Ultrasonographic Fetal Nuchal Translucency Measurements and Cytogenetic Outcomes.

Importance: Ultrasonographic measurement of fetal nuchal translucency is used in prenatal screening for trisomies 21 and 18 and other conditions. A cutoff of 3.5 mm or greater is commonly used to offer follow-up investigations, such as prenatal cell-free DNA (cfDNA) screening or cytogenetic testing. Recent studies showed a possible association with chromosomal anomalies for levels less than 3.5 mm, but extant evidence has limitations. Objective: To evaluate the association between different nuchal translucency measurements and cytogenetic outcomes on a population level. Design, Setting, and Participants: This population-based retrospective cohort study used data from the Better Outcomes Registry & Network, the perinatal registry for Ontario, Canada. All singleton pregnancies with an estimated date of delivery from September 1, 2016, to March 31, 2021, were included. Data were analyzed from March 17 to August 14, 2023. Exposures: Nuchal translucency measurements were identified through multiple-marker screening results. Main Outcomes and Measures: Chromosomal anomalies were identified through all Ontario laboratory-generated prenatal and postnatal cytogenetic tests. Cytogenetic testing results, supplemented with information from cfDNA screening and clinical examination at birth, were used to identify pregnancies without chromosomal anomalies. Multivariable modified Poisson regression with robust variance estimation and adjustment for gestational age was used to compare cytogenetic outcomes for pregnancies with varying nuchal translucency measurement categories and a reference group with nuchal translucency less than 2.0 mm. Results: Of 414 268 pregnancies included in the study (mean [SD] maternal age at estimated delivery date, 31.5 [4.7] years), 359 807 (86.9%) had a nuchal translucency less than 2.0 mm; the prevalence of chromosomal anomalies in this group was 0.5%. An increased risk of chromosomal anomalies was associated with increasing nuchal translucency measurements, with an adjusted risk ratio (ARR) of 20.33 (95% CI, 17.58-23.52) and adjusted risk difference (ARD) of 9.94% (95% CI, 8.49%-11.39%) for pregnancies with measurements of 3.0 to less than 3.5 mm. The ARR was 4.97 (95% CI, 3.45-7.17) and the ARD was 1.40% (95% CI, 0.77%-2.04%) when restricted to chromosomal anomalies beyond the commonly screened aneuploidies (excluding trisomies 21, 18, and 13 and sex chromosome aneuploidies). Conclusions and Relevance: In this cohort study of 414 268 singleton pregnancies, those with nuchal translucency measurements less than 2.0 mm were at the lowest risk of chromosomal anomalies. Risk increased with increasing measurements, including measurements less than 3.5 mm and anomalies not routinely screened by many prenatal genetic screening programs.

First and second trimester maternal serum markers for prenatal aneuploidy screening: An update on the adjustment factors for race, smoking, and insulin dependent diabetes mellitus.

OBJECTIVES: The concentrations of maternal serum markers for aneuploidy screening are influenced by maternal characteristics such as race, smoking, insulin dependent diabetes mellitus (IDDM), and in vitro fertilization (IVF). Accurate risk estimation requires adjustment of initial values for these characteristics. This study aims to update and validate adjustment factors for race, smoking, and IDDM. METHODS: The study included singleton pregnancies that received multiple marker screening in Ontario, Canada between January 2012, and December 2018, and had their information collected in the Better Outcomes Registry & Network (BORN) Ontario. Serum markers assessed included first trimester pregnancy-associated plasma protein A (PAPP-A), free ß and total human chorionic gonadotropin (hCG), placental growth factor (PlGF) and αlpha-fetoprotein (AFP); second trimester AFP, unconjugated estriol (uE3), total hCG and inhibin A. The Mann-Whitney U test was used to assess the differences in the median multiple of the median (MoM) of serum markers between study and reference groups. New adjustment factors were generated by dividing the median MoM of a particular race, individuals who smoke tobacco, or have IDDM by those of the reference groups. RESULTS: The study included 624,789 pregnancies. There were statistically significant differences in serum marker concentrations among pregnant individuals who were Black, Asian, or First Nations compared to a White group, those who smoked compared to Non-smoking individuals, and those with IDDM compared to Non-IDDM group. New adjustment factors for race, smoking, and IDDM were validated by comparing median MoM of serum markers corrected using the current adjustment factors and new adjustment factors generated in this study. CONCLUSION: The adjustment factors generated in this study can adjust the effects of race, smoking, and IDDM on serum markers more accurately.

Perinatal and pediatric outcomes associated with the use of fertility treatment: a population-based retrospective cohort study in Ontario, Canada.

BACKGROUND: Around 2% of births in Ontario, Canada involve the use of assisted reproductive technology (ART), and it is rising due to the implementation of a publicly funded ART program in 2016. To better understand the impact of fertility treatments, we assessed perinatal and pediatric health outcomes associated with ART, hormonal treatments, and artificial insemination compared with spontaneously conceived births. METHODS: This population-based retrospective cohort study was conducted using provincial birth registry data linked with fertility registry and health administrative databases in Ontario, Canada. Live births and stillbirths from January 2013 to July 2016 were included and followed to age one. The risks of adverse pregnancy, birth and infant health outcomes were assessed by conception method (spontaneous conception, ART - in vitro fertilization and non-ART - ovulation induction, intra-uterine or vaginal insemination) using risk ratios and incidence rate ratios with 95% confidence intervals (CI). Propensity score weighting using a generalized boosted model was applied to adjust for confounding. RESULT(S): Of 177,901 births with a median gestation age of 39 weeks (IQR 38.0-40.0), 3,457 (1.9%) were conceived via ART, and 3,511 (2.0%) via non-ART treatments. There were increased risks (adjusted risk ratio [95% CI]) of cesarean delivery (ART: 1.44 [1.42-1.47]; non-ART: 1.09 [1.07-1.11]), preterm birth (ART: 2.06 [1.98-2.14]; non-ART: 1.85 [1.79-1.91]), very preterm birth (ART: 2.99 [2.75-3.25]; non-ART: 1.89 [1.67-2.13]), 5-min Apgar < 7 (ART: 1.28 [1.16-1.42]; non-ART: 1.62 [1.45-1.81]), and composite neonatal adverse outcome indicator (ART: 1.61 [1.55-1.68]; non-ART: 1.29 [1.25-1.34]). Infants born after fertility treatments had increased risk of admission to neonatal intensive care unit (ART: 1.98 [1.84-2.13]; non-ART: 1.59 [1.51-1.67]) and prolonged birth admission (≥ 3 days) (ART: 1.60 [1.54-1.65]; non-ART: 1.42 [1.39-1.45]). The rate of emergency and in-hospital health services use within the first year was significantly increased for both exposure groups and remained elevated when limiting analyses to term singletons. CONCLUSION(S): Fertility treatments were associated with increased risks of adverse outcomes; however, the overall magnitude of risks was lower for infants conceived via non-ART treatments.

Cytogenetic outcomes following a failed cell-free DNA screen: a population-based retrospective cohort study of 35,146 singleton pregnancies.

BACKGROUND: Cell-free fetal DNA screening is routinely offered to pregnant individuals to screen for aneuploidies. Although cell-free DNA screening is consistently more accurate than multiple-marker screening, it sometimes fails to yield a result. These test failures and their clinical implications are poorly described in the literature. Some studies suggest that a failed cell-free DNA screening result is associated with increased likelihood of cytogenetic abnormalities. OBJECTIVE: This study aimed to assess the association between a failed cell-free DNA test and common aneuploidies. The objectives were to determine: (1) the proportion of test failures on first and subsequent attempts, and (2) whether a failed cell-free DNA screen on first attempt is associated with increased likelihood of common aneuploidies (trisomies 21, 18, and 13, and sex chromosome aneuploidies). STUDY DESIGN: This was a population-based retrospective cohort study using data from Ontario's prescribed maternal and child registry, Better Outcomes Registry and Network Ontario. The study included all singleton pregnancies in Ontario with an estimated date of delivery from September 1, 2016 to March 31, 2019 that had a cell-free DNA screening record in the registry. Specific outcomes (trisomies 21, 18, and 13, and sex chromosome aneuploidies) of pregnancies with a failed cell-free DNA screen on first attempt were compared with those of pregnancies with low-risk cell-free DNA-screening results using modified Poisson regression adjusted for funding status (publicly funded vs self-paid), gestational age at screening, method of conception, and maternal age for autosomal aneuploidies. RESULTS: Our cohort included 35,146 pregnancies that had cell-free DNA screening during the study period. The overall cell-free DNA screening failure rate was 4.8% on first attempt and 2.2% after multiple attempts. An abnormal cytogenetic result for trisomies 21, 18, and 13, or sex chromosome aneuploidies was identified in 19.4% of pregnancies with a failed cell-free DNA screening for which cytogenetic testing was performed. Pregnancies with a failed cell-free DNA screen on first attempt had a relative risk of 130.3 (95% confidence interval, 64.7-262.6) for trisomy 21, trisomy 18, or trisomy 13, and a risk difference of 5.4% (95% confidence interval, 2.6-8.3), compared with pregnancies with a low-risk result. The risk of sex chromosome aneuploidies was not significantly greater in pregnancies with a failed result compared with pregnancies with a low-risk result (relative risk, 2.7; 95% confidence interval, 0.9-7.9; relative difference, 1.2%; 95% confidence interval, -0.9 to 3.2). CONCLUSION: Cell-free DNA screening test failures are relatively common. Although repeated testing improves the likelihood of an informative result, pregnancies with a failed cell-free DNA screen upon first attempt remain at increased risk for common autosomal aneuploidies, but not sex chromosome aneuploidies.

The effect of the Ontario Fertility Program on IVF utilization and outcomes in women of advanced reproductive age.

RESEARCH QUESTION: Are the demographics and clinical outcomes similar for patients aged ≥40 but <43 years seeking IVF in Ontario, Canada, before and after implementation of the Ontario Fertility Program (OFP), which supports public funding of IVF up to age 43? DESIGN: Retrospective database review using the Canadian Assisted Reproductive Technologies Registry Plus (CARTR Plus) and Better Outcomes Registry & Network (BORN) Ontario databases. Cycles from women who underwent autologous IVF and who were aged ≥40 and <43 years were analysed during a 2-year period prior to (2014-2015) and after (2016-2017) introduction of publicly funded IVF through the OFP. RESULTS: There was an almost doubling of treatment cycles in women aged 40-42 in Ontario after the OFP launch. Clinical pregnancy rate per cycle start (17.0% versus 13.3%, P < 0.001) and cumulative clinical pregnancy rate per stimulation cycle (20.5% versus 16.8%, P < 0.001) were statistically higher in women before OFP implementation. While cumulative live birth rate per cycle start was statistically lower after funding was introduced (12.5% versus 10.5%, P = 0.027), the clinical importance of this difference appears small. Outcomes were above the 10% live birth per cycle threshold recommended by the Advisory Process for Infertility Services panel, commissioned by the Ministry of Health, to determine access to publicly funded IVF. CONCLUSIONS: Use of IVF in women over age 40 doubled with access to OFP funding; however, eligibility criteria based on age still meet the target of achieving a cumulative live birth rate of at least 10%.

A descriptive qualitative study exploring the postpartum confinement experiences among first-time mothers from the three major ethnic groups in Singapore.

OBJECTIVE: Modern Singaporean mothers still embrace traditional confinement practices after childbirth, which often marks a significant milestone in maternal experiences. However, limited studies have explored in-depth the collective confinement experiences of mothers in Singapore. This study hence aimed to explore the postpartum confinement experiences of first-time mothers from the three major ethnic groups in Singapore, namely Chinese, Malay, and Indian. DESIGN: A descriptive qualitative study was conducted. Purposive sampling was adopted to recruit participants. Individual semi-structured face-to-face/telephone interviews were used to collect data, which were analysed using thematic analysis. SETTING AND PARTICIPANTS: Sixteen first-time mothers were recruited from two obstetric clinics in a tertiary hospital in Singapore. FINDINGS: Five themes emerged: "Specific diets adopted and avoided for different purposes", "Complexity of various traditional confinement practices (TCPs) adopted", "Reasons for adopting TCPs", "Reasons for modifying TCPs", and "Postpartum challenges". KEY CONCLUSIONS: Our study provided unique insights about Singapore's Chinese, Malay and Indian first-time mothers' postpartum confinement experiences. While confinement practices were still observed, many mothers no longer subscribed to guidelines followed by previous generations and were modifying or forgoing practices they deemed impractical. Mothers faced challenges adapting to new motherhood and often felt restrained or stressed by confinement practices. IMPLICATIONS FOR PRACTICE: Healthcare professionals should take the lead to educate mothers and their families on harmful traditional confinement practices and their misconceptions. Future studies could explore alternative methods of postpartum check-up to improve first-time mothers' confinement experiences, and focus specifically on lower-income families to explore their unique confinement experiences.

Optimal endometrial thickness in fresh and frozen-thaw in vitro fertilization cycles: an analysis of live birth rates from 96,000 autologous embryo transfers.

OBJECTIVE: To study the effect of increasing endometrial thickness on live birth rates in fresh and frozen-thaw embryo transfer (FET) cycles. DESIGN: Retrospective cohort study. SETTING: National data from Autologous in vitro fertilization (IVF) embryo transfer and FET cycles in Canada from the Canadian Assisted Reproductive Technology Registry Plus (CARTR Plus) database for records between January 2013 and December 2019. PATIENTS: Thirty-three Canadians clinics participated in voluntary reporting of IVF and pregnancy outcomes to the Canadian Assisted Reproductive Technology Registry Plus database, and a total of 43,383 fresh and 53,377 frozen transfers were included. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Clinical pregnancy, pregnancy loss, and live birth rates. RESULTS: In fresh IVF-embryo transfer cycles, increasing endometrial thickness is associated with significant increases in the mean number of oocytes retrieved, peak estradiol levels, number of usable embryos, clinical pregnancy rates, live birth rates, and mean term singleton birth weights, and a decrease in pregnancy loss rates. However, live birth rates plateau after 10-12 mm. In contrast, in FET cycles live birth rates plateau after the endometrium measures 7-10 mm. The improvement in live birth rates with increasing endometrial thickness was independent of patient age, timing of embryo transfer (e.g., cleavage stage vs. blastocyst stage), or the number of oocytes at retrieval. CONCLUSIONS: In cycles with a fresh embryo transfer, live birth rates increase significantly until an endometrial thickness of 10-12 mm, while in FET cycles live birth rates plateau after 7-10 mm. However, an endometrial thickness <6 mm was associated clearly with a dramatic reduction in live birth rates in fresh and frozen embryo transfer cycles.

Performance of a universal prenatal screening program incorporating cell-free fetal DNA analysis in Ontario, Canada.

BACKGROUND: The emergence of cell-free fetal DNA (cfDNA) testing technology has disrupted the landscape of prenatal screening for trisomies 21 (T21) and 18 (T18). Publicly funded systems around the world are grappling with how to best integrate this more accurate but costly technology, as there is limited evidence about its incremental value in real-world conditions. The objectives of this study were to describe the population-based performance of Ontario's prenatal screening program, which incorporates publicly funded cfDNA screening for specific indications, and the effect of cfDNA testing on the screening and diagnostic choices made by pregnant people. METHODS: We conducted a retrospective, descriptive cohort study using routinely collected data from Better Outcomes & Registry Network (BORN) Ontario, which captures linked population data for prenatal and neonatal health encounters across Ontario. We included all singleton pregnancies with an estimated due date between Sept. 1, 2016, and Mar. 31, 2019, that underwent publicly funded prenatal screening in Ontario, and a comparison cohort from Apr. 1, 2012, and Mar. 31, 2013. We assessed performance of the screening program for the detection of T21 or T18 by calculating sensitivity, specificity, positive predictive value and negative predictive value against diagnostic cytogenetic results or birth outcomes. We assessed the impact of the program by calculating the proportion of T21 screen-positive pregnancies undergoing subsequent cfDNA screening and invasive prenatal diagnostic testing. RESULTS: The study cohort included 373 682 pregnancies. The prenatal screening program had an uptake of 69.9%, a screen-positive rate and sensitivity of 1.6% and 89.9% for T21, and 0.2% and 80.5% for T18, respectively. The test failure rate for cfDNA screening was 2.2%. Invasive prenatal diagnostic testing decreased from 4.4% in 2012-2013 to 2.4% over the study period; 65.2% of pregnant people who received a screen-positive result from cfDNA testing went on to have invasive prenatal diagnostic testing. INTERPRETATION: This publicly funded screening program, incorporating cfDNA analysis for common aneuploidies, showed robust performance, a substantial reduction in invasive prenatal diagnostic testing and that pregnant people exercise autonomy in their choices about prenatal screening and diagnosis.

Gastroschisis in Ontario, Canada: 2012-2018.

BACKGROUND: Gastroschisis is a congenital anomaly of the abdomen in which the intestines are found outside of the body at birth. While no clear causative factors have been identified, it is strongly associated with young maternal age. Other reported associations include low maternal socioeconomic status, low maternal body mass index (BMI), and smoking. METHODS: This is a retrospective review of epidemiologic data relating to cases of gastroschisis in Ontario from 2012-2018 in the Better Outcomes Registry & Network (BORN) Ontario database, which is the province's prescribed maternal-newborn registry. We describe the epidemiology of gastroschisis in Ontario with respect to birth prevalence, maternal age, health, exposures, and geography. RESULTS: The birth prevalence of gastroschisis is 2.31 cases/10,000 births. There was no apparent change in birth prevalence over the study period and there was no difference between male and female infants. Gastroschisis was associated with younger maternal ages and was inversely correlated with maternal BMI. Gastroschisis was associated with first completed pregnancy. Maternal diabetes was associated with a lower birth prevalence of gastroschisis than average. Mothers of babies with gastroschsis were more likely to report use of tobacco, alcohol, and drugs during pregnancy than those without gastroschisis, with marijuana use showing the largest increase in birth prevalence of gastroschisis. Mothers living in rural areas were more likely to have a baby with gastroschisis than those in urban centers, even after controlling for maternal age. CONCLUSIONS: This Ontario registry study reveals that mothers with babies with gastroschisis are more likely to be young and thin, live in rural areas, and report prenatal smoking, alcohol use, and drug use than women whose pregnancies do not have gastroschsis.

A 2-year review of publicly funded cell-free DNA screening in Ontario: utilization and adherence to funding criteria.

OBJECTIVE: Ontario offers a publicly funded modified contingent model of prenatal screening for aneuploidy in which cell-free DNA (cfDNA) screening is covered for pregnancies at higher risk of fetal aneuploidy. The objective of this study was to review utilization of provincially funded cfDNA screening and adherence to the criteria laid out in Ontario prenatal screening guidelines. METHODS: This was a descriptive cohort study using data collected by Ontario's prescribed maternal and child registry. The study population included all pregnant individuals who received cfDNA screening from January 2016 to December 2017. RESULTS: The most common criteria for provincially funded cfDNA screening were advanced maternal age ≥40 years (37.7%), positive multiple marker screen (34.1%), modifying risk factors such as ultrasound soft markers (7.1%), and previous aneuploidy (5.5%). The audit demonstrated that 2.9% of funded cfDNA screens tests did not meet funding criteria, and that 11.4% of self-paid cfDNA screens could have been publicly funded. CONCLUSION: Reviewing and auditing the application of criteria for funded cfDNA screening using prescribed registry data allows an opportunity to identify areas where targeted education may improve adherence to standardized screening protocols, and provides a basis for reassessment of the funding model.