Developmental and reproductive toxicity of inorganic arsenic: animal studies and human concerns.

Information on the reproductive and developmental toxicity of inorganic arsenic is available primarily from studies in animals using arsenite and arsenate salts and arsenic trioxide. Inorganic arsenic has been extensively studied as a teratogen in animals. Data from animal studies demonstrate that arsenic can produce developmental toxicity, including malformation, death, and growth retardation, in four species (hamsters, mice, rats, rabbits). A characteristic pattern of malformations is produced, and the developmental toxicity effects are dependent on dose, route, and the day of gestation when exposure occurs. Studies with gavage and diet administration indicate that death and growth retardation are produced by oral arsenic exposure. Arsenic is readily transferred to the fetus and produces developmental toxicity in embryo culture. Animal studies have not identified an effect of arsenic on fertility in males or females. When females were dosed chronically for periods that included pregnancy, the primary effect of arsenic on reproduction was a dose-dependent increase in conceptus mortality and in postnatal growth retardation. Human data are limited to a few studies of populations exposed to arsenic from drinking water or from working at or living near smelters. Associations with spontaneous abortion and stillbirth have been reported in more than one of these studies, but interpretation of these studies is complicated because study populations were exposed to multiple chemicals. Thus, animal studies suggest that environmental arsenic exposures are primarily a risk to the developing fetus. In order to understand the implications for humans, attention must be given to comparative pharmacokinetics and metabolism, likely exposure scenarios, possible mechanisms of action, and the potential role of arsenic as an essential nutrient.

Variation in biochemical screening for Down's syndrome in the United Kingdom.

A questionnaire survey was undertaken of all 73 laboratories performing Down's syndrome screening in 1995. An estimated 352,000 tests were performed representing 47% of maternities. Three-quarters of these tests have ultrasound dating information at the time of testing. The majority of laboratories (70%) commenced screening at 15 weeks of gestation or later, and there was considerable variation in the upper limit of screening (17 to 24 weeks). Eighty-six percent of laboratories screened all women regardless of age. The reported Down's syndrome risk was based on term in 85% of laboratories. There was an inconsistent approach to determining and reporting high risk for trisomy 18 (Edwards' syndrome): 5% reported risks on report forms and 42% notified the clinicians if the risk was considered to be raised.

Pelvic manikins as learning aids.

The use of pelvic trainers in undergraduate teaching was evaluated, using a questionnaire based on examination findings of a series of four pelvic trainers by 20 medical students and 34 gynaecologists. The main outcome measures were the ability to correctly identify pelvic findings in the trainers, and the numbers of false positive findings. There were two adnexal masses in two of the trainers. One was correctly identified by 33 (14 (70%) medical students and 19 (56%) doctors) in one trainer, whereas the other was missed by 52 of 54 examiners. Prolapse was missed by 41 of 54. The normal pelvis was correctly identified by 30 (16 (80%) medical students and 20 (59%) doctors. There were 15 false positive identifications of adnexal masses (6 by medical students and 9 by doctors) and 22 false positive identification of uterine enlargements (5 by medical students and 17 by doctors). The pelvic trainers were of value in demonstrating the process of pelvic and speculum examination. Some of the clinical conditions emulated were missed by most of the gynaecologists, suggesting that they were not suitable for training students in abnormal findings. Although the figures were not statistically significant, there was a trend for qualified doctors rather than medical students to make false positive findings.

Urinary beta-core hCG: screening for aneuploidies in early pregnancy (11-14 weeks' gestation).

Initial studies at 17-22 weeks' gestation evaluating urinary beta-core human chorionic gonadotrophin (hCG) as a marker for Down's syndrome had suggested that it may have more potential than its serum counterpart. This study measured maternal urinary beta-core-hCG and creatinine at 11-14 weeks' gestation in a series of 26 aneuploidies (nine trisomy 21, five trisomy 18, four 45,X0, and eight others). The normal range for beta-core-hCG and beta-core-hCG/ creatinine was derived from 198 normal singleton pregnancies. Trisomy 18 cases (n = 5) had low maternal urinary beta-core-hCG creatinine levels (median 0.35 MOM, range 0.08-0.82 MOM). Whereas the other aneuploidies had no particular pattern; in particular, the trisomy 21 cases (n = 9) (median 1.16 MOM, range 0.3-4.74 MOM) did not differ significantly from 1 MOM. The findings imply that maternal urinary beta-core-hCG is not as discriminating for Down's syndrome between 11 and 14 weeks as later on in pregnancy.

Selective miscarriage of Down's syndrome fetuses in women aged 35 years and older.

OBJECTIVE: To estimate the fetal loss of Down's syndrome fetuses between the time of chorionic villus sampling (10 weeks gestation) and the time of amniocentesis (16 weeks gestation) and term in women aged 35 years and older. DESIGN: The age specific prevalence rates in the first trimester of Down's syndrome were estimated using the Danish cytogenetic register in combination with results from four published studies. These were compared with the reported prevalence at the time of amniocentesis and at birth. SUBJECTS: 5927 singleton pregnancies undergoing chorionic villus sampling (71 cases of Down's syndrome and 5856 unaffected cases). This was combined with published data on a further 231 cases of Down's syndrome and 16,620 unaffected cases. MAIN OUTCOME MEASURES: Age specific prevalences at the time of chorionic villus sampling. Proportion of pregnancies lost between the time of chorionic villus sampling and the time of amniocentesis and term. RESULTS: Thirty-two percent of Down's syndrome pregnancies are lost between the time of chorionic villus sampling (10 weeks) and the time of amniocentesis (16 weeks) and 54% are lost by term. CONCLUSIONS: The high fetal loss rates of Down's syndrome between the time of chorionic villus sampling and term introduce problems when evaluating first trimester screening tests with respect to their effective detection rates at term. A recommendation for quoting term risks is made.

Crown-rump length in aneuploid fetuses: implications for first-trimester biochemical screening for aneuploidies.

This study examined the effect of estimation of gestational age from the menstrual history compared with that from crown-rump length (CRL) measurement on the detection rate of screening for aneuploidies in the first trimester. Pregnancy-associated plasma protein A (PAPP-A) was assayed in blood collected prior to chorionic villus sampling in 356 women with unaffected pregnancies and 28 women with an aneuploid pregnancy. There were 14 Down's syndrome (DS) pregnancies. All pregnancies were dated from menstrual history and CRL measurement. The average CRL gestation in the aneuploid population was 2.5 days less than that derived from the LMP (95 per cent confidence interval (CI) for LMP-CRL gestation: using the algorithm based on unaffected pregnancies 0-3.5 days; using the matched case-control approach 1-4.5 days). The average CRL gestation in the DS population was 2 days less but this did not reach statistical significance (95 per cent CI for LMP-CRL gestation: using the algorithm -1 to 4.5 days; using the matched case-control approach 0 to 5.5 days). The detection rate of aneuploidies in the first trimester using maternal serum PAPP-A was reduced by 7 per cent (and by 3 per cent for DS) for a 5 per cent false-positive rate when using CRL rather than LMP to date the pregnancy. This phenomenon is a consequence of an apparent reduction of gestational age when estimated by CRL in the aneuploid population. Further studies are required to evaluate whether CRL is an unbiased estimate of gestation for Down's syndrome pregnancies.

Screening for Down's syndrome.

Down's syndrome (DS) is the commonest cause of severe mental retardation in children. It is the result of trisomy of chromosome 21 which is usually a random event though it is commoner in older mothers. DS can be diagnosed by chorionic villus sampling (CVS) and amniocentesis followed by karyotyping. Because of the risks associated with these invasive procedures, they can only be offered to a high-risk group. At one time the sole basis for identifying this increased risk was maternal age, but within the past ten years a series of biochemical and ultrasound abnormalities have been shown in DS pregnancies. The biochemical abnormalities include changes in the levels of most fetal and placental products in the maternal circulation. The best-known of these changes are the reduced levels of alphafetoprotein (AFP) and oestriol (E3) and increased levels of human chorionic gonadotrophin (hCG). The mechanism underlying these biochemical phenomena is unknown. Screening programmes involving the measurement of hCG and AFP, with or without additional parameters such as E3, at 15-18 weeks of pregnancy can typically identify 60% or more of cases of DS with a screen-positive rate of 5%. The combined risk derived from the various biochemical parameters, together with maternal age, is calculated by one of a number of computer programmes which have been developed for this purpose. There has been considerable discussion as to the exact biochemical tests which should be used for DS screening. This had led to controversy as to whether measurement of E3 has a place, and whether or not measurement of the free beta-subunit of hCG should replace measurement of the intact molecule. A notable recent development is the suggestion that measurement of the urinary beta-core of the hCG could be a highly discriminatory marker. A number of factors can affect the results of biochemical screening for DS. These include maternal weight, gestational age, ethnic origin, smoking, and diabetes. In addition, abnormal levels of the biochemical products may be found in other chromosome abnormalities.

Maternal serum human chorionic gonadotrophin and pregnancy-associated plasma protein A, markers for fetal Down syndrome at 8-14 weeks.

Maternal serum levels of human chorionic gonadotrophin and its subunits (intact, alpha, and free beta h CG) and pregnancy-associated plasma protein A (PAPP-A) were measured in 279 women between 8 and 14 weeks' gestation. This group included 23 pregnancies in which the fetus had Down syndrome (DS), diagnosed either at birth or during the second trimester (n = 17) or from chorionic villus sampling (CVS) (n = 6). Normal medians were determined from the 258 apparently normal pregnancies. The median levels of intact hCG (1.4 MOM) and free beta hCG (2.1 MOM) were significantly raised, whereas the median level of PAPP-A (0.39 MOM) was significantly lower in the DS pregnancies when compared with the control group. Levels of alpha hCG were similar in both the control and the DS pregnancies. Analysis of samples taken prior to 14 weeks' gestation demonstrated that only PAPP-A (0.34 MOM) was significantly altered in DS pregnancies. However, after the exclusion of DS cases diagnosed at CVS, the median intact hCG (1.56 MOM), free beta hCG (2.27 MOM), and alpha hCG (1.8 MOM) were all raised in DS pregnancies. This emphasizes the problem of the interpretation of biochemical markers when DS cases are diagnosed at CVS.