Risk Of Down Research Articles

Cost‐effectiveness analysis of triple test in second‐trimester maternal serum screening for Down’s syndrome: an experience from Taiwan with decreasing birth rate but increasing population of old pregnant women

We intended to assess the cost-effectiveness of adding unconjugated oestriol (uE3) in maternal serum screening for Down's syndrome in Taiwan, where there is a decreasing birth rate but an increasing trend of old women having pregnancies. We used logistic regressions to estimate the risk of Down's syndrome with maternal age and different combinations of biomarkers. Cost-effectiveness analysis was presented in terms of the average and incremental cost-effectiveness ratios. Sensitivity analyses with different parameters were performed. Given a cut-off point of 1:270 for the confirmation of Down's syndrome with amniocentesis, the average cost per case averted for maternal age above 35 years only, double test [alpha-fetoprotein (AFP) and human chorionic gonadotrophin (hCG)] and triple test (AFP, hCG and uE3) were estimated as $14,561, $42,367 and $37,424. The additional costs per case averted for double test and triple test (compared with maternal age above 35 years) were $135,950 and $77,394, respectively. The additional cost per case averted for triple test was $15 199 compared with double test. The performance of triple test is not only more effective in detecting Down's syndrome cases but also more cost-effective than double test in this study.

Pregnant Women’s Attitudes Toward Amniocentesis Before Receiving Down Syndrome Screening Results

We sought to evaluate pregnant women's knowledge about features of second-trimester screening for Down syndrome and to assess whether knowledge and educational level influence their attitude toward amniocentesis before receiving test results. Pregnant Caucasian women (n = 300) <35 years old with no personal or family history of Down syndrome were surveyed. Women were randomized to 2 groups. One group of women (n = 150) were surveyed by questionnaire before consultation with specially trained midwives; the other group of women (n = 150) were surveyed after consultation. The questionnaire consisted of 3 sections: 1) participants' demographic data, 2) knowledge about prenatal screening for Down syndrome, and 3) readiness to undergo amniocentesis if there was an increased risk of Down syndrome. Women surveyed after consultation had greater total knowledge scores than those surveyed before consultation (p < .001). A statistically significant difference in knowledge scores in relation to educational levels was observed only in women who were surveyed before consultation (p = .007). Significantly more women were prepared to accept amniocentesis in the group surveyed after consultation (74%) than before consultation (53%; p < .001). Knowledge gained during a prescreening consultation influenced pregnant women's attitudes toward further diagnostic investigation. A smaller proportion of women who were indecisive was observed in the group surveyed after prescreening consultation. Indecisiveness was not affected by poor knowledge about screening, but rather by difficulty in knowing how they will feel and what they will do if their screening result is positive.

Fetal hydronephrosis; prevalence, natural history and postnatal consequences in an unselected population

The aim of this study was to estimate the incidence of fetal hydronephrosis, the antenatal development and the postnatal findings in a low risk population. A 2-year retrospective study included almost 9,000 patients, and all cases found to have antenatal hydronephrosis, defined as an AP diameter > or = 5 mm, had a structuralised ante- and postnatal follow-up. Some 85 cases were found in the antenatal period, and 32 of these cases had a pathologic follow-up. Of these, 13 had an increase in severity of dilatation during pregnancy, 10 had stable findings, but no case where the dilatation decreased had any postnatal pathology. Furthermore, half of the cases found in the third trimester (18 of 32) also had an abnormal follow-up. Two cases of Down's syndrome were diagnosed after birth. Antenatal hydronephrosis was found in almost 1% (n=85) of the study population. There was an almost 2% risk of Down's syndrome in this group. The majority of cases had an increase in severity and some were stable in the antenatal period, but it was not possible to predict the individual postnatal outcome. In the group where the finding diminished in the antenatal period, no patient had an abnormal postnatal follow-up. Female fetuses with hydronephrosis seem to have an adverse postnatal outcome compared to male fetuses.

Randomized Controlled Trial Comparing Three Methods of Presenting Risk of Down's Syndrome

Randomized Controlled Trial Comparing Three Methods of Presenting Risk of Down's Syndrome

Uptake of invasive prenatal diagnostic tests in women after detection of soft markers for chromosomal abnormality on ultrasonographic evaluation

Use of soft ultrasonographic markers during routine prenatal ultrasonography (USG) may be used for the screening of aneuploidy in the low-risk population. The aim of this study was to evaluate the acceptance of an invasive test for prenatal diagnosis and to assess the role of various factors in the decision-making regarding an invasive test when confronted with risk for aneuploidy after a soft marker is detected on routine antenatal ultrasonogram. Women were referred for USG in our department by primary obstetricians for indications such as a previous child with a congenital malformation, genetic disorder, stillbirth or in women with recurrent spontaneous abortions. Some of the women were referred after prenatal detection of a soft marker on USG. They were screened for soft markers associated with chromosomal abnormality. They were counseled regarding the age-specific risk and the risk of aneuploidy after detection of a marker in comparison to the general population's risk of Down's syndrome. They were also counseled regarding the risk of a procedure-related abortion (0.5%) following an invasive procedure before their decision regarding the use of amniocentesis was made. Twenty women out of 50 (40%) opted for amniocentesis. Except in one case of trisomy 21 in a fetus with short femur and humerus, all others had normal karyotype. The uptake of the test was comparable between primigravida (33%), women with poor obstetric history (46%) and women with at least one normal live child (45%). There was no statistical difference in the uptake of invasive test based on gestational age as well. Uptake of amniocentesis was higher (78%) in cases with nuchal thickening as compared to other markers (35%). Ultrasonographic detection of soft markers is associated with a high frequency of uptake for invasive prenatal testing. Increased nuchal thickening is associated with a higher acceptance of amniocentesis. Maternal age, gestational age or previous obstetric history were not associated with the decision to undergo amniocentesis.

Estimating the risk of Down's syndrome in antenatal screening and the gestation at which this risk applies

Two equations are given to estimate the risk of a woman having a Down's syndrome pregnancy according to maternal age: one for use in estimating antenatal screening performance and the other for use in estimating an individual woman's risk of having an affected pregnancy. Because Down's syndrome pregnancies have an increased tendency to result in a spontaneous fetal loss, the estimation of a woman's risk of having an affected pregnancy will be dependent on gestational age. The best estimates of the prevalence of Down's syndrome are obtained from information relating to births and can reliably be adjusted to prevalence in early second trimester. The most reliable estimates of risk of a Down's syndrome pregnancy using all the currently used markers apply to early in the second trimester. These risks cannot accurately be adjusted to apply to term, because the first trimester markers have not in general been studied in pregnancies that continue to term. Therefore the early second trimester of pregnancy is the gestational age at which all screening performances should be given for the different antenatal screening programmes for Down's syndrome.

Downʼs Syndrome in Births Near Landfill Sites

P-286 Introduction: Excess risk of non-chromosomal congenital anomalies near landfill sites in Great Britain has previously been reported. Some studies on chromosomal congenital anomalies in relation to waste handling processes have indicated small excess risks of Down's syndrome. The aim of the present study was to investigate the risk of giving birth to a baby with Down's syndrome in populations living near landfill sites. Methods: We used the National Down Syndrome Cytogenetic Register (NDSCR) which includes data on Down's syndrome cases in England and Wales. We used national postcoded birth data and NDSCR registrations for the years 1989–1998 complemented by Terminations data (1992–1998) due to Grounds E (risk of foetal handicap). We used distance from postcode of residence to landfill sites to assess potential exposure. Data provided by the national regulatory agencies were merged in a geographical information system to give a database containing 17 752 sites. We constructed a 2 km zone around each site, giving a resolution similar to or higher than that of previous studies, and at the likely limit of dispersion for landfill emissions. People living more than two km from all known landfill sites during the study period comprised the reference population. A ‘near vs. reference’ analysis was implemented within a Bayesian model, calculating expected numbers in the near area based on covariate-adjusted rates estimated from the reference data using a generalised linear model. Results: We found no excess risks of Down's syndrome related to landfill sites (RR= 1.009 (95% confidence interval 0.903–1.116). There were no differences in risk between sites licensed to carry special (= hazardous) waste and other sites. Discussion and Conclusions: Chromosomal congenital anomalies may result from long-term exposure to potential hazards in contrast to non-chromosomal anomalies, which would only be affected by exposures during pregnancy. Assuming a long latency and migration over a long period of time, this would most likely result in substantial exposure misclassification; hence results in our study (and others) may be biased towards the null. Some reports have indicated that low socio-economic status increases the risk of giving birth to a baby with Down syndrome. However, the small changes in risk after adjustment for deprivation in our study supports the concept that factors associated with deprivation, such as smoking, do not strongly influence risk of Down's syndrome. In conclusion, we found no evidence that living near a landfill increases the risk of having a baby with Down syndrome.

Randomised controlled trial comparing three methods of presenting risk of Down's syndrome

Objective To compare three simple methods of presenting information to patients about the risk of Down's syndrome Study design Randomised controlled trial of 150 “ low risk” women booking for antenatal care before 19 weeks gestation at Sunderland Royal Hospital. After informing the women about the purpose of the study and reassuring them that they were “low risk”, each patient was given a questionnaire, which used one of three different methods (graphic, written and interactive) to present information about the risk of Down's syndrome. A visual analogue scale allowed us to assess their level of understanding and anxiety before and after the information about risk was given to them. Results All three methods significantly altered patients’ perception and anxiety about the risk of Down's syndrome. The interactive method was found to be the most effective of the three. Conclusion This pilot study suggests that discussing the patients’ worries about fetal anomalies with medical staff can markedly reduce their degree of anxiety. The interactive method was most effective at putting information across to the patient. It significantly reduced their level of anxiety as well as their overall worry about pregnancy.

Medians for second-trimester maternal serum markers: geographical differences and variation caused by median multiples-of-median equations

Objectives: To establish gestational age-specific mid-trimester normal medians for the prenatal serum markers α fetoprotein (AFP), human chorionic gonadotropin (HCG) and unconjugated oestriol (uE3) for a Belgian population by using...

If nuchal translucency screening is combined with first‐trimester serum screening the need for fetal karyotyping decreases

This case-control study was performed to evaluate whether adding first-trimester maternal serum testing to nuchal translucency measurement would improve the antenatal detection of Down's syndrome and decrease the number of women offered fetal karyotyping. In the Swedish Nuchal Translucency Trial (the NUPP trial), 39,572 pregnant women were randomized to a routine scan at 12-14 gestational weeks including nuchal translucency screening for Down's syndrome, or a routine scan at 16-18 gestational weeks. From the early scan group 47 pregnancies with Down's syndrome were identified and for each case three controls were chosen. Of the 189 women asked to participate, 31 cases and 108 controls with a singleton pregnancy and frozen serum from 8-14 gestational weeks available for analysis accepted participation. Maternal sera were analyzed for free beta human chorionic gonadotrophin and pregnancy-associated plasma protein A. The risk for Down's syndrome was calculated using combinations of maternal age, crown-rump length, nuchal translucency, and biochemistry. A risk > or =1/250 was considered increased and an indication for fetal karyotyping. Risk calculated on the basis of maternal age alone would have identified 21 of the 31 Down's syndrome cases by karyotyping 61 of the 139 fetuses. Maternal age and nuchal translucency would have identified 29 cases by karyotyping 51 fetuses. Maternal age, nuchal translucency, and biochemistry would also have identified 29 cases by karyotyping 37 fetuses. By adding first trimester biochemistry to nuchal translucency measurement the detection rate of fetuses with Down's syndrome seems to remain unchanged whereas the antenatal risk group to be offered fetal karyotyping decreases.

Grandparents’ age and the risk of Down's syndrome in Norway

High maternal age is a well-recognized risk factor for Down's syndrome. There are also several studies of a possible effect of paternal age, but no consistent evidence of an association is found. Less is known about any effects of the age of grandparents. Objective. To assess whether maternal or paternal grandparents' age is associated with the risk of Down's syndrome. We used logistic regression analyses with data from the Medical Birth Registry of Norway, adjusting for possible confounding factors. We found no evidence of an association with the risk of Down's syndrome either for a maternal grandmother's age (odds ratio 0.9, 95% confidence interval 0.6-1.5 per 10-year increase in grandmother's age) or for any of the other grandparents' age. High maternal age remains the only well-established age-related risk factor for Down's syndrome. There is little evidence that the increased risk represented by older mothers is passed on to offspring of her non-affected daughters.

Estimation du risque de trisomie 21 fœtale par les marqueurs sériques maternels. Étude du facteur tabac

Smoking habits may affect the calculated risk of Down's syndrome (DS). The effect of smoking increases αFP and decreases hCG. The aim of our study is to obtain correction factors for smokers, as well as to discuss the properties of these factors, the way to obtain them and the impact on DS risk. The magnitude of correction factors we found are of 20% for hCG and 2% for αFP. The amplitude of correction strongly depend on the nature of the population used to define the mathematical models for medians: heterogeneous population (smoking and non smoking) or homogeneous (non smoking). The overall consequence on the screening performance is moderate but still remains significant at the level of each individual.

No association between common polymorphisms in genes of folate and homocysteine metabolism and the risk of Down's syndrome among French mothers

The cause of the non-disjunction leading to trisomy 21 remains unclear. Recent evidence has suggested that 5,10-methylenetetrahydrofolate reductase (MTHFR) and/or methionine synthase reductase (MTRR) might contribute to the maternal risk of trisomy 21. The purpose of the present study was to analyse these findings among the French population and to investigate whether common polymorphisms in genes of the folate and homocysteine pathway, including the MTHFR 677C > T, MTHFR 1298A > C, the methionine synthase (MTR) 2756A > G, the cystathionine beta-synthase (CBS) 844Ins68 and the reduced folate carrier (RFC-1) 80G > A polymorphisms, contribute to the risk of trisomy 21. The risk was studied by analysing independent and combined genotypes in 119 case mothers and 119 control mothers. The MTHFR 677T, MTHFR 1298C, MTR2756G, MTRR66G, CBSIns68+ and the RFC-1 80G allele frequencies were not significantly different among French case mothers, compared with control mothers. The risk of having a child with trisomy 21 did not appear to be linked to polymorphisms in genes associated with folate and homocysteine metabolism.

The future of prenatal diagnosis: rapid testing or full karyotype? An audit of chromosome abnormalities and pregnancy outcomes for women referred for Down's Syndrome testing

To assess the implications of a change in prenatal diagnosis policy from full karyotype analysis to rapid trisomy testing for women referred primarily for increased risk of Down's Syndrome. Retrospective collection and review of data. The four London Regional Genetics Centres. Pregnant women (32,674) in the London area having invasive prenatal diagnosis during a six-year three-month period. Abnormal karyotypes and total number of samples referred for raised maternal age, raised risk of Down's Syndrome following serum screening or maternal anxiety were collected. Abnormal karyotypes detected by molecular trisomy detection were removed, leaving cases with residual abnormal karyotypes. These were assessed for their clinical significance. Pregnancy outcomes were ascertained by reviewing patient notes or by contacting obstetricians or general practioners. Proportion of prenatal samples with abnormal karyotypes that would not have been detected by rapid trisomy testing, and the outcome of those pregnancies with abnormal karyotypes. Results from 32,674 samples were identified, of which 24,891 (76.2%) were from women referred primarily for Down's Syndrome testing. There were 118/24,891 (0.47%) abnormal sex chromosome karyotypes. Of the samples with autosomal abnormalities that would not be detected by rapid trisomy testing, 153/24,891 (0.61%) were in pregnancies referred primarily for Down's Syndrome testing. Of these, 98 (0.39%) had a good prognosis (46/98 liveborn, 3/98 terminations, 1/98 intrauterine death, 1/98 miscarriage, 47/98 not ascertained); 37 (0.15%) had an uncertain prognosis (20/37 liveborn, 5/37 terminations; 12/37 not ascertained) and 18 (0.07%) had a poor prognosis (1/18 liveborn, 2/18 miscarriage, 11/18 terminations, 4/18 not ascertained). For pregnant women with a raised risk of Down's Syndrome, a change of policy from full karyotype analysis to rapid trisomy testing would result in the failure to detect chromosome abnormalities likely to have serious clinical significance in approximately 0.06% (1 in 1659) cases. However, it should be noted that this figure may be higher (up to 0.12%; 1 in 833) if there were fetal abnormalities in some of the pregnancies in the uncertain prognosis group for which outcome information was not available.

Maternal use of nutritional supplements during the first month of pregnancy and decreased risk of Down’s syndrome: case-control study

Objective We studied the association between the use of nutritional supplements during the first gestational month and the origin of Down’s syndrome. Methods We compared 781 subjects with Down’s syndrome caused by pure trisomy 21 with their matched controls who had no defect. We also compared subjects who had Down’s syndrome with groups of 22 843 patient controls (i.e., subjects with other congenital abnormalities) and 38 151 population controls (without defects). Subjects with Down’s syndrome and other congenital abnormalities were identified in the large population-based dataset of the Hungarian Congenital Abnormality Registry between 1980 and 1996, and matched population controls were selected from the National Birth Registry. There were three sources of exposure data: 1) prospective and medically recorded data based on prenatal logbooks, 2) retrospective maternal information based on questionnaires, and 3) home visits in non-respondent cases of Down’s syndrome and congenital abnormalities. A possible association between the use of nutritional supplements, mainly folic acid and antioxidant vitamins C and E, during the first month of pregnancy and the incidence of Down’s syndrome was studied. Results A significant protective effect was seen with large doses of folic acid (∼6 mg/d) and iron (150–300 mg/d of ferrous sulfate) during the first gestational month against Down’s syndrome (adjusted odds ratio 0.4, 95% confidence interval 0.2 to 0.7 for both). In general, folic acid and iron were used together, so it was difficult to separate these effects due to the limited number of subjects and controls. Only iron alone showed a protective effect against Down’s syndrome (odds ratio 0.4, 95% confidence interval 0.1 to 0.9). The use of antioxidant vitamins was a rare event in the first month of pregnancy. Conclusion Pharmacologic doses of folic acid and iron appear to have a preventive effect against Down’s syndrome.

Primary prevention of Down's syndrome

Antenatal screening has the capacity to detect more than 90% of Down's syndrome pregnancies leading to therapeutic abortion. Successes in recent years with such so-called 'secondary' prevention have not been matched with progress in primary prevention. Despite considerable research over many decades the principle cause of the disorder is unknown. This paper considers three potential primary prevention strategies, (1) avoiding reproduction at advanced maternal age, (2) pre-implantation genetic diagnosis for couples who are at high risk of Down's syndrome, and (3) folic acid supplementation. The principle aetiological hypotheses are also reviewed. A strategy of completing the family before a maternal age of 30 could more than halve the birth prevalence of this disorder. Women with a high a priori risk should have access to pre-implantation genetic diagnosis, which can lead to a reasonably high pregnancy rate with an extremely low risk of a Down's syndrome. The evidence suggesting an aetiological role for defective folate and methyl metabolism is not sufficient to justify an active preventative strategy of folic acid supplementation without performing a large clinical trial. Current supplementation policies designed to prevent neural tube defects may incidentally prevent Down's syndrome, provided a sufficiently high dose of folic acid is used. Further progress in primary prevention is hampered by limited aetiological knowledge and there is an urgent need to refocus research in that direction.

Cost utility of prenatal diagnosis and the risk-based threshold

Prenatal testing guidelines recommend offering amniocentesis or chorionic villus sampling to women aged 35 years or older, or who have been found by screening to be at a similarly high risk of giving birth to an infant with Down's syndrome or another chromosomal abnormality. This threshold was chosen, in part, because 35 was the approximate age at which amniocentesis was cost beneficial when testing guidelines were developed in the USA in the 1970s. We aimed to assess the economic validity of thresholds based on age or risk for offering invasive prenatal diagnosis. We did a cost-utility analysis of chorionic villus sampling and amniocentesis versus no invasive testing using data from randomised trials, case registries, and a utility assessment of 534 diverse pregnant women aged 16-47 years. In the USA, compared with no diagnostic testing, amniocentesis costs less than US15000 dollars per quality-adjusted life year gained for women of all ages and risk levels. The results do not depend on maternal age or risk of Down's syndrome-affected birth. The cost-utility ratio for any individual woman depends on her preferences for reassurance about the chromosomal status of her fetus, and, to a lesser extent, for miscarriage. Prenatal diagnostic testing can be cost effective at any age or risk level. Current guidelines should be changed to offer testing to all pregnant women, not just those whose risk of carrying an affected fetus exceeds a specified threshold.

Parity and the risk of Down's syndrome.

Interpretation of studies that have examined parity as a risk factor for Down's syndrome has been hindered by inadequate control for maternal age and/or failure to account for the differential use of prenatal diagnosis and pregnancy termination between low-parity and high-parity women. In this case-control study, the authors used exact matching on maternal age-minimize confounding and evaluated the potential impact of differential termination. A total of 898 cases of Down's syndrome and 4,488 controls were identified using Washington State birth certificates from 1984-1998. There was a trend towards increasing risk of Down's syndrome with increasing parity in both younger (age <35 years) and older (age > or =35 years) mothers. Restriction to women with no indication of amniocentesis (for whom differential termination is unlikely) resulted in a blunting of the odds ratios; however, a trend for parity remained. After restriction, odds ratios were as high as 1.65 (95% confidence interval: 1.13, 2.40) in younger women with a parity of three (compared with a parity of zero) and 2.41 (95% confidence interval: 1.41, 4.12) in older women with a parity of four or more. Although the odds ratios for older women were probably biased upwards because of underreporting of amniocentesis on birth certificates, these data support an association between parity and Down's syndrome.

The influence of smoking on the pregnancy‐associated plasma protein A, free β human chorionic gonadotrophin and nuchal translucency

To analyse the effects of smoking on first trimester parameters used in prenatal screening for Down's Syndrome. A chart study. Primary care centres and maternity clinics of the participating universities' and central hospitals. Three thousand and one hundred fifteen women screened by nuchal translucency measurement and 4436 women screened by maternal serum samples. Only normal singleton pregnancies were included. The mean multiples of median of pregnancy associated plasma protein A (PAPP-A), free beta human chorionic gonadotrophin (beta-hCG) and nuchal translucency were compared by independent samples t test after logarithmic transformation of the data between smokers and non-smokers. PAPP-A and free beta-hCG concentrations and nuchal translucency measurements. PAPP-A was significantly reduced and nuchal translucency increased if the mother smoked. The smokers were more frequently considered as being at high risk for Down's Syndrome. Correcting PAPP-A median for smokers down by 20% might improve the accuracy of the risk evaluations given to individual women. If the association between increased nuchal translucency and smoking can be confirmed, it poses interesting questions as to the reasons for increased nuchal translucency among normal pregnancies.

The influence of smoking on the pregnancy-associated plasma protein A, free β human chorionic gonadotrophin and nuchal translucency

Objective To analyse the effects of smoking on first trimester parameters used in prenatal screening for Down's Syndrome. Design A chart study. Setting Primary care centres and maternity clinics of the participating universities' and central hospitals. Population Three thousand and one hundred fifteen women screened by nuchal translucency measurement and 4436 women screened by maternal serum samples. Only normal singleton pregnancies were included. Methods The mean multiples of median of pregnancy associated plasma protein A (PAPP-A), free beta human chorionic gonadotrophin (β-hCG) and nuchal translucency were compared by independent samples t test after logarithmic transformation of the data between smokers and non-smokers. Main outcome measures PAPP-A and free β-hCG concentrations and nuchal translucency measurements. Results PAPP-A was significantly reduced and nuchal translucency increased if the mother smoked. The smokers were more frequently considered as being at high risk for Down's Syndrome. Conclusions Correcting PAPP-A median for smokers down by 20% might improve the accuracy of the risk evaluations given to individual women. If the association between increased nuchal translucency and smoking can be confirmed, it poses interesting questions as to the reasons for increased nuchal translucency among normal pregnancies.