Review of epidemiological factors (other than maternal age) that determine the prevalence of common autosomal trisomies

The birth prevalence of each common autosomal trisomy (21, 18 and 13) increases with advancing maternal age and this is the most important epidemiological risk factor. Prevalence during pregnancy is also dependent on gestational age. Other factors claimed to influence prevalence include paternal age, ethnicity, family history, premature reproductive aging, parity, twinning, smoking, environmental exposures, maternal medical conditions, and predispositions. We review the evidence for these associations since they may provide insights into causal mechanisms. When investigating potential co-factors it is important to adequately allow for maternal age and minimize its confounding contribution. This is well illustrated by reports of an inverse paternal age effect where there is strong correlation between parental ages. Gestational age at diagnosis, availability of prenatal screening, diagnostic testing, and elective termination of affected pregnancies and healthcare disparities also confound the studies on ethnicity, medical conditions, and predispositions or environmental factors. Data from twin zygosity studies demonstrate the importance of differences in fetal viability for affected pregnancies. We conclude that existing epidemiological evidence for most of the co-factors discussed should currently be considered tenuous; history of Down syndrome, albeit biased, may be an exception. The co-factors may yet provide clues to hitherto poorly understood causal pathways.     

Economic assessment of maternal serum screening for Down's syndrome using human chorionic gonadotropin

The effectiveness and costs of prenatal screening programmes for Down's syndrome using maternal serum markers will vary significantly depending on the biological cut-off values chosen in order to select women, at each maternal age, who will be sent for amniocentesis. On the basis of the first French prospective study of human chorionic gonadotropin (hCG) measurement in maternal serum, this paper shows that the screening protocol currently used in France, where hCG cut-off values are defined in order to offer amniocentesis to women of all ages with a 1 percent fetal risk of Down's syndrome, would detect 64·06 per cent of all cases of trisomy 21 at birth and would be highly profitable for the French social security system. On the basis of a representative sample of 100 000 pregnant women, the total costs of screening would reach $8 302 000 but would generate net potential savings of $32 186 000 in terms of life-long costs of care for trisomic 21 children which would be ‘avoided’ by termination of pregnancy following a positive diagnosis of Down's syndrome. Economic assessment shows that cost-benefit analysis would justify lower hCG cut-off values and a higher detection rate of fetal Down's syndrome (74·45 per cent) than the current French protocol. This paper concludes that it is ethical and value-laden issues, such as the consequences for women and couples of false positives and false negatives of screening, rather than economic and financial arguments that may set limits to the utilization of screening for Down's syndrome using maternal serum markers like hCG.     

Maternal serum leptin concentration during the second trimester of pregnancy: association with fetal chromosomal abnormalities

Recent studies suggest that leptin, the product of the obese gene, is produced by the placenta during pregnancy. The present study addressed the question whether second trimester maternal serum leptin could be altered by fetal Down syndrome or Edwards syndrome. Maternal serum leptin concentrations were measured in 18 pregnancies complicated with Down syndrome, six pregnancies complicated with Edwards syndrome and 183 uncomplicated pregnancies during the second trimester of pregnancy. The present results demonstrate that leptin concentrations in uncomplicated pregnancies slightly decrease from the 16th week of pregnancy, reaching a minimum of 18.8 ng/ml around the 20th week, and then rapidly increase to 28.2 ng/ml by the 24th week. Leptin correlation with maternal body weight decreases from r=0.695 at 16–17 week of gestation to r=0.544 at >22 weeks of gestation. There was no significant difference between the mean MoMs of Down syndrome- (0.926) or Edwards syndrome- (0.960) affected pregnancies and normal pregnancies (1.002). A weak correlation (r=0.18, p<0.02) was observed between corrected leptin MoMs and human chorionic gonadotrophin (hCG) MoMs in normal pregnancies. It is assumed that around the 20th week of pregnancy placental leptin production is activated or at least is accelerated and it is added to the amount of leptin produced by maternal adipose tissue. Fetal Down syndrome or Edwards syndrome does not seem to alter maternal leptin concentration and therefore leptin cannot be used as a marker for these chromosomal abnormalities in the early second trimester of pregnancy. Copyright © 2002 John Wiley & Sons, Ltd.     

Effects of mid-trimester induced abortion on the subsequent pregnancy

The outcome of the pregnancy following (a) a mid-trimester termination of pregnancy (TOP) for fetal neural tube defect (NTD) (77 women=group 1); (b) mid-trimester TOP for fetal Down's syndrome (13 women=group 2); (c) delivery of a baby with NTD (119 women=group 3) was studied. The prenatal fetal loss was relatively high in all groups. In group 1 it was similar to that found in other studies after first trimester TOP, in group 2 it was associated with advanced maternal age and the unexpected finding in group 3 was not attributable to advanced maternal age. It is suggested that a previous NTD per se might increase the risk of fetal loss in the next pregnancy. A previous mid-trimester TOP for NTD was not associated with an increase in premature labour, small for dates babies or congenital abnormality in the next pregnancy, but there was a slight increase in the number of babies weighing less than 2500 g.     

New estimates of down syndrome risks at chorionic villus sampling,amniocentesis, and livebirth in women of advanced maternal age from a uniquely defined population

Current measures of livebirth prevalence of Down syndrome are derived from data obtained up to 20 years ago, before the introduction of the prenatal diagnostic tests amniocentesis and chorionic villus sampling (CVS). For women aged 36–52 years, but who were not tested prenatally, we proposed to make a direct estimate of current livebirth prevalence of Down syndrome. We could also determine prevalence at the time of CVS and amniocentesis in women of the same age undergoing prenatal testing. Differences in these prevalences allow an estimation of the relative loss of Down syndrome during pregnancy. In Victoria, Australia, we identified 3041 women having CVS, 7504 having amniocentesis, and 13 139 having no test. Smoothed regression estimates of age-specific livebirth prevalence were found to be higher than in the early studies. The estimate of spontaneous loss was 17 per cent between the time of CVS and amniocentesis, and 18 per cent after the time of amniocentesis. The latter figure is lower than previous estimates and may be explained by a greater likelihood of a Down syndrome fetus surviving to be liveborn, given the modern approach to early obstetric intervention. These current risk estimates of livebirth may be useful updates for genetic counselling, but perhaps more importantly, may be used as precise maternal age-related risk figures, necessary in the design and implementation of prenatal screening programmes for Down syndrome.     

Variation in prenatal cytogenetic diagnosis: Policies in 13 european countries, 1989–1991

The livebirth prevalence of autosomal chromosomal anomalies is determined by several factors, including maternal age distribution and the impact of prenatal cytogenetic diagnosis (PCD). The impact of PCD varies between countries, as the indications and the uptake vary. In a previous study we described differences in Down syndrome prevalence and the proportion of older mothers. We have now made a survey of the official PCD policies in 25 regions in 13 European countries for the period 1989–1991. In two countries, termination of pregnancy was not available. In the other 11 countries, international agreement existed on five indications: advanced maternal age, a previous child with a chromosomal anomaly, parents who are carriers of a balanced translocation, mothers who are carriers of an X-linked disorder, and malformations at ultrasound. The exact limit for advanced maternal age varied from 35 to 38 years. There was a considerable variation for the indications advanced paternal age, amniocentesis for AFP or DNA, parental anxiety, a previous child with a congenital anomaly, abnormal maternal serum markers, and exposure to radiation/chemotherapy. The PCD uptake for mothers above the maternal age limit varied from 10 to 88 per cent. International harmonization of the indications for PCD is not considered feasible at present, because of the rapid changes in PCD policies even within countries.     

Evaluation of transcervical chorionic villus sampling with a completed follow-up of 1550 consecutive pregnancies

Data from 1550 consecutive pregnancies after first-trimester prenatal diagnosis by transcervical chorionic villus sampling (TC-CVS) are presented. The sampling efficacy was 97.8 per cent; the mean amount of collected villus tissue was 23 mg (range 5–100 mg). There were 97 affected fetuses, mainly (73.2 per cent) with a chromosomal abnormality or a male karyotype in carriers of X-linked disease. Pregnancy termination in these and four other women for social reasons resulted in 1449 continuing pregnancies. In these pregnancies, the fetal loss rate up to 28 weeks of gestation was 5.1 per cent with the highest loss rate (3.9 per cent) before 16 weeks. When relating this fetal loss rate to maternal age, this was 6.1 per cent in the advanced maternal age group (⩾36 years) against 3.1 per cent in the younger age group. In 1376 pregnancies continuing beyond 28 weeks, the perinatal mortality rate was 1.1 per cent; the percentage of non-genetic congenital anomalies was 0.9 per cent. The reproductive pattern of women at high genetic risk after CVS followed by pregnancy termination was evaluated. Within 12 months after the first CVS followed by pregnancy termination, 70 percent of women again requested CVS in a subsequent pregnancy.     

Comparison of fetal and maternal chromosome polymorphisms: Applications in prenatal diagnosis

By comparing the polymorphisms of Q-banded karyotypes of a mother and her female fetus, it is possible to confirm that maternal cell contamination is a rare event in prenatal diagnosis. The frequency with which any given polymorphism is distinctive is directly correlated to its prevalence in the population. Hence, since the polymorphisms on bands 3c, 13p and 21s are the most prevalent in the population, comparison of these maternal bands with the corresponding fetal ones is most likely to yield a distinctive pattern between a mother and her female fetus. However, in light of the rarity of maternal cell contamination, comparison of chromosomal polymorphisms is not cost-effective for all cases, and is recommended only for high-risk situations such as prenatal diagnosis of recessive or X-linked diseases, where maternal age is over 40, or when amniotic fluid is grossly bloody.     

Reproductive behaviour and prenatal diagnosis following genetic termination of pregnancy in women of advanced maternal age

One hundred and fifty-one women of advanced maternal age who underwent genetic termination of pregnancy (TOP) were studied for their reproductive behaviour and the type of procedure for prenatal diagnosis in a subsequent pregnancy. A total of 59 women (39 per cent) had a further pregnancy. In all continuing pregnancies prenatal diagnosis was performed, of which 75 per cent consisted of chorionic villus sampling (CVS). Reproductive behaviour following a genetic termination was negatively correlated with maternal age and parity. Both reproductive behaviour and the choice to undergo a diagnostic procedure in the next pregnancy were independent of the type of diagnostic procedure in the previous affected pregnancy.     

Prenatal diagnosis of monosomy 4p14→pter and trisomy 11q25→qter: clinical presentations and outcomes

We present the case of a pregnant woman with low free β-HCG in maternal serum Down syndrome screening that led to prenatal diagnosis of a fetus with 46,XY,der(4)t(4;11)(p14; q25). This chromosomal aneuploidy resulted from unbalanced segregation of a paternal balanced translocation, t(4;11)(p14;q25). Prenatal ultrasound revealed intrauterine growth restriction, cleft lip and palate, a thick nuchal fold, a single umbilical artery, and pyelectasis. Array-based comparative genomic hybridization and short tandem repeat markers further located the exact breakpoint of translocation. The woman had her pregnancy terminated at 23 weeks of gestational age. The proband had general appearance of Wolf–Hirschhorn syndrome and some unique findings, including single umbilical artery, severe immunoglobulin deficiency, scalp defect, and underlying bony defect. Our case underscores the importance of fetal karyotyping when low maternal serum free β-HCG is found. It also adds information on the fetal presentations of monosomy 4p14→pter and trisomy 11q25→qter. Copyright © 2005 John Wiley & Sons, Ltd.     

Elevated mid-trimester hCG and maternal lupus anticoagulant

An association is described between women with lupus anticoagulant and abnormal prenatal serum screening results. Three cases of positive second-trimester serum screening for Down syndrome, with karyotypically normal fetuses, in women demonstrated to have lupus anticoagulant are presented. Serum screening positivity was principally due to a disproportionately elevated maternal serum human chorionic gonadotrophin (hCG) level. In each case, early, severe intrauterine growth restriction was documented, with only one fetus surviving the neonatal period. As maternal lupus anticoagulant may have a profoundly adverse effect on the course of pregnancy, we suggest that an elevated hCG level on prenatal screening prompt consideration of maternal lupus anticoagulant testing if ultrasonography demonstrates an otherwise normal singleton gestation and the fetal karyotype is normal.     

Risk-based prenatal screening for trisomy 18 using alpha-fetoprotein,unconjugated oestriol and human chorionic gonadotropin

Nine centres collaborated to examine the feasibility of a screening method for trisomy 18 that was based on assigning individual risk, using a combination of maternal age and measurements of alpha-fetoprotein (AFP), unconjugated oestriol (uE3), and human chorionic gonadotropin (hCG). Second-trimester measurements of these analytes were obtained from 94 trisomy 18 pregnancies. In the 89 pregnancies without an associated open defect, the median levels for AFP, uE3, and hCG were 0.65, 0.43 and 0.36 multiples of the unaffected population median, respectively. The strongest individual predictor of risk for trisomy 18 was uE3, followed by hCG, AFP, and maternal age, in that order. Using a method of individual risk estimation that is based on the three markers and maternal age, 60 per cent of pregnancies associated with trisomy 18 would be detected at a risk cut-off level of 1:100, with a false-positive rate of about 0.2 per cent. One in nine pregnancies identified as being at increased risk for trisomy 18 would be expected to have an affected pregnancy. This risk-based screening method is more efficient than an existing method that is based on fixed analyte cut-off levels. Even though the birth prevalence of trisomy 18 is low, prenatal screening can be justified when performed in conjunction with Down syndrome screening and when a high proportion of women offered amniocentesis have an affected fetus.     

Prospective intervention trial of a screening protocol to identify fetal trisomy 18 using maternal serum alpha-fetoprotein,unconjugated oestriol,and human chorionic gonadotropin

Two prenatal centres in New England, routinely using a screening protocol for fetal Down syndrome that included maternal serum alpha-fetoprotein (AFP), unconjugated oestriol (uE3), and human chorionic gonadotropin (hCG) measurements in combination with maternal age, adopted a separate screening protocol for trisomy 18. That protocol identified a pregnancy as being at high risk when AFP, uE3, and hCG measurements all fell at or below specified cut-offs (0.75, 0.60, and 0.55 multiples of the median, respectively), regardless of maternal age. Among the first 19 491 women screened, 98 (0.5 per cent) were found to have values which placed them in the high-risk category. Four of these women were subsequently found not to be pregnant. In two others, samples from non-pregnant individuals were found to have been incorrectly submitted for analysis in place of the samples from the pregnant women. All of the remaining 92 women were counselled and offered amniocentesis and fetal karyotyping. Eighty-eight (96 per cent) accepted. Karyotypes or birth outcomes were available on all 92 pregnancies. Six cases of trisomy 18 and one case of Turner syndrome were identified by karyotype. One case of trisomy 18 was identified for every 14 unaffected pregnancies offered amniocentesis. In the present prospective study, an estimated 85 per cent of the cases of trisomy 18 were identified. However, given the small number ofcases (six), the 95 per cent confidence interval for the detection rate is broad (40–95 per cent).     

Adverse perinatal outcome in patients screen-positive for neural tube defects and fetal down syndrome

An association between various abnormal mid-trimester maternal serum analyte values and adverse perinatal outcome has been reported. From an original sample of 14 857 women, we observed five women who were ‘screen-positive’ for both neural tube defects [maternal serum alpha-fetoprotein (MSAFP) ≥2·5 multiples of the median] and Down syndrome [risk ≥1/274 using MSAFP, maternal serum unconjugated oestriol (MSuE3), maternal serum human chorionic gonadotropin (MShCG), and maternal age]. The four patients who elected to undergo amniocentesis all demonstrated both normal karyotype and normal amniotic fluid AFP levels. All five cases were associated with intrauterine growth retardation (IUGR) and abnormal pregnancy outcomes. Two cases exhibiting severe IUGR on ultrasound examination were terminated at 19·1 and 21·2 weeks, respectively; the former also exhibited fetal calcifications and positive maternal serology for toxoplasmosis. In another case, fetal demise occurred at 36 weeks' gestation in a patient who had been treated for syphilis in the second trimester. Neither infection was confirmed in fetal tissue studies. Though resulting in live births, the remaining two cases required operative deliveries; emergency Caesarean sections for fetal distress were performed at 38 and 32 weeks, respectively, the latter case being associated with severe pre-eclampsia. We conclude that elevated mid-trimester MSAFP levels concurrent with maternal serum analyte values associated with increased risk for fetal Down syndrome may presage a poor perinatal outcome, particularly IUGR and possibly congenital infection.     

Maternal genetic disorders and fetal development

With improvements in early diagnosis and management of genetic diseases, more women with genetic disorders are reaching reproductive age and becoming pregnant. While pregnancy can have a significant impact on a woman's health when there is an underlying genetic disorder, there can also be fetal effects, including embryopathy, fetal growth restriction, and brain injury. Some maternal genetic disorders are associated with adverse perinatal outcomes, including a high risk of perinatal loss and preterm birth. In this article, we review several maternal genetic disorders associated with fetal risk that are important for clinicians and patients to understand and manage appropriately. These include phenylalanine hydroxylase (PAH) deficiency and other inborn errors of metabolism, tuberous sclerosis complex, myotonic dystrophy, cystic fibrosis, Turner syndrome, sickle cell disease, and connective tissue disorders.     

Maternal serum hyperglycosylated human chorionic gonadotrophin (HhCG) in the first trimester of pregnancies affected by Down syndrome,using a sialic acid-specific lectin immunoassay

In a series of 54 cases of pregnancies complicated by Down syndrome and 224 unaffected pregnancies we examined maternal serum levels of hyperglycosylated human chorionic gonadotrophin (HhCG) in samples collected in the first trimester (11–13 weeks) using a sialic acid-specific lectin immunoassay. We compared these levels with those of other potential first trimester serum markers [free β-hCG, pregnancy-associated plasma protein A (PAPP-A) and total hCG (ThCG)] and modeled detection rates and false-positive rates of various biochemical markers in conjunction with fetal nuchal translucency (NT) and maternal age using an maternal age standardized population. Maternal serum HhCG in cases of Down syndrome were significantly elevated (median MoM 1.97) with 24/54 (44%) of cases above the 95th centile for unaffected pregnancies. Free β-hCG was also elevated (median MoM 2.09) with 33% of cases above the 95th centile. PAPP-A levels were reduced (median MoM 0.47) with 38% below the 5th centile. ThCG levels, whilst elevated (median MoM 1.34), had only 20% of cases above the 95th centile. Maternal serum HhCG levels were not correlated with fetal NT but showed significant correlation with ThCG and free β-hCG and with PAPP-A in the Down syndrome group (r=0.536). Maternal serum HhCG levels in cases with Down syndrome had a significant correlation with gestational age, increasing as the gestation increased. When HhCG was combined together with fetal NT, PAPP-A and maternal age, at a 5% false-positive rate the modeled detection rate was 83%, some 6% lower than when free β-hCG was used and some 4% better than when ThCG was used. Maternal serum HhCG is unlikely to be of additional value when screening for Down syndrome in the first trimester. Copyright © 2002 John Wiley & Sons, Ltd.     

Second trimester ultrasound screening for chromosomal abnormalities

The use of prenatal ultrasound has proven efficacious for the prenatal diagnosis of chromosomal abnormalities. The first sonographic sign of Down syndrome, the thickened nuchal fold, was first described in 1985. Since that time, multiple sonographically-identified markers have been described as associated with Down syndrome. The genetic sonogram, involving a detailed search for sonographic signs of aneuploidy, can be used to both identify fetuses at high risk for aneuploidy and, when normal, can be used to decrease the risk for aneuploidy for a pregnancy when no sonographic markers are identified. Combining the genetic sonogram with maternal serum screening may be the best method of assessing aneuploidy risk for women who desire such an assessment in the second trimester. Trisomy 18, Trisomy 13, and triploidy are typically associated with sonographically identified abnormalities and have a high prenatal detection rate. The use of the described sonographic signs in low-risk women requires further investigation, however, patients at increased risk for aneuploidy due to advanced maternal age or abnormal serum screening can benefit from a genetic sonogram screening for sonographic signs of aneuploidy to adjust their baseline risk of an affected fetus. Copyright © 2002 John Wiley & Sons, Ltd.     

‘False-negative’ and ‘false-positive’ prenatal cytogenetic results due to ‘true’ mosaicism

A 37-year-old gravida was referred for CVS because of advanced maternal age. A trisomy 21 was present in all cells after short-term incubation (direct processing (DP)) and long-term culture. According to our policy, a retap was offered for confirmation of the result during the legally required 3-day waiting period between communication of the result and termination of pregnancy. Unexpectedly all cells after DP showed a normal male chromosome complement. Further investigations revealed mosaicism in trophoblast tissue and a normal karyotype in amniotic fluid cells and fetal blood (50 mitoses each). The parents elected to continue the pregnancy after extensive ultrasound examinations did not show suspicious findings. After the birth of a healthy child, cell cultures from ten different placental sites confirmed mosaicism. Four out of 100 mitoses from a lymphocyte culture showed an additional chromosome 21. The child had no dysmorphic features and the development was normal at the age of 10 weeks. This case demonstrates the restricted validity of prenatal cytogenetic analysis in the presence of true fetal mosaicism. It also stresses the benefit of our policy to offer a retap in cases with abnormal cytogenetic results prior to termination of pregnancy which is considered unnecessary by many cytogeneticists.     

High-resolution array genomic hybridization in prenatal diagnosis

Array genomic hybridization (AGH) can detect chromosomal gains or losses that are 100 times smaller than those identifiable by conventional cytogenetic methods. Genome-wide AGH can identify genomic imbalance that causes birth defects and mental retardation at least twice as frequently as conventional cytogenetic analysis. Using AGH as a prenatal test for fetal genomic imbalance offers the promise of detecting pathogenic gain or loss of genomic material more quickly and much more frequently than current methods. However, the chance of finding a result of uncertain clinical significance is much greater than with conventional cytogenetic analysis, and the benefit–cost ratio of doing AGH in addition to conventional cytogenetic analysis in pregnancies at high risk for Down syndrome is likely to be poor. Very little is known about the natural history and range of clinical variability associated with most pathogenic submicroscopic copy number variants (CNVs). It seems doubtful that patients can be adequately counseled for prenatal AGH testing in most cases because the risks and benefits are unknown. At present, AGH should be offered for prenatal diagnosis only if the pregnancy is at especially high risk of having a pathogenic CNV or if AGH is being done as part of a clinical trial. Copyright © 2008 John Wiley & Sons, Ltd.     

Prenatal diagnosis of carbamoyl-phosphate synthetase deficiency by fetal liver biopsy

In a pregnancy at risk for carbamoyl-phosphate synthetase (CPS) deficiency, prenatal diagnosis was attempted by fetal liver biopsy, performed at 18 weeks of gestation. CPS activity was absent and the diagnosis was confirmed after termination of the pregnancy. The technique employed for fetal liver biopsy is described together with an evaluation of its possible role in prenatal diagnosis.