Maternal serum alpha-fetoprotein (MSAFP), human chorionic gonadotropin (hCG), and unconjugated oestriol (UE3) are used as second-trimester screening markers for the detection of various fetal abnormalities. Previous studies have suggested that second-trimester MSAFP is consistently elevated after late first-trimester transabdominal multifetal pregnancy reduction (MFPR). The present study was undertaken to evaluate the levels of all three markers after early transvaginal MFPR. Maternal serum was examined for MSAFP, hCG, and UE3 at 16-18 weeks' gestation in 28 patients who underwent transvaginal MFPR at approximately 10 weeks' gestation. The mean interval between the reduction procedure and the screening test was 7.2 +/- 0.9 weeks. The mean MSAFP value in 24 patients carrying viable twins was 2.49 +/- 0.99 multiples of the median (MOM). Two patients had elevated MSAFP values: one in association with omphalocoele and the other in relation to an adverse pregnancy outcome. All but two patients had normal hCG values (mean 1.98 +/- 1.26 MOM). Two cases with elevated hCG were associated with an adverse pregnancy outcome. Unconjugated oestriol values were within the normal range in all patients (mean 1.69 +/- 0.61 MOM). These results suggest that early transvaginal MFPR, at approximately 10 weeks' gestation, does not appear to influence second-trimester MSAFP, hCG, and UE3 levels. The values of these markers may therefore be interpreted by using the same criteria as those for the general obstetric population.

As screening for Down syndrome becomes increasingly sophisticated, it is important to evaluate the newer technologies in terms of their cost-effectiveness. One recent addition to Down syndrome screening programmes is maternal serum unconjugated oestriol (uE3), especially when used in conjunction with maternal serum alpha-fetoprotein and human chorionic gonadotropin. Using assumptions used in a California proposal to justify an expanded screening programme for Down syndrome, we calculated both the average and the incremental cost-effectiveness of adding uE3. Using the base case assumptions, including an $8 fee for the uE3, the incremental cost-effectiveness of adding uE3 to the proposed California programme is $119,100 per case detected, a value that compares favourably with other Down syndrome screening programmes. The sensitivity analysis supports this conclusion over a wide range of assumptions. However, because of the uncertainty with some key data, it is still too early to fully support the inclusion of uE3 in Down syndrome screening programmes.

Serum placental lactogen (hPL) and unconjugated oestriol (E3) levels were measured in 392 women at weekly intervals from 36-40 wk gestation. The levels of both hPL and E3 were reduced in subjects delivering a growth-retarded child. The clinical significance of this observation was similar for the two compounds, with a marginal advantage to hPL. There was a higher incidence of falling levels of hPL and E3 in cases of growth retardation but the finding had very little predictive value in an individual patient.

The present study concerns the diurnal variations of free plasma oestriol and their relationship to maternal plasma cortisol in late human pregnancy. Four pregnant women volunteered for the study. According to the half-life time of oestriol blood was drawn at intervals of 30 and 60 minutes, respectively, over a period of 24 hours. Free oestriol was measured by radioimmunoassay and cortisol was quantitated by a protein binding method. All patients exhibited a circadian rhythm for free oestriol with higher values in the evening and early night (14.4 +/- 3.7 ng/ml) than in the morning (11.3 +/- 2.3 ng/ml, P less than 0.001). The course of oestriol followed plasma cortisol in a significant negative correlation (r = -0.566, P less than 0.001). During the period of low cortisol concentration oestriol levels demonstrated the phenomenon of episodic secretion. The results suggest that the maternal adrenals predominantly regulate the circadian rhythm of free oestriol by a negative feed-back action on the foetal hypothalamus.

Profiles of daily salivary oestriol concentrations throughout the third trimester of pregnancy have been constructed for 14 normal and 11 abnormal pregnancies. Day-to-day variations were significantly higher than those reported for unconjugated oestriol in plasma or serum. A sustained decline in salivary oestriol concentrations was observed in one pregnancy in which intrauterine death occurred. Sustained falls were also observed in two pregnancies in which a healthy infant was born at term. In all other patients a normal salivary oestriol profile correlated with a favourable outcome. Salivary oestriol measurements provide similar information to plasma unconjugated oestriol measurements while offering the advantages of a simple, non-invasive sample collection procedure.

The value of serial estimations of plasma CAP, HCS and urinary oestriol assays in pregnancies complicated with diabetes has been studied. The material consists of 31 patients, 16 of whom delivered normal infants and 15 delivered newborns with diabetic foetopathy. It is concluded that the levels of CAP, HCS and urinary oesteriol excretion in diabetic pregnancies are comparable to those found in normal pregnancy. No significant differences in the biochemical parameters were detected between diabetic women who delivered infants with foetopathy compared to diabetic women who delivered normal infants. The maternal oestriol excretion was, however, somewhat higher in diabetic women who delivered infants with macrosomia.

Unconjugated oestriol levels in cord vein and artery and in retroplacental and maternal blood were measured in 43 women delivered by Caesarean section. The highest oestriol levels were found in retroplacental blood followed by decreasing levels in cord vein, cord artery, and maternal compartments respectively. A strong correlation was found between cord artery and maternal levels and significant correlations existed between cord vein and artery and maternal levels. This supports the suggestion of direct transmission of free oestriol across the placenta from the fetus into the mother.

Six post-menopausal women were submitted, at 1 month interval, to oral oestriol treatment for 14-day periods at daily doses of 2 and 6 mg. Blood samples were collected for LH, FSH and PRL measurements (by RIA) every other day during treatments as well as during a 14-day control period. Through the effect on LH levels was questionable, oestriol resulted in a clear and significant, although moderate, gradual decrease of mean FSH levels. At the doses used, which are effective in thetreatment of menopausal symptoms, but are devoid of any proliferative effect upon the endometrium, oestriol failed to induce any stimulatory effect on basal PRL secretion in these post-menopausal women.

Serial plasma oestriol levels were determined by radioimmunoassay in 24 patients with severe hypertension in pregnancy. No significant correlation could be found between plasma oestriol and percentage change in diastolic blood pressure. It seems unlikely that hypotensive therapy significantly improves fetoplacental function.

Serial measurements of serum oestriol (E3) were made in 56 normal pregnancies from 10 to 40 weeks gestation using a radioreceptor assay. Several parameters of the assay and its intrapatient variability were examined. The mean curve for pregnancy E3 levels and limits of normal variation have been identified and compared with those of other series. A positive correlation was found to exist between infant birth weight and the last E3 value in normal pregnancies prior to the onset of labour. Advantages of serum E3 assays over urinary E3 determinations are discussed.

OBJECTIVE

Evaluation of maternal serum screening for Down's syndrome (DS) and neural tube defects (NTDs).

METHODS

Longitudinal study.

METHODS

Department of Obstetrics and Gynaecology, University Hospital Utrecht, the Netherlands.

METHODS

6362 pregnant women underwent serum screening for DS and (or) NTD between the 15th and 21st weeks of pregnancy between March 1991 and March 1996. Screening was performed using alpha-foetoprotein, unconjugated oestriol, human chorionic gonadotrophin and maternal age. The result of each individual test was a calculated risk for delivering a child with DS and (or) NTD.

RESULTS

Nine out of 12 singleton pregnancies of a foetus with DS were detected. To this purpose, 573 women who, according to the serum screening had an increased risk of a child with the abnormality, were offered amniocentesis, which was performed in 471 of them. Two twin pregnancies with a total of 3 DS affected foetuses were also detected; one twin pregnancy of a DS foetus was screen-negative. The one case of spina bifida was screen-positive. The proportion of women eligible for invasive prenatal diagnosis because of maternal age increased from 9% to 25% in the course of the study. Of 1118 women aged>> or = 36 years 913 (82%) declined invasive investigation compared with 40% in the general population.

CONCLUSIONS

The results of the maternal serum screening program in Utrecht were comparable with other studies. Maternal serum screening is accepted as an alternative by women above 36 years, and allows to decrease the need for amniocentesis without a significant loss in detection rate.

Lower urinary tract symptoms are a common, distressing and embarrassing problem for women of all ages, but become increasingly more common with advancing age. Oestrogen preparations have been used for many years to manage urinary symptoms, but there is still controversy over the efficacy of these preparations. The purpose of this review is to provide a critical overview of the epidemiological evidence when considering hormone replacement therapy for treatment of urinary symptoms in women. Various studies have demonstrated that oestrogen replacement can improve, or even cure, urinary stress and urge incontinence. High dose oestrogen can reduce the total number of voids in 24 hours, including nocturnal voids. Vaginal oestriol significantly reduces the risk of recurrent infections in postmenopausal women with a history of recurrent urinary tract infections. Data on combining oestrogen with a progestogen are limited, but suggest it may negate the benefit and more research is still required in this area to clarify their role.

The plasma concentrations for unconjugated and conjugated oestrone, oestradiol-17 beta and oestriol, were measured in 25 male patients with chronic alcoholism and 25 healthy male blood donors of the same age. All persons had normal weight and were free of medication. The patients with chronic alcoholism consisted of 15 persons with and 10 without hepatomegaly. Liver biopsy was performed in the persons with hepatomegaly. Unconjugated oestrogens were separated on LH-20 micro columns after extraction with diethyl ether. Oestrogen sulphates were extracted and separated after hydrolysis with sulphatase, and glucuronides were extracted and separated after hydrolysis with glucuronidase. In the patients with hepatomegaly the plasma concentrations of unconjugated oestrone, oestradiol-17 beta and oestriol were significantly increased, and the plasma levels for the same oestrogen sulphates were significantly decreased, whereas a moderate increase was observed for oestriol glucuronide. The patients without hepatomegaly revealed a significantly lower plasma concentration for oestrone sulphate, whereas no difference was seen for the remaining oestrogen components. The ratio oestrone sulphate to oestrone was significantly reduced in both groups of patients. A significant decrease for the ratio oestradiol sulphate to oestradiol and oestriol sulphate to oestriol was seen only in the patients with hepatomegaly.

To examine the effect on oestrogen metabolism of the stimulus which causes the passage of meconium, we measured maternal venous and cord artery and vein serum unconjugated oestriol levels in 46 patients with meconium staining of the amniotic fluid and 19 controls. Mean cord vein oestriol levels were significantly lower than in controls in the presence of meconium stained amniotic fluid and no fetal acidosis (cord artery buffer base of 36.2 meq/l or more) (P less than 0.02). The same tendency was seen with acidotic infants (P less than 0.05). There is thus evidence of a change in oestrogen metabolism associated with meconium staining of the amniotic fluid.

The aim of this trial was to study the vaginal absorption of oestriol and to investigate whether morning rather than evening oestriol administration would produce different plasma oestriol patterns. The influence of food intake on plasma oestriol levels was also investigated. Nine post-menopausal women were given 0.5 mg oestriol (ovula supplied by Leo AB, Sweden) intravaginally every evening for 16 days. Thereafter, 1 mg oestriol was given every evening for another 5 days, except on treatment days 18 and 19 when 1 mg oestriol was given in the morning instead. Venous blood samples were collected at frequent intervals on day 19 (morning administration) and a meal was allowed 4 h later. On the day 21 (evening administration), venous blood samples were taken at frequent intervals during the night and no meal was given until the next morning. Plasma concentrations of unconjugated oestriol were measured by means of a specific radioimmunoassay (RIA). A difference was seen in the plasma oestriol patterns when the results following morning and evening administration were compared. However, no significant difference as regards the total 24-h systemic availability of oestriol was observed. A minimal increase in plasma oestriol levels was seen after a meal in the case of both morning and evening intravaginal oestriol administration, possibly as a result of enterohepatic recirculation.

A rapid radioimmunoassay, using a specific antiserum against oestriol (Oe3) was developed for the analyses of unconjugated oestriol in post-menopausal women and before and after oral administration of oestriol. One ml plasma was extracted once with 10 ml diethyl ether and assayed without further purification. The plasma levels of oestriol in post-menopausal women appear to be below 5 pg/ml. when 10 ml plasma from a pool was assayed 2.9 pg/ml was found. When 1 ml was assayed from individual patients levels between 10-20 pg was found, which was not different from the plasma blank. A rise in plasma oestriol was found already 15 min after oral administration of 6 mg or 12 mg oestriol (Ovesterin). On the average there was a plasma oestriol peak after 45 min and then a gradual decrease to low levels within 3 to 4 h. It is concluded that oestriol is rapidly absorbed when administered orally. However, the duration of the plasma oestriol elevation is short. Oestriol is rapidly metabolized. The short elevation probably explains the weak oestrogenic effect exerted by oestriol when administered once a day as receptor affinity for oestriol is low.

The effect of gravidity on maternal serum alpha-fetoprotein (AFP), unconjugated oestriol (uE3), and human chorionic gonadotrophin (hCG) levels was investigated in 27,592 women being screened for Down's syndrome. There was no difference in the median AFP level in primigravid and multigravid women, but the median hCG level in multigravid women was 5.9 per cent lower than in those tested in their first pregnancy (P < 0.0001) and the median uE3 level was 3.9 per cent lower (P < 0.0001). Among multigravid women, there was no material difference in hCG levels according to the number of previous pregnancies or livebirths, whereas uE3 levels declined steadily with increasing numbers. Both markers declined with advancing maternal age: for hCG this was an independent effect, but for uE3 it was due to the correlation between age and gravidity. Allowing for these effects will not greatly alter the Down's syndrome screening detection and false-positive rates.

The effect of the choice of maternal age-specific prevalence curve on the model predicted Down syndrome detection rate was examined. All 19 published regression curves from 11 birth prevalence series in four meta-analyses were included. The detection rate for a five per cent false-positive rate was estimated for three combinations of markers. For free beta human chorionic gonadotropin and alpha-fetoprotein the lowest predicted detection rate was 62.3 per cent and the highest 64.1 per cent, a range of 1.8 per cent. When unconjugated oestriol was added as a third marker it was 65.6-67.3 per cent, a 1.7 per cent range, and when inhibin A was the fourth marker the detection rate was 72.0-73.4 per cent, a 1.4 per cent range. The number of series included in the regression had the biggest effect: when the authors had used a subset thought to have the highest ascertainment the predicted detection rate generally increased. The type of regression equation used and restrictions on the age range over which the regression was performed were less important factors. The effect of the choice of curve on the predicted increase in detection achieved by incorporating additional markers was relatively small: 3.1-3.3 per cent for unconjugated oestriol and a further 6.1-6.5 per cent for inhibin A. This analysis shows that the model inaccuracy caused by the maternal age curve is not small but is unlikely to be large enough to influence Down syndrome screening policy decisions.

A review of literature, mainly the results of studies conducted in America, shows obesity, diabetes mellitus, hypertension, infertility/nulliparity, late menopause, high endogenous oestrogen production, and the use of oestrogens to be the main factors associated with the development of endometrial carcinoma. Whilst most of these factors undoubtedly apply irrespective of country, doubt in Finland about the use of oestrogens being a risk factor was one of the reasons prompting the study reported here. This study, which was conducted in Turku, Finland, involved 318 endometrial carcinoma patients, 282 of whom could be paired with controls matched for age, height and weight, and social class. The data show the use of oestrogens per se not to be a risk factor. The fact that there appears to be a risk in America, where most of the oestrogenic preparations used are based on conjugated equine oestrogens, but not in Finland, where the preference is for preparations based on oestriol and oestradiol and where conjugated oestrogen preparations are relatively rarely used, supports the hypothesis that the risk depends on the type of oestrogen used.

The effect of oxytetracycline (1 g/day for five days) on the enterohepatic recycling of oestrogens and on plasma sex hormone concentrations was assessed in healthy men. Plasma oestrone (E1), oestradiol-17 beta (E2), 4-androstenedione (A), 5 alpha-dihydrotestosterone (5 alpha-DHT), total and free testosterone (T and free T), binding capacity of sex hormone binding globulin, luteinizing hormone, dehydroepiandrosterone-sulphate, urinary total E1, E2, and oestriol (E3), and oestriol-3-glucuronide (E3-3G) and faecal unconjugated and conjugated E1, E2, and E3 were measured by radioimmunoassay (RIA). Treatment with the antibiotic significantly increased the excretion of faecal conjugated oestrogens, which parallelled a decrease in urinary oestrogen excretion, especially of E3. The effect on urinary E3 could be explained almost entirely by the simultaneous decrease of urinary E3-3G concentrations. In urine and faeces the E2/E3 and E1 + E2/E3 ratios increased, probably because of the diminished reductive metabolism of oestrogens in the gut. No significant effects on plasma unconjugated oestrogen concentrations were observed. Moreover, in the present study oxytetracycline had no remarkable effect on plasma total, or free T concentrations, nor on other plasma hormones measured. Our results suggest that enterohepatic recycling and intestinal metabolism of oestrogens may be significant in men. The mechanism of action of antibiotics on oestrogen metabolism probably involves decreased hydrolysis by beta-glucuronidase of oestrogen conjugates by the intestinal contents, diminishing the reabsorption of aglycones of oestrogen conjugates and resulting in faecal loss of the steroids.

BACKGROUND

Down's syndrome occurs when a person has three copies of chromosome 21, or the specific area of chromosome 21 implicated in causing Down's syndrome, rather than two. It is the commonest congenital cause of mental disability and also leads to numerous metabolic and structural problems. It can be life-threatening, or lead to considerable ill health, although some individuals have only mild problems and can lead relatively normal lives. Having a baby with Down's syndrome is likely to have a significant impact on family life. The risk of a Down's syndrome affected pregnancy increases with advancing maternal age.Noninvasive screening based on biochemical analysis of maternal serum or urine, or fetal ultrasound measurements, allows estimates of the risk of a pregnancy being affected and provides information to guide decisions about definitive testing. Before agreeing to screening tests, parents need to be fully informed about the risks, benefits and possible consequences of such a test. This includes subsequent choices for further tests they may face, and the implications of both false positive and false negative screening tests (i.e. invasive diagnostic testing, and the possibility that a miscarried fetus may be chromosomally normal). The decisions that may be faced by expectant parents inevitably engender a high level of anxiety at all stages of the screening process, and the outcomes of screening can be associated with considerable physical and psychological morbidity. No screening test can predict the severity of problems a person with Down's syndrome will have.

OBJECTIVE

To estimate and compare the accuracy of first and second trimester urine markers for the detection of Down's syndrome.

METHODS

We carried out a sensitive and comprehensive literature search of MEDLINE (1980 to 25 August 2011), EMBASE (1980 to 25 August 2011), BIOSIS via EDINA (1985 to 25 August 2011), CINAHL via OVID (1982 to 25 August 2011), The Database of Abstracts of Reviews of Effectiveness (The Cochrane Library 2011, Issue 7), MEDION (25 August 2011), The Database of Systematic Reviews and Meta-Analyses in Laboratory Medicine (25 August 2011), The National Research Register (archived 2007), Health Services Research Projects in Progress database (25 August 2011). We studied reference lists and published review articles.

METHODS

Studies evaluating tests of maternal urine in women up to 24 weeks of gestation for Down's syndrome, compared with a reference standard, either chromosomal verification or macroscopic postnatal inspection.

METHODS

We extracted data as test positive or test negative results for Down's and non-Down's pregnancies allowing estimation of detection rates (sensitivity) and false positive rates (1-specificity). We performed quality assessment according to QUADAS (Quality Assessment of Diagnostic Accuracy Studies) criteria. We used hierarchical summary ROC (receiver operating characteristic) meta-analytical methods to analyse test performance and compare test accuracy. We performed analysis of studies allowing direct comparison between tests. We investigated the impact of maternal age on test performance in subgroup analyses.

RESULTS

We included 19 studies involving 18,013 pregnancies (including 527 with Down's syndrome). Studies were generally of high quality, although differential verification was common with invasive testing of only high-risk pregnancies. Twenty-four test combinations were evaluated formed from combinations of the following seven different markers with and without maternal age: AFP (alpha-fetoprotein), ITA (invasive trophoblast antigen), ß-core fragment, free ßhCG (beta human chorionic gonadotrophin), total hCG, oestriol, gonadotropin peptide and various marker ratios. The strategies evaluated included three double tests and seven single tests in combination with maternal age, and one triple test, two double tests and 11 single tests without maternal age. Twelve of the 19 studies only evaluated the performance of a single test strategy while the remaining seven evaluated at least two test strategies. Two marker combinations were evaluated in more than four studies; second trimester ß-core fragment (six studies), and second trimester ß-core fragment with maternal age (five studies).In direct test comparisons, for a 5% false positive rate (FPR), the diagnostic accuracy of the double marker second trimester ß-core fragment and oestriol with maternal age test combination was significantly better (ratio of diagnostic odds ratio (RDOR): 2.2 (95% confidence interval (CI) 1.1 to 4.5), P = 0.02) (summary sensitivity of 73% (CI 57 to 85) at a cut-point of 5% FPR) than that of the single marker test strategy of second trimester ß-core fragment and maternal age (summary sensitivity of 56% (CI 45 to 66) at a cut-point of 5% FPR), but was not significantly better (RDOR: 1.5 (0.8 to 2.8), P = 0.21) than that of the second trimester ß-core fragment to oestriol ratio and maternal age test strategy (summary sensitivity of 71% (CI 51 to 86) at a cut-point of 5% FPR).

CONCLUSIONS

Tests involving second trimester ß-core fragment and oestriol with maternal age are significantly more sensitive than the single marker second trimester ß-core fragment and maternal age, however, there were few studies. There is a paucity of evidence available to support the use of urine testing for Down's syndrome screening in clinical practice where alternatives are available.

A mother carrying a fetus affected with 21-hydroxylase deficiency received prenatal treatment with dexamethasone (0.5 mg, tid, p.o.) started from the very beginning of the 8th week of gestation. Prenatal diagnosis had to rely on amniocentesis with karyotyping and steroid hormone determination, because HLA and DNA data from the deceased index case or direct molecular genetic techniques were not available. The pre- and postnatal diagnosis of 21-hydroxylase deficiency was based on mass spectrometric determination of 17-hydroxyprogesterone. Dexamethasone was discontinued for 5 days prior to amniocentesis. Monitoring of cortisol, dehydroepiandrosterone-sulphate and oestriol in maternal plasma revealed suppressed maternal and fetal adrenal glands throughout pregnancy. Plasma dexamethasone levels confirmed excellent maternal compliance. At term, an eutrophic girl with normal female genitalia was delivered. The diagnosis of 21-hydroxylase deficiency and salt loss was confirmed postnatally. Regarding the side-effects of dexamethasone, the benefit/risk ratio was in favour of prenatal dexamethasone therapy.