Parental origin of the extra chromosome in prenatally diagnosed fetal trisomy 21

Trisomy 21 (Down syndrome) is one of the most common chromosomal abnormalities. Of cases of free trisomy 21 causing Down syndrome, about 95% result from nondisjunction during meiosis, and about 5% are due to mitotic errors in somatic cells. Previous studies using DNA polymorphisms of chromosome 21 showed that paternal origin of trisomy 21 occurred in only 6.7% of cases. However, these studies were conducted in liveborn trisomy 21-affected infants, and the possible impact of fetal death was not taken into account. Using nine distinct DNA polymorphisms, we tested 110 families with a prenatally diagnosed trisomy 21 fetus. Of the 102 informative cases, parental origin was maternal in 91 cases (89.2%) and paternal in 11 (10.8%). This percentage differs significantly from the 7.0% observed in previous studies (P<0.001). In order to test the influence of genomic parental imprinting, we determined the origin of the extra chromosome 21 in relation to different factors: advanced maternal age, maternal serum human chorionic gonadotropin (hormone of placental origin), severity of the disease, gestational age at diagnosis and fetal gender. We found that the increased frequency of paternal origin of nondisjunction in trisomy 21-affected fetuses cannot obviously be explained by factors leading to selective loss of paternal origin fetuses.     

Prenatal diagnosis, pregnancy terminations and prevalence of Down syndrome in Atlanta

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

Spontaneous pregnancy loss mediated by abnormal maternal inflammation in rats is linked to deficient uteroplacental perfusion

Abnormal maternal inflammation during pregnancy is associated with spontaneous pregnancy loss and intrauterine fetal growth restriction. However, the mechanisms responsible for these pregnancy outcomes are not well understood. In this study, we used a rat model to demonstrate that pregnancy loss resulting from aberrant maternal inflammation is closely linked to deficient placental perfusion. Administration of LPS to pregnant Wistar rats on gestational day 14.5, to induce maternal inflammation, caused fetal loss in a dose-dependent manner 3-4 h later, and surviving fetuses were significantly growth restricted. Pregnancy loss was associated with coagulopathy, structural abnormalities in the uteroplacental vasculature, decreased placental blood flow, and placental and fetal hypoxia within 3 h of LPS administration. This impairment in uteroplacental hemodynamics in LPS-treated rats was linked to increased uterine artery resistance and reduced spiral arteriole flow velocity. Pregnancy loss induced by LPS was prevented by maternal administration of the immunoregulatory cytokine IL-10 or by blocking TNF-α activity after treatment with etanercept (Enbrel). These results indicate that alterations in placental perfusion are responsible for fetal morbidities associated with aberrant maternal inflammation and support a rationale for investigating a potential use of immunomodulatory agents in the prevention of spontaneous pregnancy loss.     

Prospective study of human parvovirus (B19) infection in pregnancy. Public Health Laboratory Service Working Party on Fifth Disease.

OBJECTIVE--To determine the fetal infection rate and outcome of pregnancy among women who acquire infection with human parvovirus (B19) in the antenatal period. DESIGN--Prospective study of infected pregnancies till time of delivery or abortion with virological investigation of fetuses, neonates, and 1 year old infants. SETTING--England and Wales during 1985-8. PATIENTS--190 Pregnant women with serologically confirmed B19 infection in pregnancy, their fetuses, neonates, and 1 year old infants. RESULTS--Of 186 mothers who elected to go to term, 156 (84%) delivered a normal baby. Follow up of 114 of these infants to the age of 1 year disclosed no appreciable abnormalities, although 27 had serological evidence of intrauterine infection. The overall fetal loss rate (30 cases; 16%) was similar to that in an uninfected antenatal sample (unmatched), but there was a pronounced excess of fetal loss in the second trimester in the B19 infected mothers (11.8%; 95% confidence interval 6.8% to 17.8%). Based on virological findings in the aborted fetuses the risk of fetal death due to B19 in an infected pregnancy was estimated to be 9%. The transplacental transmission rate was estimated to be 33%. CONCLUSIONS--Most women with B19 infection in pregnancy had a satisfactory outcome, but there was nevertheless a substantial risk of fetal loss in the second trimester. In view of the absence to date of any evidence of damage to babies who survive maternal infection therapeutic termination of pregnancy is not indicated.     

A maternal serum screen for trisomy 18: an extension of maternal serum screening for Down syndrome.

The feasibility of extending second-trimester maternal blood screening for Down syndrome so as to include screening for trisomy 18 was examined using stored maternal serum samples collected for neural tube-defect screening. There were 12 samples from trisomy 18 pregnancies and 390 controls. The median maternal serum concentration of alpha-fetoprotein, free alpha-subunit human chorionic gonadotrophin, free beta-subunit human chorionic gonadotrophin, intact human chorionic gonadotrophin, total estriol, unconjugated estriol, estradiol, human placental lactogen, and progesterone were lowered in those pregnancies affected by trisomy 18 when compared with unaffected pregnancies matched for racial origin, maternal age, gestational age, and sample-storage duration. At an estimated odds risk of 1:400, 83.3% of affected pregnancies were detected using an algorithm which combines the maternal age-related risk with the maternal serum concentrations of unconjugated estriol, free alpha-subunit human chorionic gonadotrophin, free beta-subunit human chorionic gonadotrophin, estradiol, and human placental lactogen. The associated false-positive rate was 2.6%. At high risk odds of 1:10, the detection rate was 58.3%, with an associated false-positive rate of 0.3%. beta-Subunit human chorionic gonadotrophin and unconjugated estriol were the most powerful discriminators. It is possible to incorporate into existing Down syndrome screening programs an algorithm for detecting trisomy 18 with high sensitivity and specificity.     

Evaluation of 100 autopsies performed in the maternity service of the H?tel-Dieu in Lyon during an 18 month period

100 Necropsies have been performed from January 1983 to June 1984, on 53 abortus and stillborn and 47 therapeutic terminations of pregnancy. All fetuses came from the same obstetric unit. Half spontaneous fetal deaths remained of unknown aetiology; in 18 cases (34%) placental, maternal or pregnancy pathology existed; fetal abnormalities were discovered in 10 (18%). As for therapeutic interruptions of pregnancy (the indications of which are detailed) the importance of ultrasonography emphasized since this technique allowed 25 of the 47 prenatal diagnosis. The importance of necropsy to help precise diagnosis and subsequent counselling is also recalled.     

Effect of maternal restraint stress on fetal development of ICR mice.

The present study was conducted to elucidate the susceptibility of embryos and fetuses at different gestational stages to the maternal stress in mice. Groups of pregnant ICR mice were subjected to daily 12-h restraint stress, taped in the supine position on a plastic board, on gestational days (GD) 1-4, 5-8, 9-12 and 13-16, respectively. Caesarean sections were performed on gestational day 18, and the fetuses were weighed and examined for morphological defects. During the daily restraint for 4 days, the maternal body weights markedly decreased. Although the body weights recovered gradually after termination of the stress, the recovery was not full until the final stage of pregnancy. Interestingly, restraint stress caused growth retardation of the fetuses, leading to a significant decrease in their body weights, and increased early and late resorptions of embryos and fetuses according to the stress periods. Although the preceding (GD1-4) and concurrent (GD5-8) stresses did not affect embryonic implantation, restraint stress on GD9-12 caused cleft palate. Whereas vertebral abnormalities, mainly bipartite ossification, were observed only in animals stressed on GD5-8, abnormalities of sternebrae, exhibiting asymmetric or bipartite ossification, were enhanced by the stress at all of the gestational stages. On the other hand, the incidence of other malformations including renal malposition and costal abnormalities was not increased by stress at any of the 4 stages. Taken together, the results suggest that intensive restraint stress influences the maternal body weight resulting in growth retardation and increased mortality of embryos and fetuses, in addition to gestational stage-specific ventricular dilatation, cleft palate and sternal abnormalities.     

Effect of interleukin-10 null mutation on maternal immune response and reproductive outcome in mice

Interleukin-10 (IL-10) is an anti-inflammatory and immune-deviating cytokine expressed in the endometrium and placenta. IL-10 null mutant (IL-10-/-) mice have been employed to examine the role of IL-10 in regulating immune events in early pregnancy and its significance in implantation and pregnancy success. The inflammatory response elicited in endometrial tissue by insemination was amplified in IL-10-/- mice, with a 66% increase in leukocytes in the endometrial stroma on Day 3 of pregnancy. Despite this, no evidence of abnormal type 1/type 2 skewing was seen in T-lymphocytes from lymph nodes draining the uterus. On Day 18 of gestation, IL-10-/- females mated with IL-10-/- males had 15% more implantation sites and 27% more viable fetuses than pregnant wild-type (IL-10+/+) mice. Placental weight was unaffected, but fetal weight and the fetal:placental weight ratio were higher in IL-10-/- pregnancies. Similar data were obtained in allogeneic pregnancies when IL-10-/- females were mated with major-histocompatibility complex (MHC) disparate IL-10-/- males. Pups delivered by IL-10-/- mothers had increased birth weight and followed an altered growth trajectory, with growth impairment evident from early postnatal life into adulthood, which was reflected in alterations in body composition at 14 wk of age. This study shows that although IL-10 is not essential for maternal immune tolerance or successful pregnancy irrespective of MHC disparity in the fetus, maternal IL-10 is a determinant of growth trajectory in progeny in utero and after birth.     

Maternal Smoking during Pregnancy and Fetal Organ Growth: A Magnetic Resonance Imaging Study

Objective

To study whether maternal cigarette smoking during pregnancy is associated with alterations in the growth of fetal lungs, kidneys, liver, brain, and placenta.

Design

A case-control study, with operators performing the image analysis blinded.

Setting

Study performed on a research-dedicated magnetic resonance imaging (MRI) scanner (1.5 T) with participants recruited from a large teaching hospital in the United Kingdom.

Participants

A total of 26 pregnant women (13 current smokers, 13 non smokers) were recruited; 18 women (10 current smokers, 8 nonsmokers) returned for the second scan later in their pregnancy.

Methods

Each fetus was scanned with MRI at 22–27 weeks and 33–38 weeks gestational age (GA).

Main outcome measures

Images obtained with MRI were used to measure volumes of the fetal brain, kidneys, lungs, liver and overall fetal size, as well as placental volumes.

Results

Exposed fetuses showed lower brain volumes, kidney volumes, and total fetal volumes, with this effect being greater at visit 2 than at visit 1 for brain and kidney volumes, and greater at visit 1 than at visit 2 for total fetal volume. Exposed fetuses also demonstrated lower lung volume and placental volume, and this effect was similar at both visits. No difference was found between the exposed and nonexposed fetuses with regards to liver volume.

Conclusion

Magnetic resonance imaging has been used to show that maternal smoking is associated with reduced growth of fetal brain, lung and kidney; this effect persists even when the volumes are corrected for maternal education, gestational age, and fetal sex. As expected, the fetuses exposed to maternal smoking are smaller in size. Similarly, placental volumes are smaller in smoking versus nonsmoking pregnant women.     

Quantitation of fetal DNA in maternal serum in normal and aneuploid pregnancies

We investigated whether the amount of circulating cell-free fetal DNA in maternal serum is influenced by fetal karyotype, using real-time quantitative polymerase chain reaction assay. Serum samples were obtained from pregnant women at gestational ages ranging from 15 to 17 weeks, prior to their undergoing amniocentesis. In total, we examined 70 samples consisting of 55 cases of pregnancy with 46,XY, 5 cases with 47,XY,+21, 3 cases with 47,XY,+18, a single case with 46,XY,dup(1) and 2 cases with twins of 46,XY, and 4 cases with 46,XX which were used as negative controls. We measured the concentration of the SRY sequence as a molecular marker for fetal DNA. The SRY sequence was detectable and measurable when the fetuses were male except for one case with 47,XY,+18. This case showed fetal growth retardation and bradycardia. No amplification signals of the SRY sequence were detected when the fetuses were female. The mean concentration of fetal DNA in maternal serum was 31.5 copies/ml in the pregnancy with 46,XY, 23.5 copies/ml in the pregnancies with 47,XY,+21 and 21.5 copies/ml in the pregnancies with 46,XY,+18. There were no significant differences in the concentration of fetal DNA between pregnancies with fetuses of normal karyotype and those with fetuses of abnormal karyotype.     

妊娠高血压疾病对妊娠结局的影响及防治对策探讨

目的：研究妊娠高血压疾病对妊娠结局的影响及防治对策讨论。方法：选择回顾性研究方法,选择2010年9月到2012年8月到我院的妊娠高血压患者60名作为观察组,并且同期选择60名正常妊娠妇女作为对照组,比较妊娠高血压患者的母体并发症（早产、胎盘早剥、产后出血）等及胎儿妊娠结局等情况与对照组的比较。结果：妊娠高血压患者不同程度对妊娠结局的影响不同P〈0．05,并且妊娠高血压患者的母体并发症与对新生儿的影响与对照组比较有差异P〈0．05,异常情况均较正常妊娠妇女要高。结论：妊娠高血压患者对妊娠结局的影响较为严重,对母婴危害严重,需积极预防。     

Paternal age and Down syndrome in British Columbia

Among Down syndrome cases born in 1964--1976 reported to the British Columbia Registry for Handicapped Children, the mean parental age was about half a year greater than in the entire population of live births after controlling for maternal age, a difference significant at the .05 level. After adjustment for maternal age, a regression analysis was consistent with an increase of 1.024-fold for each year of paternal age. Among Down syndrome cases in 1952--1963, however, for which ascertainment appears likely to be less complete, there was no evidence for a significant paternal age effect. The reasons for the variation between the two groups investigated here and the heterogeneity in results among studies of other populations are discussed.     

Diagnosis and monitoring of pregnancy in mice: correlations between maternal weight, fetal and placental mass and the maternal serum levels of progesterone, pregnancy-associated murine protein-2 and alpha-fetoprotein

Outbred Bom:NMRI mice were weighed daily for 18 days from observation of a vaginal plug. In a separate experiment, fetuses and placentae were weighed on each day of pregnancy. Pregnancy can be determined with 99% certainty on day 12 of gestation by the maternal body weight increase from day 1. The pregnancy-specific proteins alpha-fetoprotein (m-AFP) and pregnancy-associated murine protein-2 (PAMP-2), of fetal and placental origin respectively, were detectable on days 8 and 10 in the maternal circulation. Significant correlations were observed between m-AFP and fetal weight and PAMP-2 and placental weight. These markers may therefore be useful in the monitoring of fetal growth and placental growth respectively.     

The effects of maternal undernutrition on maternal and fetal serum insulin-like growth factors, thyroid hormones and cortisol in the guinea pig.

The insulin-like growth factors (IGF-I and -II) are potential mediators of the effects of maternal undernutrition on fetal growth and muscle development. The effects of a 40% reduction in maternal feed intake on serum levels of the IGFs, the thyroid hormones and cortisol, were investigated for the last two trimesters (day 25 to birth). This level of undernutrition is known to cause a 35% reduction in fetal and placental weights, and a 20-25% reduction in muscle fibre number. Maternal IGF-I level was greater than non-pregnant levels on day 25 gestation, in both control and restricted dams, and declined with gestational age. The increase in IGF-I level in the 40% restricted group was approximately two-thirds that of control animals. Fetal serum IGF-I was also reduced in undernourished fetuses throughout gestation. Maternal IGF-II did not change with gestational age and was unaffected by undernutrition. Fetal IGF-II reached a peak at day 55 of gestation, this peak was greatly diminished by maternal feed restriction. Both IGF-I and IGF-II tended to be related to fetal, placental and muscle weights at day 65 of gestation. Thyroid hormone concentration declined in maternal serum and increased in fetal serum with increasing gestational age. Levels were not significantly affected by undernutrition. Both triiodothyronine (T3) and thyroxine (T4) were correlated with IGF-I in maternal serum (P < 0.05), but not in fetal serum. Cortisol levels were elevated by undernutrition in both maternal and fetal serum, and increased with gestational age. Cortisol was inversely correlated with serum IGF-I in both maternal and fetal serum. Maternal serum IGF-I may mediate the effects of undernutrition on fetal growth by affecting the growth and establishment of the feto-placental unit in mid-gestation. Fetal IGF-I may mediate the effects on muscle growth, whereas IGF-II seems to be related to hepatic glycogen deposition. Cortisol may play a role via its effect on the IGFs, but the thyroid hormones are unlikely to be important until the late gestation/early postnatal period.     

Experimental study of umbilical cord length as a marker of fetal alcohol syndrome

Umbilical cord length has long been investigated as a potential marker of intrauterine events that may place the neonate at risk for future adverse developmental sequelae. Experimentally, significantly shortened cords have been reported in association with prenatal exposure to common drugs of abuse. This study in rats reports the time course of effects on umbilical cord length of a daily maternal ethanol gavage (3,200 mg/kg) from gestational day 6 through termination of pregnancy at either day 17, 18, 19, or 20. A total of 786 fetuses derived from 60 litters were examined. Control fetuses demonstrated a linear increase in umbilical cord length and body weight gain during late gestation, findings that support previous studies. The body weights of the ethanol-exposed fetuses were reduced significantly on all gestational days examined, indicating intrauterine growth retardation, a characteristic of fetal alcohol syndrome. Similarly, acute fetal akinesia as well as long-term sequelae stemming from impaired neurological development would result from the elevated blood ethanol levels achieved in this study. The umbilical cords of ethanol-exposed fetuses were significantly shorter on gestational days 19 and 20 in comparison to their controls, while cord lengths on days 17 and 18 were not shortened significantly. A stretch hypothesis has been proposed suggesting that the degree of fetal activity is the main determinant of umbilical cord length. In rats, there is a physiologic diminution of the volume of amniotic fluid (oligohydramnios) in late gestation (day 19 to term), which restricts fetal movements but does not appear to alter the linear relationships between gestational age and cord length in controls, thus arguing against the stretch hypothesis. However, cord lengths in the ethanol-exposed fetuses plateaued in late gestation, suggesting possible adherence to a stretch hypothesis. This dichotomy is discussed emphasizing fetal growth and activity as well as intrauterine space.     

Contribution of ultrasonographic examination to the prenatal detection of chromosomal abnormalities in 19 centres across Europe.

The objective of this study was to evaluate the prenatal detection of chromosomal abnormalities by fetal ultrasonographic examination in a large database provided by 19 Registries of Congenital Anomalies from 11 European countries. This study included 1738 cases of chromosomal abnormalities, liveborn, stillborn or termination of pregnancy regardless of maternal age from a population of 664,340 births during the period 1996 - 1998. The most frequent chromosomal anomalies were Down syndrome (n=1050), trisomy 18 (n=191), Turner syndrome (n=125), trisomy 13 (n=86), and triploidy (n=56). Fetal ultrasonographic examination resulted in the prenatal detection of 37.7% of the chromosomal abnormalities, thereby resulting in a reduction of 28.6% in their prevalence at birth due to terminations of pregnancy. The detection rate by ultrasound examination varied according to local policies of prenatal diagnosis : it was lower in countries where routine scan were not performed and higher in countries in which at least one routine anomaly scan during the second trimester of pregnancy was performed. The ultrasound detection varied according to the specific chromosomal anomaly and was lowest for Klinefelter syndrome (5.7%) and highest for triploidy (78.6%). For Down syndrome it was 26.4%. Termination of pregnancy was performed in 75.9% of the cases. Among the 655 cases detected by ultrasound, the most frequent ultrasound signs by category of chromosomal abnormalities were analysed. This study shows that ultrasound screening is an important tool in the prenatal detection of chromosomal abnormalities in Europe, leading to a significant reduction in the prevalence of livebirth children with chromosomal anomalies.     

Studies on experimental growth retardation in sheep. The effects of a small placenta in restricting transport to and growth of the fetus

Fetal and placental growth rate in sheep has been manipulated by removal of endometrial caruncles prior to conception. This produced two groups of fetuses, one in which prenatal growth rate was similar to normal and a second group in which the fetuses were about half of the normal size. The mortality in the latter group was high, particularly after catheterisation, and there was evidence of early intra-uterine death and fetal reabsorption. Prior to 125 days the relationship between fetal and placental size was poor, but after 126 days a close correlation between the two was apparent. The small fetuses had comparably small placentas and in all cases there was a close relationship between fetal and placental weight. The experimental growth retardation was associated with hypoglycaemia, hypoxia and hypoinsulinaemia. Plasma T3, T4 and particularly prolactin were very low in the small fetuses whilst levels of cortisol and alanine were high. In contrast to the controls these fetuses showed little evidence of net glucose, alanine or lactate consumption. Infusion of 50% glucose into the pregnant ewe, sufficient to elevate maternal plasma glucose concentrations 2 to 3 fold, caused a comparable increase in the plasma concentrations of normal fetuses but only a 50% rise in the concentration in small fetuses. In contrast administration of 50% O2 to the ewes sufficient to cause a 2 to 3-fold increase in maternal PO2 caused only a small increase of arterial PO2 of normal fetuses but doubled that to normal levels in small fetuses. The results are discussed in relation to the effect of reduced placental size causing a fall in placental and transport and transport capacity and significance of this to the associated fetal growth retardation.     

Cellular accumulation of heat shock protein (Hsp) 72i in fetuses of trained rats

Forty-five Sprague-Dawley rats (60-80 days old) were randomly placed into one of three groups: sedentary pregnant control (PC); prepregnancy trained animals that exercised throughout pregnancy (PR); and nonpregnant trained animals (NPR). Each exercising animal ran at approximately 60-70% aerobic capacity (VO2max) for 1 hour/day up to and including day 18 of gestation (term = 21 days). On day 20 of gestation, fetuses were excised from each pregnant animal and scrutinized for gross abnormalities. In 3 randomly chosen fetuses from each litter, brain, heart, kidney, hind limb, and placental tissues were removed to assess the accumulation of the inducible isoform of the 70-kilodalton heat shock protein (Hsp 72i). No significant differences were detected between fetal hearts, hind limbs, or placental tissues of PC or PR groups. No Hsp 72i signal could be detected in fetal kidney or brain tissues from either pregnant group. Results indicate that maternal core temperature did not reach the threshold that would induce either gross fetal abnormalities or a fetal heat shock protein response. However, fetal and placental growth was reduced by the exercise protocol.     

Prenatal Treatment for Serious Neurological Sequelae of Congenital Toxoplasmosis: An Observational Prospective Cohort Study

Background

The effectiveness of prenatal treatment to prevent serious neurological sequelae (SNSD) of congenital toxoplasmosis is not known.

Methods and Findings

Congenital toxoplasmosis was prospectively identified by universal prenatal or neonatal screening in 14 European centres and children were followed for a median of 4 years. We evaluated determinants of postnatal death or SNSD defined by one or more of functional neurological abnormalities, severe bilateral visual impairment, or pregnancy termination for confirmed congenital toxoplasmosis. Two-thirds of the cohort received prenatal treatment (189/293; 65%). 23/293 (8%) fetuses developed SNSD of which nine were pregnancy terminations. Prenatal treatment reduced the risk of SNSD. The odds ratio for prenatal treatment, adjusted for gestational age at maternal seroconversion, was 0.24 (95% Bayesian credible intervals 0.07–0.71). This effect was robust to most sensitivity analyses. The number of infected fetuses needed to be treated to prevent one case of SNSD was three (95% Bayesian credible intervals 2–15) after maternal seroconversion at 10 weeks, and 18 (9–75) at 30 weeks of gestation. Pyrimethamine-sulphonamide treatment did not reduce SNSD compared with spiramycin alone (adjusted odds ratio 0.78, 0.21–2.95). The proportion of live-born infants with intracranial lesions detected postnatally who developed SNSD was 31.0% (17.0%–38.1%).

Conclusion

The finding that prenatal treatment reduced the risk of SNSD in infected fetuses should be interpreted with caution because of the low number of SNSD cases and uncertainty about the timing of maternal seroconversion. As these are observational data, policy decisions about screening require further evidence from a randomized trial of prenatal screening and from cost-effectiveness analyses that take into account the incidence and prevalence of maternal infection. Please see later in the article for the Editors'' Summary     

Maternal age-specific rates of 47,+21 and other cytogenetic abnormalities diagnosed in the first trimester of pregnancy in chorionic villus biopsy specimens: comparison with rates expected from observations at amniocentesis.

Results are presented on chromosome analyses made on 4,481 embryos or fetuses studied through chorionic villus sampling (CVS) in whom there was no known bias to presence of a chromosome abnormality except advanced parental age. We excluded from the analysis most cases in which mosaicism was diagnosed or in which there were cytogenetic discrepancies among samples obtained from the conceptus. There remain 48 cases of 47,+21, 39 cases of other nonlethal abnormalities, and 12 lethal abnormalities diagnosed in 4,481 studied. A regression analysis (restricted to the 3,848 cases diagnosed in the 35-49-year maternal age interval) was done on rates of (1) 47,+21, (2) other abnormalities excluding lethals or (3) including them, and (4) all abnormalities excluding lethals or (5) including them. The model used was y = exp(bx + c), where y is the rate of abnormality, x is maternal age at time of CVS (the modal age of the procedure was 10 gestational weeks from the last menstrual period), and b and c were, respectively, (1) 0.288 and -15.527; (2) 0.272 and -15.173; (3) 0.253 and -14.141; (4) 0.282 and -14.753; and (5) 0.271 and -14.195. We also derived rates of abnormalities at the time of CVS that would be predicted from rates (of nonmosaics) at amniocentesis after adjustment for the difference in gestational age between the usual times that these two procedures are done. The difference between the numbers of abnormalities predicted on the basis of these adjusted amniocentesis rates and the numbers observed at CVS provides an estimate of the spontaneous loss of embryos and fetuses between the usual gestational ages of these procedures. In these data, for 47,+21 the estimated proportion lost is 21% but the result is not significant at the .05 level. For other abnormalities excluding lethals the estimated spontaneous loss is 29% (P approximately .05); including lethals it is 44%. For all abnormalities, excluding lethals, pooled together, the estimate is 24%; including lethals it is 33%. The last three values are all significant at the .05 level or lower. The observed rates of abnormalities at CVS would be approximately 10% to 15% higher if one pooled diagnosed mosaics with the nonmosaics, but the estimated proportion of spontaneous fetal loss would be lower.