Prevalence and Risk of Down Syndrome in Monozygotic and Dizygotic Multiple Pregnancies in Europe

Background The incidence of autosomal trisomy in livebirths is strongly dependent on maternal age. Special consideration is given to the provision of prenatal screening and cytogenetic testing to women of advanced maternal age (AMA). The aim of this study was to evaluate the effectiveness of second trimester prenatal screening and amniocentesis for Down syndrome (DS) and compare the trends of choice of screening and amniocentesis among AMA women. Methods A total of 5404 AMA patients with natural singleton pregnancy were recruited for this prospective study from January 2008 to December 2010. The gestational weeks were from 15 weeks to 20+6 weeks. The patients referred were grouped into a screening group (2107 cases) and an amniocentesis group (3297 cases) by their own decision. The prevalence of DS was compared between the two groups by chi-square test. Choice rates for each maternal age with trends were compared by regression analysis. Results There were 18 cases of fetal DS detected in the screening group with a prevalence of 8.54‰ (18/2107). Twenty-five cases of fetal DS were diagnosed in the amniocentesis group with a prevalence of 7.58‰ (25/3297). No statistical difference was observed in the prevalence of DS between the screening and amniocentesis group (P=0.928). The invasive testing rate for DS in the amniocentesis group was 5.54 times higher than that of the screening group (1/131.88 vs. 1/23.78). With the increase of the maternal age, the choice of amniocentesis increased while the choice of the screening showed an opposite trend. The choice of the AMA women between the screening and amniocentesis was significantly age relevant (P=0.012). Conclusions The second trimester serum screening in combination with maternal age was more effective than maternal age alone to screen for DS. We suggest educating the patients by recommending AMA women be informed of both screening and amniocentesis options.

Down syndrome (DS) is the most common chromosomal disorder that causes mental retardation. In 2009, a population-based birth defects study was implemented in three provinces in southern Thailand. This study aimed to determine the prevalence of DS in the studied regions, and the proportion of DS fetuses detected by prenatal screening. Data were obtained from a population-based surveillance study undertaken during 2009-2013. Entries in the birth defects registry included live births, stillbirths after 24 weeks gestational age, and terminations of pregnancy following prenatal diagnosis. Infants with clinical characteristics of DS had a chromosomal study to make a definite diagnosis. Of the total 186 393 births recorded during the study period, 226 DS cases were listed, giving a prevalence of 1.21 per 1000 births [95% confidence interval (CI) 1.05-1.37]. The median maternal age was 36.5 years with a percentage of maternal age ≥35 years of 60.6%. Seventy-seven cases (34.1% of all cases) were diagnosed prenatally and these pregnancies were terminated. The prevalence of DS per 1000 births was significantly higher in older women, from 0.47 (95% CI 0.28-0.67) in mothers aged <30 years to 0.88 (95% CI 0.59-1.17) in mothers 30-<35 years (P<0.01), and to 4.74 (95% CI 3.95-5.53) in mothers ≥35 years (P<0.001). The prevalence of DS significantly increased with maternal age. About 35% of DS cases were detected prenatally and later terminated. Hence, examining only registry live births will result in an inaccurate prevalence rate of DS.

The impact of prenatal diagnosis on the live birth prevalence of Down syndrome (trisomy 21) has been described. This study examines the prevalence of Down syndrome before (1990-1993) and after inclusion of prenatally diagnosed cases (1994-1999) in a population-based registry of birth defects in metropolitan Atlanta. We identified infants and spontaneous fetal deaths with Down syndrome (n = 387), and pregnancies electively terminated after a prenatal diagnosis of Down syndrome (n = 139) from 1990 to 1999 among residents of metropolitan Atlanta from a population-based registry of birth defects, the Metropolitan Atlanta Congenital Defects Program (MACDP). Only diagnoses of full trisomy 21 were included. Denominator information on live births was derived from State of Georgia birth certificate data. We compared the prevalence of Down syndrome by calendar period (1990-1993, 1994-1999), maternal age (<35 years, 35+ years), and race/ethnicity (White, Black, other), using chi-square and Fisher's exact tests. During the period when case ascertainment was based only on hospitals (1990-1993), the prevalence of Down syndrome was 8.4 per 10,000 live births when pregnancy terminations were excluded and 8.8 per 10,000 when terminations were included. When case ascertainment also included perinatal offices (1994-1999), the prevalence of Down syndrome was 10.1 per 10,000 when terminations were excluded and 15.3 when terminations were included. During 1990-1993, the prevalence of Down syndrome was 24.7 per 10,000 among offspring to women 35+ years of age compared to 6.8 per 10,000 among offspring to women <35 years of age (rate ratio [RR] = 3.65, 95% confidence interval [CI] = 2.53-5.28). During 1994-1999, the prevalence of Down syndrome was 55.3 per 10,000 among offspring to women 35+ years compared to 8.5 per 10,000 among offspring to women <35 years (RR = 6.55, 95% CI = 5.36-7.99). There was no statistically significant variation in the prevalence of Down syndrome by race/ethnicity within maternal age and period of birth strata. During 1994-1999, the proportion of cases that were electively terminated was greater for women 35+ years compared to women <35 years (RR = 5.10, 95% CI = 3.14-8.28), and lower for Blacks compared to Whites among women 35+ years of age (RR = 0.33, 95% CI = 0.16-0.66). In recent years, perinatal offices have become an important source of cases of Down syndrome for MACDP, contributing at least 34% of cases among pregnancies in women 35+ years of age. Variation in the prevalence of Down syndrome by race/ethnicity, before or after inclusion of cases ascertained from perinatal offices, was not statistically significant. Among Down syndrome pregnancies in mothers 35+ years we found a lower proportion of elective termination among Black women compared to White women. We suggest that future reports on the prevalence of Down syndrome by race/ethnicity take into account possible variations in the frequency of prenatal diagnosis or elective termination by race/ethnicity.

This study aimed to assess the risk of adverse maternal and perinatal complications between twin and singleton pregnancies affected by gestational diabetes mellitus and the respective group without gestational diabetes mellitus (controls). A literature search was performed using MEDLINE, Embase, and Cochrane from January 1980 to May2023. Observational studies reporting maternal and perinatal outcomes in singleton and/or twin pregnancies with gestational diabetes mellitus vs controls were included. This was a systematic review and meta-analysis. Pooled estimate risk ratios with 95% confidence intervals were generated to determine the likelihood of adverse pregnancy outcomes between twin and singleton pregnancies with and without gestational diabetes mellitus. Heterogeneity among studies was evaluated in the model and expressed using the I2 statistic. A P value of <.05 was considered statistically significant. The meta-analyses were performed using Review Manager (RevMan Web). Version 5.4. The Cochrane Collaboration, 2020. Meta-regression was used to compare relative risks between singleton and twin pregnancies. The addition of multiple covariates into the models was used to address the lack of adjustments. Overall, 85 studies in singleton pregnancies and 27 in twin pregnancies were included. In singleton pregnancies with gestational diabetes mellitus, compared with controls, there were increased risks of hypertensive disorders of pregnancy (relative risk, 1.85; 95% confidence interval, 1.69-2.01), induction of labor (relative risk, 1.36; 95% confidence interval, 1.05-1.77), cesarean delivery (relative risk, 1.31; 95% confidence interval, 1.24-1.38), large-for-gestational-age neonate (relative risk, 1.61; 95% confidence interval, 1.46-1.77), preterm birth (relative risk, 1.36; 95% confidence interval, 1.27-1.46), and admission to the neonatal intensive care unit (relative risk, 1.43; 95% confidence interval, 1.38-1.49). In twin pregnancies with gestational diabetes mellitus, compared with controls, there were increased risks of hypertensive disorders of pregnancy (relative risk, 1.69; 95% confidence interval, 1.51-1.90), cesarean delivery (relative risk, 1.10; 95% confidence interval, 1.06-1.13), large-for-gestational-age neonate (relative risk, 1.29; 95% confidence interval, 1.03-1.60), preterm birth (relative risk, 1.19; 95% confidence interval, 1.07-1.32), and admission to the neonatal intensive care unit (relative risk, 1.20; 95% confidence interval, 1.09-1.32) and reduced risks of small-for-gestational-age neonate (relative risk, 0.89; 95% confidence interval, 0.81-0.97) and neonatal death (relative risk, 0.50; 95% confidence interval, 0.39-0.65). When comparing relative risks in singleton vs twin pregnancies, there was sufficient evidence to suggest that twin pregnancies have a lower relative risk of cesarean delivery (P=.003), have sufficient adjustment for confounders, and have lower relative risks of admission to the neonatal intensive care unit (P=.005), stillbirths (P=.002), and neonatal death (P=.001) than singleton pregnancies. In both singleton and twin pregnancies, gestational diabetes mellitus was associated with an increased risk of adverse maternal and perinatal outcomes. In twin pregnancies, gestational diabetes mellitus may have a milder effect on some adverse perinatal outcomes and may be associated with a lower risk of neonatal death.

This study documents the screening performance, in practice, of a published protocol for interpreting second-trimester Down syndrome risk in twin pregnancies, using maternal serum biochemical markers. Within a cohort of 35,150 pregnancies, 410 twin pregnancies were identified. The rate of twinning was positively associated with maternal age. Of the 274 twin pregnancies known prior to screening, 15 (5.5 per cent) were classified as being screen-positive for Down syndrome. When maternal age and dating method were taken into account, the screen-positive rates in twin and singleton pregnancies did not differ significantly. Nine of the 14 screen-positive women with viable twin pregnancies chose amniocentesis [64 per cent, 95 per cent confidence interval (CI) 35-87]. No cases of Down syndrome were identified. Based on modelling, an estimated 73 per cent of monozygotic twin pregnancies and 43 per cent of dizygotic twin pregnancies with Down syndrome would be identified at a 5 per cent false-positive rate. The overall detection rate would be about 53 per cent. When laboratories offer multiple marker screening to women with twin pregnancies, the false-positive rate ought to be similar to that found in singleton pregnancies; the detection rate is, however, likely to be lower for dizygotic twins.

The decreased rates of triplet births: Temporal trends and biologic speculations

ObjectiveTo determine risk of Down syndrome (DS) in multiple relative to singleton pregnancies, and compare prenatal diagnosis rates and pregnancy outcome.DesignPopulation-based prevalence study based on EUROCAT congenital anomaly registries.SettingEight European countries.Population14.8 million births 1990–2009; 2.89% multiple births.MethodsDS cases included livebirths, fetal deaths from 20 weeks, and terminations of pregnancy for fetal anomaly (TOPFA). Zygosity is inferred from like/unlike sex for birth denominators, and from concordance for DS cases.Main outcome measuresRelative risk (RR) of DS per fetus/baby from multiple versus singleton pregnancies and per pregnancy in monozygotic/dizygotic versus singleton pregnancies. Proportion of prenatally diagnosed and pregnancy outcome.Statistical analysisPoisson and logistic regression stratified for maternal age, country and time.ResultsOverall, the adjusted (adj) RR of DS for fetus/babies from multiple versus singleton pregnancies was 0.58 (95% CI 0.53–0.62), similar for all maternal ages except for mothers over 44, for whom it was considerably lower. In 8.7% of twin pairs affected by DS, both co-twins were diagnosed with the condition. The adjRR of DS for monozygotic versus singleton pregnancies was 0.34 (95% CI 0.25–0.44) and for dizygotic versus singleton pregnancies 1.34 (95% CI 1.23–1.46). DS fetuses from multiple births were less likely to be prenatally diagnosed than singletons (adjOR 0.62 [95% CI 0.50–0.78]) and following diagnosis less likely to be TOPFA (adjOR 0.40 [95% CI 0.27–0.59]).ConclusionsThe risk of DS per fetus/baby is lower in multiple than singleton pregnancies. These estimates can be used for genetic counselling and prenatal screening.

Trends and geographic inequalities in the prevalence of Down syndrome in Europe, 1980-1999

Down syndrome (DS) ranks as one of the most common birth defects in the United States. The relaxed filter hypothesis (RFH) asserts that mothers with no previous children but nearing reproductive senescence reduce fetal selectivity against DS pregnancies in the first trimester given the high probability of having no offspring at all if the DS pregnancy is not carried to term. We test the parity prediction of RFH-specifically, that pregnancies to older mothers with no previous live births show an elevated prevalence of DS above values expected from the separate contributions of older maternal age and primiparity. We retrieved maternal age and parity information on 2,748 DS cases (live, stillborn, or terminated due to anomaly) from the Paris Birth Defects Registry, 1983-2015. We used two waves of the Enquête Fertility Survey (n = 5,460) and counts of stillbirths to calculate total prevalence of DS by maternal age and parity. Primiparous mothers 35+ years show the greatest prevalence of any parity group (9.78 cases per 1,000 deliveries). Tests for additive interaction of primiparity and older maternal age reject the null (relative excess risk due to interaction = 1.01; 95% confidence interval: 0.33, 1.69; null value on additive scale is 0). Relaxed selection may account for 10% of the increase in the prevalence, among older primiparous mothers, of DS detected during or after the 11th week. Future work may hold implications for understanding, among older mothers, the strength of this maternal screen against other defects.

To identify mortality trends and risk factors associated with stillbirths and neonatal deaths 1982-2011. Population-based cross-sectional study based on reported pregnancy history in Iganga-Mayuge Health and Demographic Surveillance Site (HDSS) in Uganda. A pregnancy history survey was conducted among women aged 15-49 years living in the HDSS during May-July 2011 (n = 10 540). Time trends were analysed with cubic splines and linear regression. Potential risk factors were examined with multilevel logistic regression with adjusted odds ratios (AOR) and 95% confidence intervals (CI). 34 073 births from 1982 to 2011 were analysed. The annual rate of decrease was 0.9% for stillbirths and 1.8% for neonatal mortality. Stillbirths were associated with several risk factors: multiple births (AOR 2.57, CI 1.66-3.99), previous adverse outcome (AOR 6.16, CI 4.26-8.88) and grand multiparity among 35- to 49-year-olds (AOR 1.97, CI 1.32-2.89). Neonatal deaths were associated with multiple births (AOR 6.16, CI 4.80-7.92) and advanced maternal age linked with parity of 1-4 (AOR 2.34, CI 1.28-4.25) and grand multiparity (AOR 1.44, CI 1.09-1.90). Education, marital status and household wealth were not associated with the outcomes. The slow decline in mortality rates and easily identifiable risk factors calls for improving quality of care at birth and a rethinking of how to address obstetric risks, potentially a revival of the risk approach in antenatal care.

To investigate the prevalence of live birth Down syndrome (DS) in the region of Primorsko-goranska County (PGC) in Croatia from 1996 to 2005 and to evaluate the impact of second-trimester maternal serum screening (MSS) and amniocentesis on live birth DS prevalence. Study was based on databases from the Department of Gynecology and Obstetrics, University Hospital Centre Rijeka, the Department of Biology and Medical Genetics, School of Medicine, University of Rijeka, and the Croatian National Institute of Public Health. The regional policy of prenatal diagnosis for DS includes amniocentesis for pregnant women aged 35 or over and MSS for younger women. We estimated live birth and total prevalence of DS and measured the proportion of pregnant women using MSS and amniocentesis. Trends of live birth and total prevalence of DS were tested by linear regression analysis. The live birth prevalence of DS was 1.4/1000 in the period 1996-2005. A decreasing, but nonsignificant, trend of prevalence was observed over time (P = 0.577). Women aged 35 or over represented 11.6% of all pregnant women included in the study. The proportion of women who had MSS was 33.9%. The proportion who underwent amniocentesis was 6.1%. No marked decrease in prevalence of live birth DS was observed in the region of PGC during the last 10 years. The usage of MSS and amniocentesis was too low to have any significant impact on live birth DS prevalence. Women's, as well as physician's, knowledge and attitudes towards prenatal diagnosis of DS should be evaluated.

To determine the influence of maternal smoking on the birth prevalence of Down syndrome and on second trimester screening performance. First, a meta-analysis of cohort and case-control studies was performed to estimate the effect of maternal smoking on the live birth prevalence of Down syndrome. Then, data from 8779 women screened using the quadruple test (alphafetoprotein (AFP), unconjugated estriol (uE(3)), human chorionic gonadotrophin (free beta-hCG), and inhibin-A levels with maternal age) were used to determine the effect of smoking on the serum markers. A Monte Carlo simulation was used to assess the impact of adjusting for smoking status on screening performance. The relative risk of Down syndrome in smokers (versus non-smokers) was 0.95 (95% confidence interval (CI) 0.87 to 1.03). Serum marker levels were determined as multiples of the median for non-smokers of the same gestational age and adjusted for maternal weight (MoM). The MoM values for AFP were 5% higher (95% CI 2-7%), uE(3) 4% lower (95% CI 2-5%), free beta-hCG 20% lower (95% CI 17-23%) and inhibin-A 62% higher (95% CI 57-67%) in smokers compared with non-smokers. Adjusting marker levels for smoking resulted in less than a 1 percentage point increase in the detection rate for a 5% false positive rate with the double, triple or quadruple tests. There is no evidence of an association between the birth prevalence of Down syndrome and maternal smoking. The case for adjusting screening marker levels for smoking is not compelling. But if smoking data are collected routinely adjustment could be made and this would yield similar detection and false positive rates in smokers and non-smokers.

Severity of prematurity risk in spontaneous and in vitro fertilization twins: does conception mode serve as a risk factor?

To estimate the association of advanced maternal age with pregnancy complications in twin pregnancies and compare it with that observed in singleton pregnancies. A population-based retrospective cohort study of all patients with a singleton or twin hospital birth in Ontario, Canada, between 2012 and 2019. The primary outcome was preterm birth (PTB) less than 34 weeks. Pregnancy outcomes were stratified by maternal age groups in twin pregnancies and, separately, in singleton pregnancies. A total of 935 378 patients met the study criteria: 920503 (98.4%) had a singleton pregnancy and 14 875 (1.6%) had twins. In singletons, the rate of PTB less than 34 weeks increased progressively with increasing maternal age and was highest for patients aged 45 years or more (3.4%; adjusted risk ratio [aRR] 1.56, 95% confidence interval [CI] 1.05-2.33). By contrast, in twins, although the rate of PTB less than 34 was highest patients under 20 years of age (25.3%) and was lowest among patients aged 35-39 years (11.7%), the associations between maternal age group and the risk of PTB were not statistically significant in the adjusted analysis. Although the absolute rates of pregnancy complications are higher in twin pregnancies, there are considerable differences in the relationship between maternal age and the risk of certain complications between twin and singleton pregnancies.

Background COVID-19 vaccines in pregnancy protect both pregnant individuals and young infants from severe illness via transplacental transfer of maternally-derived IgG. However, the impact of multiple (e.g. twin) pregnancy on transplacental transfer of SARS-CoV-2 IgG is unknown. We aimed to evaluate anti-Spike (S) antibody transfer among infants from twin pregnancies compared to singleton pregnancies. Methods We conducted a prospective cohort study among individuals with twin and singleton pregnancies who received at least 2 doses of an mRNA COVID-19 vaccine prior to delivery. We tested paired maternal and cord samples for anti-S IgG and used linear regression to evaluate associations between multiple or singleton pregnancy and anti-S antibody. We included as covariates timing of last vaccine dose, gestational age at delivery, number of doses prior to delivery, and small for gestational age (&amp;lt; 10th percentile) birthweight. Results We tested maternal/cord anti-S IgG from 25 twin and 291 singleton pregnancies. The median gestational age at delivery was 36 weeks for twin infants compared to 39 weeks for singleton infants. Median maternal anti-S IgG was 5812 BAU/mL (IQR:754, 16061) and 2971 BAU/mL (IQR:706, 14000) for twin and singleton pregnancies, respectively. Median cord anti-S IgG was 4110 BAU/mL (IQR: 527, 15937) and 3636 BAU/mL (IQR: 1019, 15465) for twin and singleton infants, respectively (Figure 1). Cord:maternal IgG ratios were significantly lower in twin pregnancies compared to singleton pregnancies (p &amp;lt; 0.01; Figure 2). After adjustment for covariates, there was no difference between maternal anti-S IgG concentrations (beta: -0.54; 95% confidence interval [CI]: -1.26,0.18; p=0.14), cord anti-S IgG concentrations (beta: -0.77; 95% CI: -1.68,0.13; p=0.10) or cord:maternal IgG ratios (beta: -0.07; 95% CI: -0.32,0.19; p=0.61) between twin and singleton pregnancies. Conclusion Twin and singleton infants benefit similarly from maternal COVID-19 vaccine during pregnancy. Higher risk pregnancies including multiple pregnancies should be considered in health policy discussions regarding COVID-19 vaccine timing in pregnancy. Disclosures Alisa B. Kachikis, MD, MSc, Merck: Grant/Research Support|Pfizer: Grant/Research Support Mindy Pike, PhD, Merck: Grant/Research Support Alexander L. Greninger, MD, PhD, Cepheid: central contracts|Hologic: central contracts|Janssen: central contracts|Novavax: central contracts|Pfizer: central contracts Janet A. Englund, MD, Ark Biopharma: Advisor/Consultant|AstraZeneca: Advisor/Consultant|AstraZeneca: Grant/Research Support|GlaxoSmithKline: Grant/Research Support|Meissa Vaccines: Advisor/Consultant|Merck: Grant/Research Support|Moderna: Advisor/Consultant|Moderna: Grant/Research Support|Pfizer: Advisor/Consultant|Pfizer: Grant/Research Support|Sanofi Pasteur: Advisor/Consultant