program's support in reducing feelings of worry and anxiety, 87.9% of the total sample reported high satisfaction (70%-100%). The level of clinically significant symptoms of anxiety did not differ significantly between low- and high-risk groups (8% vs 10.8%, respectively). CONCLUSION: Overall, first-trimester preeclampsia screening was associated with high patient satisfaction and did not lead to differences in patient anxiety between those with high- and low-risk screen results.

RNA analysis of the GALNS transcript reveals novel pathogenic mechanisms associated with Morquio syndrome A.

Morquio syndrome A (Mucopolysaccharidosis IVA, MPS IVA) is an autosomal recessive lysosomal storage disorder caused by deficiency of N-acetyl-galactosamine-6-sulfatase (GALNS) which catabolizes the glycosaminoglycans (GAG), keratan sulfate and chondroitin-6-sulfate. Homozygous or compound heterozygous pathogenic variants in the GALNS result in the deficiency of the enzyme and consequent GAG accumulations. DNA sequence and copy number analysis of the GALNS coding region fails to identify biallelic causative pathogenic variants in up to 15% of patients with Morquio syndrome A. RNA transcript analysis was performed to identify pathogenic alterations in two unrelated families with Morquio syndrome A in whom a single heterozygous or no pathogenic alteration was detected by standard analysis of the GALNS gene. RNA sequencing and quantitative expression analysis identified the overabundance of an aberrant GALNS transcript isoform and a reduction of the clinically relevant isoform (NM_000512.4) in the Morquio syndrome A patients from both families. The aberrant isoform (ENST00000568613.1) was produced by alternative splicing and contained intronic sequence that was likely a cryptic exon predicted to result in a reading frame shift and generation of a premature termination codon. These findings indicated that the aberrant splicing is likely the novel molecular defect in our patients. RNA transcript analysis could be useful to identify pathogenic alterations and increase the yield of molecular diagnosis in patients with Morquio syndrome A whose genetic variants are not found by standard sequencing or gene dosage analysis.

Preeclampsia and postpartum mental health: mechanisms and clinical implications.

Preeclampsia is one of the leading causes of maternal morbidity and mortality worldwide, with the short and long-term implications for maternal health being increasingly recognized. Yet the effects of preeclampsia on mental health are often overlooked, effects which can be evident both immediately postpartum and decades later. In particular, preeclampsia has been associated with increased risk and severity of cognitive impairment, psychosocial distress, and psychiatric disorders including depression, anxiety, and post-traumatic stress disorder. While these outcomes are reported, few have proposed how the pathophysiology of preeclampsia may contribute to changes in postpartum mental health. Studies have suggested that anti-angiogenic factors and pro-inflammatory cytokines released from the preeclamptic placenta may damage the blood-brain barrier endothelium, leading to long-term structural and functional cerebral changes. These changes may contribute to subsequent impairments in mental health. In addition, the pro-inflammatory profile and patterns of cerebral damage observed in preeclampsia are similar to that of psychiatric disorders and cognitive impairment, suggesting they may share common mechanisms. Yet, there is limited evidence on how these mechanisms may interact. The purpose of this review is to summarize the evidence for these pathophysiological mechanisms and propose how they may work synergistically to affect brain structure, cognition, and postpartum mental health in preeclampsia. The role of psychosocial factors, disease severity, and psychological treatment in the mental health of preeclampsia patients will also be discussed.

Measurement of lipid profiles in the early postpartum period after hypertensive disorders of pregnancy.

BACKGROUND: The hypertensive disorders of pregnancy (HDP), including preeclampsia (PE) and gestational hypertension (GHTN), are independent risk factors for future maternal cardiovascular disease. Epidemiologic evidence has demonstrated that women with HDP have abnormal cardiovascular risk factors in the early postpartum period, but this has not been fully characterized. OBJECTIVE: This study aimed to assess the lipid profiles among women with PE, GHTN, and normal blood pressure in the first 4 years postpartum. METHODS: Discharge Abstract Database was used to identify women hospitalized for a delivery in Calgary, Alberta, Canada, between January 2010 and December 2012 (N = 27,300). This was linked with Calgary Laboratory Services (for lipid levels) and the Pharmaceutical Information Network database (for lipid medication prescriptions) over the first 4 years postpartum (2010-2016). Logistic regression analysis was used to compare the frequency of lipid tests among HDP subtypes, adjusted for maternal age, gestational age at delivery, and parity. RESULTS: Only about half of the women with HDP had a lipid test in the first 4 years postpartum: 50.8% (PE) and 48.8% (GHTN) vs 41.5% in normotensive women (P < .001). Low-density lipoprotein cholesterol levels were significantly higher in women with HDP: 106.3 ± 35.2 mg/dL (2.75 ± 0.91 mmol/L) in PE, 102.5 ± 30.5 mg/dL (2.65 ± 0.79 mmol/L) in GHTN, and 96.7 ± 29.0 mg/dL (2.50 ± 0.75 mmol/L) in normotensive women (P < .001). CONCLUSION: Postpartum lipid screening helps identify women at risk of cardiovascular disease; however, only 50% of women with HDP were tested in the first years postpartum. As such, an early opportunity for primary CVD prevention strategies in young women may be lost.

Risks of Dysglycemia Over the First 4 Years After a Hypertensive Disorder of Pregnancy.

BACKGROUND: Women with the hypertensive disorders of pregnancy (HDP) (preeclampsia [PE] and gestational hypertension [GHTN]) have increased risks of future diabetes. Postpartum glycemic testing offers early identification and treatment of dysglycemia, but evidence-based recommendations for this high-risk population are lacking. The objective of this study was to describe the risks of developing dysglycemia in women with normotensive and hypertensive pregnancies over the first 4 years postpartum. METHODS: The Discharge Abstract Database was used to identify women who delivered singleton live-born infants in Calgary, Alberta, Canada, between January 2010 and December 2012 (N=27,300). This was linked with Calgary Laboratory Services (for glycemic tests) and the Pharmaceutical Information Network databases (for antidiabetes medication prescriptions) over the first 4 years postpartum. Logistic regression analyses compared glycemic testing and results were adjusted for maternal age, gestational age, parity and the Pampalon deprivation index. RESULTS: Women with HDP had more glycemic testing (GHTN 67.8% and PE 69.9% vs normotensive 60.9%; p<0.001) and significantly higher results for fasting plasma glucose (GHTN 4.82±0.51 mmol/L and PE 4.84±0.54 mmol/L vs normotensive 4.73±0.49 mmol/L; p<0.001), random plasma glucose (GHTN 5.20±0.96 mmol/L and PE 5.39±1.71 mmol/L vs normotensive 5.00±0.87 mmol/L; p<0.001) and glycated hemoglobin levels (PE 5.62±0.53% vs normotensive 5.49±0.32%; p<0.001). Women with HDP had a higher adjusted odds (95% confidence interval) of developing type 2 diabetes compared with normotensive women (GHTN: 2.26, 1.50 to 13.4; PE: 2.02, 0.91 to 4.46). CONCLUSIONS: The high prevalence of early dysglycemia highlights the importance of targeted postpartum glycemic testing in women after HDP. Further research on optimal glycemic testing (specific tests and timing) in these high-risk women is needed.

Prospective head-to-head comparison of accuracy of two sequencing platforms for screening for fetal aneuploidy by cell-free DNA: the PEGASUS study.

We compared clinical validity of two non-invasive prenatal screening (NIPS) methods for fetal trisomies 13, 18, 21, and monosomy X. We recruited prospectively 2203 women at high risk of fetal aneuploidy and 1807 at baseline risk. Three-hundred and twenty-nine euploid samples were randomly removed. The remaining 1933 high risk and 1660 baseline-risk plasma aliquots were assigned randomly between four laboratories and tested with two index NIPS tests, blind to maternal variables and pregnancy outcomes. The two index tests used massively parallel shotgun sequencing (semiconductor-based and optical-based). The reference standard for all fetuses was invasive cytogenetic analysis or clinical examination at birth and postnatal follow-up. For each chromosome of interest, chromosomal ratios were calculated (number of reads for chromosome/total number of reads). Euploid samples' mean chromosomal ratio coefficients of variation were 0.48 (T21), 0.34 (T18), and 0.31 (T13). According to the reference standard, there were 155 cases of T21, 49 T18, 8 T13 and 22 45,X. Using a fetal fraction ≥4% to call results and a chromosomal ratio z-score of ≥3 to report a positive result, detection rates (DR), and false positive rates (FPR) were not statistically different between platforms: mean DR 99% (T21), 100%(T18, T13); 79%(45,X); FPR < 0.3% for T21, T18, T13, and <0.6% for 45,X. Both methods' negative predictive values in high-risk pregnancies were >99.8%, except for 45,X(>99.6%). Threshold analysis in high-risk pregnancies with different fetal fractions and z-score cut-offs suggested that a z-score cutoff to 3.5 for positive results improved test accuracy. Both sequencing platforms showed equivalent and excellent clinical validity.

A Practical Approach for the Verification and Determination of Site- and Trimester-Specific Reference Intervals for Thyroid Function Tests in Pregnancy.

BACKGROUND: Population-, assay-, and trimester-specific reference intervals for thyroid function tests are necessary to assess thyroid status accurately and manage thyroid disease throughout pregnancy. This study's objective was to verify if the manufacturer's recommended trimester-specific reference intervals for thyroid tests and the American Thyroid Association's recommended total thyroxine (TT4) pregnancy reference intervals were verifiable and appropriate for use in the authors' multicultural population. METHODS: Blood samples were obtained from the following sources: stored frozen surplus blood from women undergoing routine aneuploidy screening (first- and second-trimester samples, n = 274), women participating in an observational cohort study (second- and third-trimester samples, n = 135), and blood collected from women presenting for assessment to the labor and delivery ward (third-trimester samples, n = 35). Exclusions included thyroid medication or disease and positive thyroid peroxidase antibodies (anti-TPO). Samples were analyzed for thyrotropin (TSH), free T4 (fT4), free triiodothyronine (fT3), TT4, and anti-TPO using the Roche Cobas 8000 Modular e602 electrochemiluminescence immunoassay. RESULTS: Nine percent of the aneuploidy screening samples were excluded prior to thyroid testing due to maternal use of thyroid medication. Six percent of analyzed samples were excluded: 5.9% with positive anti-TPO and one with a TSH >10 mIU/L. The manufacturer's recommended trimester-specific reference intervals for TSH were not verified by described standardized methods. Therefore, 95th percentile reference intervals were determined using a minimum number of samples. Reference intervals for TSH and fT4 were as follows: 9-12 weeks, 0.18-2.99 mIU/L and 11-19.2 pmol/L; second trimester, 0.11-3.98 mIU/L and 10.5-18.2 pmol/L; and third trimester, 0.48-4.71 mIU/L and 9.0-16.1 pmol/L, respectively. The TT4 reference interval after 19 weeks' gestation was 77-186 nmol/L. CONCLUSIONS: This study provides a simple approach to verify or establish trimester-specific thyroid function reference intervals in local populations. The TT4 reference interval was lower than the interval proposed by the American Thyroid Association, suggesting the need for further study of TT4 in pregnancy and reliance on locally established fT4 reference intervals after 19 weeks, especially when there are no equivalent reference intervals for TT4.

Obstetrical provider knowledge and attitudes towards cell-free DNA screening: results of a cross-sectional national survey.

BACKGROUND: Cell-free DNA (cfDNA) screening has recently acquired tremendous attention, promising patients and healthcare providers a more accurate prenatal screen for aneuploidy than other current screening modalities. It is unclear how much knowledge regarding cfDNA screening obstetrical providers possess which has important implications for the quality and content of the informed consent patients receive. METHODS: A survey was designed to assess obstetrical provider knowledge and attitudes towards cfDNA screening and distributed online through the Society of Obstetricians & Gynecologists of Canada (SOGC). Chi-squared tests were used to detect differences in knowledge and attitudes between groups. RESULTS: 207 respondents completed the survey, composed of 60.6% Obstetricians/Gynecologists (OB/GYN), 15.4% Maternal Fetal Medicine (MFM) specialists, 16.5% General Practitioners (GP), and 7.5% Midwives (MW). MFM demonstrated a significant trend of being most knowledgeable about cfDNA screening followed by OB/GYN, GP, and lastly MW in almost all aspects of cfDNA screening. All groups demonstrated an overall positive attitude towards cfDNA screening; however, OB/GYN and MFM demonstrated a significantly more positive attitude than GP and MW. Despite not yet being a diagnostic test, 19.4% of GP would offer termination of pregnancy immediately following a positive cfDNA screen result compared to none of the MFM and only few OB/GYN or MW. CONCLUSIONS: We have demonstrated that different types of obstetrical providers possess varying amounts of knowledge regarding cfDNA screening with MFM currently having greater knowledge to all other groups. All obstetrical providers must have adequate prenatal screening understanding so that we can embrace the benefits of this novel and promising technology while protecting the integrity of the informed consent process.

No-271-Delayed Child-Bearing.

OBJECTIVE: To provide an overview of delayed child-bearing and to describe the implications for women and health care providers . OPTIONS: Delayed child-bearing, which has increased greatly in recent decades, is associated with an increased risk of infertility, pregnancy complications, and adverse pregnancy outcome . This guideline provides information that will optimize the counselling and care of Canadian women with respect to their reproductive choices . OUTCOMES: Maternal age is the most important determinant of fertility, and obstetric and perinatal risks increase with maternal age . Many women are unaware of the success rates or limitations of assisted reproductive technology and of the increased medical risks of delayed child-bearing, including multiple births, preterm delivery, stillbirth, and Caesarean section . This guideline provides a framework to address these issues . EVIDENCE: Studies published between 2000 and August 2010 were retrieved through searches of PubMed and the Cochrane Library using appropriate key words (delayed child-bearing, deferred pregnancy, maternal age, assisted reproductive technology, infertility, and multiple births) and MeSH terms (maternal age, reproductive behaviour, fertility) . The Internet was also searched using similar key words, and national and international medical specialty societies were searched for clinical practice guidelines and position statements . Data were extracted based on the aims, sample, authors, year, and results . VALUES: The quality of evidence was rated using the criteria described in the Report of the Canadian Task Force on Preventive Health Care. SPONSOR: The Society of Obstetricians and Gynaecologists of Canada.

No. 348-Joint SOGC-CCMG Guideline: Update on Prenatal Screening for Fetal Aneuploidy, Fetal Anomalies, and Adverse Pregnancy Outcomes.

OBJECTIVE: To review the available prenatal screening options in light of the recent technical advances and to provide an update of previous guidelines in the field of prenatal screening. INTENDED USERS: Health care providers involved in prenatal screening, including general practitioners, obstetricians, midwives, maternal fetal medicine specialists, geneticists, and radiologists. TARGET POPULATION: All pregnant women receiving counselling and providing informed consent for prenatal screening. EVIDENCE: Published literature was retrieved through searches of Medline, PubMed, and the Cochrane Library in and prior to March 2016 using an appropriate controlled vocabulary (prenatal diagnosis, amniocentesis, chorionic villi sampling, non-invasive prenatal screening) and key words (prenatal screening, prenatal genetic counselling). Results were restricted to systematic reviews, randomized control trials/controlled clinical trials, and observational studies written in English and published from January 1985 to May 2016. Searches were updated on a regular basis and incorporated in the guideline. Grey (unpublished) literature was identified through searching the websites of health technology assessment and health technology-related agencies, clinical practice guideline collections, clinical trial registries, and national and international medical speciality societies. GUIDELINE UPDATE: Evidence will be reviewed 5 years after publication to determine whether all or part of the guideline should be updated. However, if important new evidence is published prior to the 5-year cycle, the review process may be accelerated for a more rapid update of some recommendations.

No. 343-Routine Non-invasive Prenatal Prediction of Fetal RHD Genotype in Canada: The Time is Here.

The optimal management of the D-negative pregnant woman is now based on the non-invasive antenatal prediction of fetal D-blood group by cell-free DNA (cfDNA) in maternal plasma, with targeted prophylaxis for women carrying RHD-positive fetuses. This provides the optimal care for D-negative pregnant women and has been adopted as the standard approach in a growing number of countries around the world. This paper is the result of a consensus meeting of the Canadian National Rh Working Group, an interdisciplinary group formed to review the current status of fetal RHD genotyping based on cfDNA in Canada. The group, in collaboration with the SOGC Genetics committee, reviewed the benefits and challenges of implementing RHD genotyping with targeted prophylaxis in the context of the existing routine antenatal anti D prophylaxis program in Canada. The following summary statements and recommendations are based on this review. SUMMARY STATEMENTS: RECOMMENDATIONS.