Determinants of parental decisions after the prenatal diagnosis of Down syndrome

We evaluated demographic factors and factors specific to the current pregnancy, and their relationship to the decision to continue or terminate a pregnancy after prenatal diagnosis of Down syndrome. All cases of Down syndrome (DS) managed at a tertiary care center from 1989–1997 were retrospectively analyzed with respect to maternal age, parity, gestational age, sonographic findings, insurance status, and race. Of 145 cases of trisomy 21, 19 (13.1%) of women chose continuation of pregnancy, while 126 (86.9%) chose termination. There were no differences between groups in parity, sonographic findings, insurance status, or race at the time of diagnosis. However, patients who chose termination were significantly older and earlier in gestation than those electing to continue their pregnancy. When Down syndrome is diagnosed prenatally, the choice of termination is related to maternal age and gestational age, but only gestational age is a significant independent predictor of pregnancy termination. Am. J. Med. Genet. 79:172–174, 1998. © 1998 Wiley-Liss, Inc.     

Autosomal mosaicism in amniotic fluid cells from a twin pregnancy

Amniocentesis was performed on a 39-year-old gravida 4 woman because of maternal age. Ultrasonography demonstrated a twin pregnancy, and two amniotic fluid specimens were obtained under direct ultrasound guidance. All cells analyzed from the first specimen were 46,XX. In the second specimen, one colony in each of two flasks had trisomy 9; the remaining 3 colonies analyzed were 46, XX. The total cell count in the second specimen was 14 (24%) of 58 cells which were trisomic for chromosome 9. The parents elected to continue the pregnancy, which resulted in two live-born infants, a male and a female, both chromosomally normal. The most likely explanation for the amniotic fluid finding is that fluid from one sac was sampled twice and that trisomic cells from the amnion were obtained during the second tap.     

Spontaneous fetal loss rates in a non‐selected population

The objective of this work was to determine the rate of spontaneous fetal loss up to 28 weeks of gestation in uncomplicated pregnancies of a low‐risk population after sonographically identified intact intrauterine pregnancy during the first trimester. Transvaginal ultrasounds were given to 2,534 women at between six and 12 weeks of gestation. Inclusion criteria were a positive fetal cardiac activity and no antecedent signs of vaginal bleeding. Gestational age was confirmed by measurement of the crown‐rump length and/or biparietal diameter (BIP). Patients were followed until delivery or up to a fetal loss. The mean fetal loss rate between 12 and 28 weeks was 3.86% (n = 99). Fetal loss increased with maternal age: fetal loss rate under 20 yr: 2.94% (OR 0.75; CI 0.23–2. 46), 20–24 yr: 3.20% (OR 0.77; CI 0.48–1.23), 25–29 yr: 3.39% (OR 0.77; CI 0.50–1.19), 30–34 yr: 3.89% (OR 1.01; CI 0.59–1.71), 35–39 yr: 7.82% (OR 2.13; CI 1.04–4.32), 40–45 y: 50% (OR 13.84; CI 6.67–28.72) and > 45 yr: 50% (OR 13.05; CI 1.96–86.71) respectively. The frequency of spontaneous fetal loss before 28 weeks gestation was assessed systematically in a low‐risk population. There was a very clear correlation with advancing maternal age. These data now can be used as background loss rate information for evaluating the safety of invasive prenatal diagnosis, and they will be more valid for this purpose than the available data taken from selected cohorts of women, such as those from hospital clinics or from infertility programs. © 2001 Wiley‐Liss, Inc.     

Effect of chorionic villus sampling on utilization of prenatal diagnosis in women of advanced maternal age

The effect of the introduction of chorionic villus sampling on the utilization rate of prenatal diagnosis in advanced maternal age was studied during the period 1 January 1985-1 January 1991. On the first of January 1985, the age limit for prenatal diagnosis in The Netherlands was lowered from 38 to 36 years of age. The overall uptake rate during the studied period increased significantly, but only because of the increased uptake rate in the group 36 and 37 years. In the maternal age group of 42 years and older, an uptake rate as low as 15.9% was established. This was mainly determined by the relatively high percentage (73.0%) of women from ethnic minorities in this age group. The number of CVS procedures increased significantly during the study period, but the utilization rate was not influenced, since the number of amniocenteses decreased accordingly. An increase in acceptability of prenatal diagnosis by women of advanced maternal age due to early testing and early termination of pregnancy could not be substantiated in the present study.     

One hundred twin pregnancies in a prenatal diagnosis program

One hundred pairs of twins were encountered in 8,500 pregnancies having genetic amniocentesis. Only 5 of 27 (18.5%) pairs were recognized before the institution of routine ultrasonic examination, while 69 of 73 (94%) twin pairs were found after ultrasound use. Amniotic fluid was obtained from both sacs in 71 of the 73 (97%) identified twin gestations in which both twins were living at the time of amniocentesis.     

Repeated pregnancy loss

Debate persists over the value of chromosome analysis of couples with repeated pregnancy loss. Therefore, we studied the records of all patients referred to the Genetics Division at Thomas Jefferson University for repeated pregnancy loss. Couples were divided into three groups according to the reason for evaluation. In group I (two consecutive abortions) significant chromosome abnormalities were found in 1.8% of individuals; in group II (three or more consecutive abortions) 2.3% of individuals had a chromosome abnormality; and in group III (50% fetal loss) 1.8% of persons had abnormal chromosomes. These rates are lower than those reported by others, but are still ten times higher than those expected in the general population and affirm the value of doing a chromosome study in such couples. In addition, we found increased incidence of liveborn offspring with congenital abnormalities in couples evaluated for the above indications, and found a high incidence of a family history of repeated suboptimal pregnancy outcome. The significance of these findings is discussed.     

Acceptance of chorionic villus sampling in the southwest region of the Netherlands: A 5-Year evaluation

The acceptance of chorionic villus sampling (CVS) for monitoring pregnancies at risk for chromosomal and genetic disorders was studied from its introduction in the Centre for Clinical Genetics in Rotterdam in 1984 until 1988. Special attention was given to increasing acceptance in the group with advanced maternal age (AMA) (12.6% CVS in 1984, 52.2% CVS in 1988) and the group with a high genetic risk (HGR) (42.7% in 1984, 86.7% in 1988). The odds-growth-rate in CVS was 1.64 and 1.67 respectively, which was not significantly different. The relatively limited use of CVS at AMA is most likely determined by the fact that a considerable number of patients are referred too late in pregnancy to have the option of CVS.     

Clinical aspects of pregnancy after the age of 35 years: a review of the literature

The objective of this report is to provide an update of ourcurrent knowledge about the impact of maternal age on pregnancyoutcome. Pregnancy in women =" BORDER="0">35 years old is associatedwith a higher maternal and perinatal mortality. The older gravidaalso has a higher chance of being delivered by Caesarean section.Most of the complications associated with older age are causedby age-related confounders such as leiomyomas, type II diabetes,hypertension and multiparity. Diabetes and hypertension increasealmost linearly with age. Pregnant women with diabetes or hypertensionare at increased risk of adverse pregnancy outcome irrespectiveof age. The currently available literature indicates that premenopausalpregnant women of advanced age who are in good health do notneed special care besides the normal obstetric practice. Atpresent, establishing pregnancy in postmenopausal women is morean ethical than a medical issue, partly because the informationreported on pregnancy in postmenopausal women is insufficientto determine a reliable risk profile. In these women cardiovascularageing accelerates. Therefore, until proven otherwise, postmenopausalwomen should be considered particularly at increased risk forvascular complications during pregnancy. This risk is likelyto increase progressively with the number of years elapsed sincethe onset of postmenopause.     

Reproductive behaviour of families segregating for Cooley''s anaemia before and after the availability of prenatal diagnosis.

The reproductive behaviour of couples with heterozygous beta thalassaemia, with at least one affected child, was investigated for the period 1955 to 1984 and was compared to the behaviour of control couples matched for age, age at marriage, and presence of at least one child. The comparisons were made as a function of knowledge of the risk and availability of prenatal diagnosis and abortion. It was found that the couples segregating for Cooley's anaemia, before knowledge of the risk, had a higher reproductive rate than that of control couples. Knowledge of the genetic risk had a different effect on reproductive behaviour in the 1950s from that in later years. The difference was attributed both to the influence of cultural factors and to technical, therapeutic, and diagnostic advances.     

Psychological aspects of amniocentesis: anxiety feelings in three different risk groups

A review of the literature about parents' experiences with amniocentesis is given in the first part of this paper. In the second part the results of a follow-up study in Belgium are presented. Three groups of women who had amniocentesis performed because of advanced maternal age, a previous child with Down syndrome or a previous child with neural tube defect, respectively, were interviewed at home about their experiences. Anxiety feelings were different between groups but also showed considerable variation within each group. The overall psychological evaluation of the procedure was positive, so that the majority of the women would opt for amniocentesis in a subsequent pregnancy and would recommend it to others. Later follow-up contact by mailed questionnaire revealed that almost all women elected for their subsequent pregnancies to be monitored by amniocentesis.     

The association between anti-thyroid antibodies and pregnancy loss

The incidence of thyroid autoantibodies in women with recurrent fetal loss, infertility or women who miscarried appears to be increased compared with controls of reproductive age without previous abortions. There are few working hypotheses concerning the asociation between anti-thyroid antibodies and the increased risk for pregnancy loss. The first hypothesis suggests that women with high titers of anti-thyroid antibodies have underlying very mild thyroid "under function". Another theory views the anti-thyroid antibodies as simply secondary markers of a predisposition of autoimmune disease rather than the actual cause of pregnancy loss. An evolutionary explanation suggests that reproductive problems in women with high titers of autoantibodies exist in order to prevent the transmission of autoimmune genes to the next generation. The reason for the association between pregnancy loss and thyroid immunity is still not clear. The working hypotheses above supply multi-factorial explanations, which could act together, may even be in synergy, as the propulsion for the pregnancy loss. Until today the mechanism by which anti Tg are responsible for pregnancy loss is not clear. Induced animal models with high titier of anti Tg could provide direct evidence for the pathogenic role of anti-thyroid antibodies and the mechanism that is responsible for the pregnancy loss in autoimmune thyroiditis. In the current presentation we describe data concerning the association between anti-thyroid antibodies and pregnancy loss, and hypothesis which explains this association.     

Prenatal diagnosis of congenital myotonic dystrophy and counseling of the pregnant mother: Case report and literature review

The molecular basis of the myotonic dystrophy (MD) kinase gene is expansion of the CTG repeat at the 3′-untranslated region of the MD gene. Variability of the CTG repeat size in different tissues of affected individuals has been demonstrated. The objective of this report was to examine and review the feasibility of prenatal diagnosis of congenital myotonic dystrophy (CMD) in pregnant women with MD using CTG repeat sizes in amniocytes or villi. We present a case of a pregnant woman with MD who underwent prenatal diagnosis of MD using amniocytes. The repeat size in the amniocytes was smaller than the repeat size in the maternal leukocytes and smaller than the repeat size in the infant blood. The infant had CMD. We also reviewed the literature for reports on MD cases that were prenatally tested for CTG repeat size using amniocytes or chorionic villi. Data were tabulated based on the number of maternal CTG repeats, prenatal procedure [amniocentesis or chorionic villus sampling (CVS)], CTG repeat size in fetal tissue, fetal/infant blood, and pregnancy outcome. Twenty-seven pregnancies at risk for MD that underwent prenatal diagnosis were reported. Eleven (40.7%) of the 27 pregnancies underwent amniocentesis, and 16 (59.3%) underwent CVS. Fourteen patients (61%) demonstrated an increase in CTG repeat size in the amniocytes or villi compared with the maternal repeat size. Nine (33%) of the 27 pregnancies were terminated because of CMD risk. The outcomes of 11 (40.7%) pregnancies were consistent with diagnosis of CMD. CMD was diagnosed in fetuses demonstrating expansion or contraction of the CTG mutation in the amniocytes. Prenatal diagnosis of MD is possible by using mutation analysis on maternal and fetal DNA and detection of the CTG repeat expansion. Prenatal diagnosis of CMD is more complex. The possible lack of correlation between CTG repeat size in amniocytes, villi, and other fetal tissues is a potential limitation in prenatal diagnosis and counseling of CMD using CTG repeat size. Thus, prenatal diagnosis of CMD should be based on a combination of factors, including maternal pregnancy history, clinical findings, and cautious interpretation of maternal and fetal DNA analysis. Am. J. Med. Genet. 78:250–253, 1998. © 1998 Wiley-Liss, Inc.     

Impact, logistics and prospects of traditional prenatal diagnosis

Traditional second trimester prenatal diagnosis (PD) by amniocentesis was introduced about 20 years ago. It is still the most frequently used procedure for this purpose. About 85% of all requests for PD are based on maternal age alone. The commonest indication is a maternal age of 35 or higher at delivery. Attempts are being made to improve utilization of the limited laboratory capacity by evaluating the indication for PD by combining age and other indicators, ie. maternal-serum-alpha-fetoprotein and unconjugated estriol. Chorionic villus sampling so far has appealed to an additional group of pregnant women rather than being a replacement for the older procedure. While the impact of PD on the individual woman and her family is great, it has limited impact on the prevalence of Down syndrome patients in the society. Of major concern is the impact of PD on the attitude to a pregnancy with a possibly affected child, on the attitude to induced abortion in general and on the acceptance of disabled individuals. The importance of proper genetic counseling including ethical issues is stressed.     

Difficulties encountered in a randomization trial of CVS versus amniocentesis for prenatal diagnosis

In April 1985, having completed a study of the short-term complications of chorionic villus sampling (CVS), we began a randomized comparison of CVS versus amniocentesis. Our study continued over a 15-month period, and during that time we had difficulty recruiting patients, with only 10.6% of 1254 women referred for prenatal diagnosis fully participating in this study. However, 30.2% of those eligible by dates and indication chose to enter the study. CVS was available in our province only through this study, and the two most common reasons for such a low rate of recruitment were reporting too late in pregnancy and the concern about the potential risks of CVS. Patients continued to seek counselling too late for CVS despite direct and continuous contact with regional physicians. Our patients' concern about risk might well vary with the attitude of their physicians towards CVS, and with the information provided at the time of pre-test counselling. The small number of patients actually enrolled did not permit any meaningful comparison of amniocentesis to CVS. However, our experience with pregnancies lost post-CVS suggests that a pregnancy with an apparent low implantation at the time of sampling may be at a higher risk of loss.     

Identification of fetal mesenchymal stem cells in maternal blood: implications for non-invasive prenatal diagnosis

Strategies for genetic prenatal diagnosis on fetal cells in the maternal circulation have been limited by lack of a cell type present only in fetal blood. However, the recent identification of mesenchymal stem cells (MSC) in first trimester fetal blood offers the prospect of targeting MSC for non-invasive prenatal diagnosis. We developed protocols for fetal MSC enrichment from maternal blood and determined sensitivity and specificity in mixing experiments of male fetal MSC added to female blood, in dilutions from 1 in 10(5) to 10(8). We then used the optimal protocol to isolate fetal MSC from maternal blood in the first trimester, using blood taken after surgical termination of pregnancy as a model of increased feto-maternal haemorrhage. In model mixtures, we could amplify one male fetal MSC in 2.5 x 10(7) adult female nucleated cells, yielding a 100% pure population of fetal cells, but not one fetal MSC in 10(8) nucleated cells. Fetal MSC were identified in one of 20 post-termination maternal blood samples and confirmed as fetal MSC by XY fluorescence in-situ hybridization (FISH), immunophenotyping and osteogenic and adipogenic differentiation. We report the isolation of fetal MSC from maternal blood; however, their rarity in post-termination blood suggests they are unlikely to have a role in non-invasive prenatal diagnosis. Failure to locate these cells routinely may be attributed to their low frequency in maternal blood, to sensitivity limitations of enrichment technology, and/or to their engraftment in maternal tissues soon after transplacental passage. We speculate that gender microchimerism in post-reproductive maternal tissues might result from feto-maternal trafficking of MSC in early pregnancy.     

Intravenous immunoglobulin and recurrent pregnancy loss

Intravenous immunoglobulin (IVIg) has been used to prevent pregnancy loss, in unexplained recurrent miscarriage, and in antiphospholipid syndrome (APS). When used on an unselected population with recurrent miscarriage, IVIg has not been shown to improve the live birth rate. However, when patients are selected for poor prognosis or autoimmune phenomena, IVIg has been shown to be effective. This article discusses the possible immune mechanisms by which IVIg may act and the effect of confounding factors such as embryonic chromosomal aberrations or anti-β₂-glycoprotein I antibodies in APS. Hence, there may be an impression of futility, when IVIg may be highly effective in saving those pregnancies that can be saved. Additionally, in an unselected population with recurrent miscarriage, there is a relatively good prognosis for a subsequent live birth (60%). Therefore, the spontaneous prognosis must be taken into account, which has not been the case in previous trials.     

Maternal, perinatal and infant outcome of spontaneous pregnancy in the sixth decade of life

Pregnancy in the older woman is a well-known risk factor for perinatal morbidity and mortality. OBJECTIVE: To evaluate perinatal and infant morbidity and mortality in women 50 or more years old. METHODS: A retrospective population based study (1990-2004) evaluating spontaneously pregnant Chilean women more than 50 years old (217 live or stillbirths) compared to women 20-34 years old (2,817,742 neonates, control group). The comparison was performed using Chi Square with Yates's correction or exact Fisher test as appropriate. The risk analysis was performed by odds ratio (OR) and confidence interval of 95% (CI 95%). RESULTS: Women over 50 had a significantly greater risk of fetal (OR: 3.7; CI 95%: 1.2-10.5), neonatal (OR: 10.4; CI 95%: 5.7-18.7), post-neonatal (OR: 9.5; CI 95%: 4.6-19.1) and infant death (OR: 10.5; CI 95%: 6.6-16.7). There were no differences between groups in the incidences of low and very low birth weight. CONCLUSION: Pregnancy over 50 years of age entails a very high risk of fetal, neonatal and early childhood death. Unprotected sexual life for these women should be considered only after evaluation of their potential fertility.