Twenty-year trends in the prevalence of Down syndrome and other trisomies in Europe: impact of maternal age and prenatal screening

This study examines trends and geographical differences in total and live birth prevalence of trisomies 21, 18 and 13 with regard to increasing maternal age and prenatal diagnosis in Europe. Twenty-one population-based EUROCAT registries covering 6.1 million births between 1990 and 2009 participated. Trisomy cases included live births, fetal deaths from 20 weeks gestational age and terminations of pregnancy for fetal anomaly. We present correction to 20 weeks gestational age (ie, correcting early terminations for the probability of fetal survival to 20 weeks) to allow for artefactual screening-related differences in total prevalence. Poisson regression was used. The proportion of births in the population to mothers aged 35+ years in the participating registries increased from 13% in 1990 to 19% in 2009. Total prevalence per 10 000 births was 22.0 (95% CI 21.7–22.4) for trisomy 21, 5.0 (95% CI 4.8–5.1) for trisomy 18 and 2.0 (95% CI 1.9–2.2) for trisomy 13; live birth prevalence was 11.2 (95% CI 10.9–11.5) for trisomy 21, 1.04 (95% CI 0.96–1.12) for trisomy 18 and 0.48 (95% CI 0.43–0.54) for trisomy 13. There was an increase in total and total corrected prevalence of all three trisomies over time, mainly explained by increasing maternal age. Live birth prevalence remained stable over time. For trisomy 21, there was a three-fold variation in live birth prevalence between countries. The rise in maternal age has led to an increase in the number of trisomy-affected pregnancies in Europe. Live birth prevalence has remained stable overall. Differences in prenatal screening and termination between countries lead to wide variation in live birth prevalence.     

Omphalocele, advanced maternal age, and fetal morbidity outcomes

In this study we wanted to determine if the risk for adverse neonatal outcome among omphalocele-affected fetuses is increased among older gravidas. This was a retrospective cohort study on live-born infants with omphalocele delivered in New York State from 1983 through 1999. We compared infants of older (>or=35 years) with those of younger (<35 years) mothers with respect to the following fetal morbidity indices: low birth weight and very low birth weight, preterm and very preterm, and small for gestational age. We used adjusted odds ratios to approximate relative risks. Data on a total of 1,010 infants with omphalocele were analyzed. Mean gestational age and birth weight were similar in both maternal age categories: mean+/-standard deviation (SD) for infants with omphalocele born to older mothers=37.4 weeks+/-3.9 versus 38.0 weeks+/-5.1 for those of younger mothers (P=0.2); mean birth weights+/-SD for infants with omphalocele born to older mothers=2,813+/-871.1 versus 2,958+/-809.9 for those of younger mothers (P=0.08). Also, the two maternal age sub-groups did not differ with respect to the fetal morbidity outcome: low birth weight (OR=0.95; 95% CI=0.60-1.51), very low birth weight (OR=0.78; 95% CI=0.36-1.69), preterm (OR=0.95; 95% CI=0.58-1.57), very preterm (OR=0.73; 95% CI=0.34-1.58), and SGA (OR=1.00; 95% CI=0.44-2.27). Thus, advanced maternal age does not appear to be a risk factor for fetal morbidity outcomes among omphalocele-affected fetuses. This information is potentially useful in counseling affected parents.     

Recent trends in the prevalence of Down syndrome in Japan, 1980–1997

The aims of the present study were to determine recent trends in the prevalence of Down syndrome (DS) in Japan, and to determine whether recent changes in demographic and social habits and access to prenatal diagnosis have influenced the livebirth rates of DS. Livebirth statistics indicate that the birth rate in Japan has decreased for women in their 20s and has increased for those in their 30s and 40s. During an 18-year period between 1980 and 1997, 1,299 consecutive DS infants were born among a total of 2,232,694 births, a rate corresponding to approximately 10% of all births in Japan over the same period. The increasing risk of DS with advancing maternal age was confirmed. The overall prevalence was 5.82 DS births per 10,000 livebirths (8.3–9.7 per 10,000 after correction according to the estimated ascertainment ratio: 60–70%). The prevalence rate by year of child birth represents a statistically significant increase (P = 0.001). In conclusion, recent trends in the prevalence of DS in Japan from 1980 to 1997 failed to show a consistent tendency to decrease, probably because of the concomitant increase in pregnancy in advanced maternal age. Am. J. Med. Genet. 84:340–345, 1999. © 1999 Wiley-Liss, Inc.     

Sex differences for major congenital heart defects in Down Syndrome: A population based study

Background

Down syndrome (DS) is the most common autosomal chromosomal anomaly in liveborn infants. About 40% of infants with DS have a major congenital heart defect (CHD). Among them, atrioventricular septal defects (AVSD), atrial septal defects (ASD), ventricular septal defect (VSD) and Tetralogy of Fallot (ToF) are the most common. The aim of this study was to estimate the sex difference in the occurrence of CHD in infants with DS comparing it with non-DS infants.

Methionine synthase (MTR) 2756 (A --> G) polymorphism,double heterozygosity methionine synthase 2756 AG/methionine synthase reductase (MTRR) 66 AG,and elevated homocysteinemia are three risk factors for having a child with Down syndrome

Contradictory findings have been recently published on the evaluation of genetic polymorphisms of methylenetetrahydrofolate reductase (MTHFR 677 C-->T) and methionine synthase reductase (MTRR 66 A-->G) as risk factors for having a child with Down syndrome (DS); however, the influence of polymorphisms of methionine synthase (MTR 2756 A-->G) and of MTHFR 1298 A-->C has never been evaluated. In this study, the risk of being a DS case or having a DS child (case mother) was studied by multiple logistic regression analysis of the independent and combined genotypes and of plasma homocysteine, folates, and vitamin B12 in 92 DS cases and 140 control subjects as well as in 63 case mothers and 72 age-matched control mothers from Sicily. (The MTHFR 677 T allele frequency was not different in DS cases and case mothers, compared to the respective control groups). After adjustment for age, total homocysteine (t-Hcys) and MTR 2756 AG/GG genotype were significant risk factors for having a DS child, with odds ratio (OR) of 6.7 (95% CI: 1.4-32.0, P = 0.016) and of 3.5 (95% CI: 1.2-10.9, P = 0.028), respectively. By comparison, MTR 2756 AG/GG genotype increased significantly the risk of being a DS case, with an OR of 3.8 (95% CI: 1.4-10.5, P = 0.009). The double heterozygosity MTR 2756 AG/MTRR 66 AG was the single combined genotype that was a significant risk factor for having a DS child, with an OR estimated at 5.0 (95% CI: 1.1-24.1), after adjustment for t-Hcys. In conclusion, our results provide evidences that homocysteine and MTR genetic polymorphism are two potent risk factors for mothers to have a DS child in Sicily.     

Mortality and cancer incidence in persons with Down's syndrome, their parents and siblings

A cohort study of 1425 persons with Down's syndrome (DS), and of their parents (447 mothers, 435 fathers) and siblings (1176), was set up to investigate death rates from various causes and cancer incidence patterns. In individuals with DS the all-cause death rate was six times that of the national population (SMR = 622: 95% CI 559–693), the excess being attributable to many different causes. These included: leukaemia (SMR = 1304: 95% CI 651–2334); diabetes mellitus (SMR = 982: 95% CI 267–2515); Alzheimer's disease (SMR = 22028: 95% CI 7137–51326); epilepsy (SMR = 1727: 95% CI 744–3403); and congenital anomalies (SMR = 4987: 95% CI 4175–5955). The overall survival showed marked improvements for successive birth cohorts, particularly at young ages. For mothers and fathers of persons with DS, all-cause death rates were 20% lower than national rates and there were no significant excesses from any specific cause. For siblings, all-cause death rates were similar to national rates; the only condition with a significantly raised mortality ratio was colo-rectal cancer (SMR = 793: 95% CI 216–2031), but this may well be a chance finding.     

Recent trends in the prevalence of Down syndrome in Japan, 1980-1997.

The aims of the present study were to determine recent trends in the prevalence of Down syndrome (DS) in Japan, and to determine whether recent changes in demographic and social habits and access to prenatal diagnosis have influenced the livebirth rates of DS. Livebirth statistics indicate that the birth rate in Japan has decreased for women in their 20s and has increased for those in their 30s and 40s. During an 18-year period between 1980 and 1997, 1,299 consecutive DS infants were born among a total of 2,232,694 births, a rate corresponding to approximately 10% of all births in Japan over the same period. The increasing risk of DS with advancing maternal age was confirmed. The overall prevalence was 5.82 DS births per 10,000 livebirths (8.3-9.7 per 10,000 after correction according to the estimated ascertainment ratio: 60-70%). The prevalence rate by year of child birth represents a statistically significant increase (P = 0.001). In conclusion, recent trends in the prevalence of DS in Japan from 1980 to 1997 failed to show a consistent tendency to decrease, probably because of the concomitant increase in pregnancy in advanced maternal age.     

The effectiveness of IVF in unexplained infertility: a systematic Cochrane review. 2002,

BACKGROUND: IVF is an accepted treatment for unexplained infertility. The objective of this review was to determine whether, for unexplained infertility, IVF improves the probability of live birth compared with: (i) expectant management; (ii) clomiphene citrate (CC); (iii) intrauterine insemination (IUI); (iv) IUI with controlled ovarian stimulation; and (v) gamete intra-Fallopian transfer (GIFT). METHODS: This was based on a Cochrane review. Randomized controlled trials (RCTs) which compared the effectiveness of IVF with expectant management, CC, IUI with or without controlled ovarian stimulation and GIFT were included. Patients included couples with unexplained infertility. Live birth rate per woman/couple was the main outcome measure. RESULTS: Nine RCT were identified. Five RCTs were included in the final meta-analysis. There were no comparative data for CC and live birth rates for expectant management or GIFT. There was no significant difference in clinical pregnancy rates between IVF and expectant management. There was no evidence of a difference in live birth rates between IVF and IUI either without (OR 1.96, 95% CI 0.88 to 4.36) or with (OR 1.15, 95% CI 0.55 to 2.42) ovarian stimulation. Clinical pregnancy rates with IVF were significantly higher compared with GIFT (OR 2.14, 95% CI 1.08 to 4.22) as were the multiple pregnancy rates (OR 6.25, 95% CI 1.70 to 23.00). Clinical heterogeneity was present among the studies. There was no evidence of statistical heterogeneity. CONCLUSIONS: The effectiveness of IVF in unexplained infertility remains unproven. Larger trials with adequate power are warranted.     

Asthma in pregnancy--its relationship with race, insurance, maternal education, and prenatal care utilization

OBJECTIVE: This study examines racial/ethnic disparities in the rate of asthma during pregnancy, and examines insurance type, maternal education, and prenatal care initiation/utilization as potential determinants of the disparities. DESIGN AND SETTING: This historical cohort study utilizes the linked birth certificates and maternal hospital claims data for all singleton live births to New Jersey residents in New Jersey hospitals in 1989--1993 (N=556,597). RESULTS: Compared to whites, African-American (odds ratio, OR=1.56, 95% confidence interval, CI: 1.44, 1.70) and Hispanic (OR=1.35, 95% CI: 1.23, 1.49) mothers had elevated rates of asthma. Medicaid (OR=2.08, 95% CI: 1.87, 2.32) and Medicaid HealthStart (OR=2.23, 95% CI: 2.04, 2.44) enrollees, compared to those with traditional indemnity coverage, were more likely to have asthma during pregnancy. When measures of socioeconomic status were included in the model, the effect of race decreased. Insurance status was the most important of the socioeconomic factors and accounted for most of the racial/ethnic disparity in African Americans and Hispanics. CONCLUSIONS: Insurance type as a possible indicator of socioeconomic status explains much of the racial disparity in asthma during pregnancy. Monitoring the quality of medical care for disadvantaged women may have a significant public health impact.     

Factors associated with antidepressant, anxiolytic and hypnotic use over 17 years in a national cohort

BACKGROUND: In the general population, most individuals with mental disorders are not treated with psychotropic medications. The objective of this study was to identify factors associated with psychotropic medication use over a 17 year period in a birth cohort. METHOD: Members of the 1946 British birth cohort (n=2928 in 1999) reported psychotropic medication use in 1982 at age 36, in 1989 at age 43, and in 1999 at age 53. At each of the three time points, several factors were investigated for their association with antidepressant, anxiolytic or hypnotic medication use. RESULTS: After adjusting for severity of symptoms of depression and anxiety, clinical factors such as suicidal ideation, sleep difficulty and poor physical health were strongly associated with antidepressant, anxiolytic or hypnotic medication use in 1982 and 1989, but not in 1999. Non-clinical factors were infrequently associated with antidepressant, anxiolytic or hypnotic medication use in 1982 and 1989 after adjusting for severity of symptoms, however several non-clinical factors were associated with antidepressant, anxiolytic or hypnotic medication use in 1999 including being female (OR=1.4, 95% CI: 1.0, 1.9), unemployment (OR=2.9, 95% CI: 2.1, 4.1), living alone (OR=2.6, 95% CI: 1.7, 3.9), and being divorced, separated or widowed (OR=1.5, 95% CI: 1.1, 2.3). LIMITATIONS: Data were not available on help-seeking behaviour. CONCLUSIONS: Treatment of mental disorder with psychotropic medications is strongly associated with clinical factors. However, non-clinical factors continue to be significant, and may influence both treatment-seeking and prescribing behaviour.     

Idiopathic talipes equinovarus (ITEV) (clubfeet) in Texas

Idiopathic talipes equinovarus (ITEV) is the most common form of clubfoot with a birth prevalence of 1 per 1,000 births. Serial casting and surgical correction impose a substantial financial burden on families and the health care system. While the etiology of ITEV is considered to be complex, the causes remain elusive. Genetic, maternal, and environmental factors have been suggested to play an etiologic role. This study was undertaken to determine the prevalence of ITEV and define maternal and environmental factors associated with ITEV in Texas from 1996 to 1999. Data on 682 cases of nonsyndromic ITEV were compared with all births (n = 923,543) in Texas during the same period. The overall prevalence and prevalence odds ratios (PORs) were calculated for gender, year of birth, public health region (PHR), race, maternal age, education, folic acid fortification, and parity. The overall prevalence of ITEV was 0.74/1,000 or 1/1,354 live births. Adjusted PORs were similar among blacks and US and foreign-born Hispanics (POR = 0.92, 95% CI = 0.69-1.21; POR = 0.99, 95% CI = 0.79-1.25; and POR = 0.94, 95% CI = 0.74-1.19), respectively, compared to whites. College education and higher parity were significantly associated with a lower risk of giving birth to offspring with ITEV. Babies born after folic acid fortification of grains had a very small decrease in ITEV that may be due to chance.     

Epidemiology of triploidy in a population-based birth defects registry,Hawaii, 1986-1999

Triploidy is a highly lethal chromosomal abnormality with few fetuses surviving to term. Triploidy has not been extensively studied using data from a population-based birth defect registry. This investigation examined the epidemiology of triploidy using data from the Hawaii Birth Defects Program (HBDP) and compared its findings with the literature. Of the 38 identified cases of triploidy delivered in Hawaii during 1986-1999, 31 (82%) were early fetal deaths, 3 (8%) late fetal deaths, and 4 (11%) elective terminations. The distribution of cases by sex chromosome combination was 15 (39%) XXX, 22 (58%) XXY, and 1 (3%) XYY. Triploidy was prenatally diagnosed in eight (21%) of the cases, of which four were electively terminated, two resulted in early fetal death, and two resulted in late fetal death. The detected triploidy prevalence in 1993-1999 was higher than the prevalence in 1986-1992, although the difference was not statistically significant (rate ratio (RR) 1.20, 95% confidence interval (CI) 0.73-1.86). The detected triploidy prevalence for maternal age of 35 years or greater was significantly higher than the prevalence for maternal age less than 35 years (RR 4.07, 95% CI 2.22-6.83). In spite of under detection of cases, many aspects of the epidemiology of triploidy identified in a population-based birth defects registry were consistent with that reported in the literature.     

Prevalence and risk factors for Down syndrome: A hospital‐based single‐center study in Western Mexico

Although Hispanics of Mexican origin in the United States have been identified as a population with a particularly higher rate of Down syndrome (DS), there is a paucity of studies concerning this topic in Mexico. The aim of this study was to determine the prevalence and risk factors for DS in a population from Western Mexico. For prevalence, 230 liveborn infants with DS were included from a total of 89,332 births occurring during the period 2009–2017 at the Dr. Juan I. Menchaca Civil Hospital of Guadalajara (Mexico). In order to evaluate potential DS risks, a case‐control study was conducted among 633 newborns, including those 211 DS patients with full trisomy 21 (cases) and 422 infants without birth defects (controls). Data were analyzed using multivariable logistic regression analysis. The overall prevalence for DS was 25.7 per 10,000 (95% confidence interval [95% CI]: 22.4–29.1). Patients with DS had a significantly higher risk for family history of DS in distant relatives (adjusted odds ratio [aOR] = 4.4, 95% CI: 2.5–7.7), relatives with thyroid disease (aOR = 2.3, 95% CI: 1.2–4.0), maternal age ≤ 19 years (aOR = 5.1, 95% CI: 2.7–9.6) or ≥ 35 years (aOR = 3.3, 95% CI: 1.5–6.9), paternal age ≤ 19 years (aOR = 3.5, 95% CI: 1.7–7.4), pre‐pregnancy BMI ≥ 25 kg/m² (aOR = 1.6, 95% CI: 1.0–2.4), and pre‐pregnancy alcohol consumption (aOR = 1.8, 95% CI: 1.1–2.9). The identified risks in family history, and previously mentioned nutritional disadvantages were associated with DS in our sample and probably also to its increased prevalence in our population.     

Trends in maternal age distribution and the live birth prevalence of Down's syndrome in England and Wales: 1938–2010

There have been concerns about the effects of increases in maternal age since the 1980s on the prevalence of Down''s syndrome. This study examined changes in the distribution of maternal age in England and Wales from 1938 to 2010. The live birth prevalence of Down''s syndrome in the absence of screening and subsequent termination was estimated using the numbers of babies born in England and Wales according to maternal age and the maternal age-related risk of a birth with Down''s syndrome. The proportion of women age 35 years or older at the time of giving birth reached a peak of 20% in 1945, declined to 5.5% in 1977 and rose to 20% in 2007. In the absence of screening and subsequent termination, the estimated live birth prevalence of Down''s syndrome would have mirrored these changes (2.3 per 1000 births in 1945, 1.2 per 1000 in 1976 and 2.2 per 1000 in 2007). The observed live birth prevalence (recorded by the National Down Syndrome Cytogenetic Register) was1.0 per 1000 from 1989 to 2010, due to screening and subsequent termination. In conclusion since the 1980s there has been an increase in the mean maternal age and in the expected prevalence of Down''s syndrome. When put in a longer historical context the current expected live birth prevalence is similar to that in the 1940s and the observed live birth prevalence is about 54% less than expected, due to screening and subsequent termination, and has remained reasonably constant since 1989 at 1.0 per 1000 births.     

MTHFR genetic polymorphism as a risk factor in Egyptian mothers with Down syndrome children

Recent reports linking Down syndrome (DS) to maternal polymorphisms at the methylenetetrahydrofolate reductase (MTHFR) gene locus have generated great interest among investigators in the field. The present study aimed at evaluation of MTHFR 677C/T and 1298A/C polymorphisms in the MTHFR gene as maternal risk factors for DS. Forty two mothers of proven DS outcomes and forty eight control mothers with normal offspring were included. Complete medical and nutritional histories for all mothers were taken with special emphasis on folate intake. Folic acid intake from food or vitamin supplements was significantly low (below the Recommended Daily Allowance) in the group of case mothers compared to control mothers. Frequencies of MTHFR 677T and MTHFR 1298C alleles were significantly higher among case mothers (32.1% and 57.1%, respectively) compared to control mothers (18.7% and 32.3%, respectively). Heterozygous and homozygous genotype frequencies of MTHFR at position 677 (CT and TT) were higher among case mothers than controls (40.5% versus 25% and 11.9% versus 6.2%, respectively) with an odds ratio of 2.34 (95% confidence interval [CI] 0.93-5.89) and 2.75 (95% CI 0.95-12.77), respectively. Interestingly, the homozygous genotype frequency (CC) at position 1298 was significantly higher in case mothers than in controls (33.3% versus 2.1% respectively) with an odds ratio of 31.5 (95% CI 3.51 to 282.33) indicating that this polymorphism may have more genetic impact than 677 polymorphism. Heterozygous genotype (AC) did not show significant difference between the two groups. We here report on the first pilot study of the possible genetic association between DS and MTHFR 1298A/C genotypes among Egyptians. Further extended studies are recommended to confirm the present work.     

Maternal early second trimester pregnancy weight in relation to birth outcome among Bengalee Hindus of Kolkata, India

OBJECTIVE: The study examined to what degree maternal early second trimester pregnancy weight is useful and efficient in predicting birth outcome of Bengalee women. SUBJECTS AND METHODS: The cross-sectional retrospective study was conducted in a government general hospital in South Kolkata, India. This hospital serves the needs of people belonging to lower and lower middle class socio-economic groups. Data were collected by one-to-one interview for confirmation of age, history of last menstrual period (LMP) including medical disorders. Mother's weight was recorded at 14-18 weeks of pregnancy from the history of LMP. Birth weight was measured within 24h of delivery and gestational age was assessed by Ballard's method using newborn physical and neurological maturity scoring. Of the 331 Bengalees, 295 mother-baby pairs met the recruitment criteria and were included in this study. RESULT: Mean +/- SD maternal early second trimester pregnancy weight and birth weight were 45.9+/-7.0kg and 2612+/-371g, respectively. The difference in mean weight (3.74kg) between mothers who delivered low birth weight (LBW) and normal birth weight (NBW) babies was statistically significant (t = 4.497, p < 0.001). Overall, the prevalence of LBW was nearly 34%. A higher incidence of LBW and lower mean birth weight was observed in first quartile or low weight (< or =40 kg) mothers. The rate of LBW decreased (chi2 =14.47, p<0.01) and mean birth weight increased significantly with increasing maternal weight (F=9.218, p<0.001). Risk ratio (RR) for LBW, intrauterine growth retardation (IUGR) and preterm birth in low weight (first quartile or <40.0 kg) mothers were 2.72 (95% confidence interval (CI): 1.45-5.10), 3.54 (95% CI: 1.17-10.74) and 1.97 (95% CI: 0.56-6.90), respectively, compared with heavier (>50.0kg) mothers. Finally, the present data showed that the maternal weight of <46.0 kg is the best cut-off for detecting LBW with 66% sensitivity and 75% negative predictive power. CONCLUSION: The findings suggest a positive association between maternal early second trimester pregnancy weight and birth outcome. The present study provided an efficient cut-off point for detecting LBW. Antenatal caregivers in health institutions and community health workers in the field can use this cut-off value for screening pregnant women at early second trimester.     

Paternal age as a risk factor for Down syndrome

Although the effect of maternal age as a risk factor for Down syndrome (DS) is well known, the role of paternal age in the cause of DS has not been clearly established. To investigate this phenomenon we conducted a case-control study between July 1989 and February 1990. The cases were 318 children and teenagers with DS studied at the Specialized Educational Institutions of Lima City, Perú. They were paired with 1,196 control individuals that were selected from the birth records of 2 general hospitals of the city. For each case we tried to obtain 4 controls, paired by their date of birth, sex, and maternal age. The means of paternal age in the 2 groups were compared, first globally and then by groups of maternal age (<21 years, 21–29 years, 30–34 years, 35–39 years and >39 years). None of the comparisons gave a statistically significant difference between the 2 groups, using either the Student t-test or the Mann-Whitney U-test. The results obtained in this study give no evidence that paternal age can be considered a risk factor for the conception of a child with DS. © 1993 Wiley-Liss, Inc.     

Estimation of the number of people with Down syndrome in Europe

We aimed to estimate the nonselective live birth prevalence, actual live birth prevalence, reduction percentage because of selective terminations, and population prevalence for Down syndrome (DS) in European countries. The number of people with DS alive in a country was estimated by first modeling the number of live births of children with DS by year of birth. Subsequently, for these different years of birth, survival curves for people with DS were constructed and then applied to these yearly estimates of live births with DS. For Europe, 2011–2015, we estimate 8,031 annual live births of children with DS, which would have been around 17,331 births annually, absent selective terminations. The estimated reduction of live birth prevalence was, on average, 54%, varying between 0% in Malta and 83% in Spain. As of 2015, we estimate 419,000 people with DS are living in Europe; without elective terminations, there would have been about 574,000 people with DS, which corresponds to a population reduction rate of 27%. Such statistics can be important barometers for prenatal testing trends and resource allocation within countries. Disability awareness initiatives and public policy initiatives can also be better grounded with these more precise estimates.Subject terms: Neurological disorders, Population genetics, Aneuploidy