Maternal serum alpha-fetoprotein (AFP), human chorionic gonadotrophin (hCG), and unconjugated oestriol (uE3) levels were examined in 1632 women who had ovulation induction and 327 who had in vitro fertilization. There was a highly statistically significant increase in hCG and reduction in uE3 among those with ovulation induction. The median levels were respectively 1.09 and 0.92 multiples of the normal gestation-specific median (MOM) based on a total of 34582 women. Ovulation induction appeared to have no material effect on the median AFP level but this masked a significant increase when treatment was with Clomiphene (1.05 MOM) and a significant decrease when Pergonal was used (0.93 MOM). There was a highly statistically significant reduction in uE3 among women having in vitro fertilization with a median level of 0.92 MOM. Those fertilized with a donor egg (21) had significantly higher AFP and uE3 levels than when their own egg was used. Our results were confounded by differences in gravidity, but formally allowing for this factor did not materially change the findings. None of the observed effects is great enough to warrant routine adjustment of marker levels to allow for them. Moreover, women with positive Down's syndrome screening results can be reassured that this is unlikely to be due to them having had assisted reproduction.

OBJECTIVE

We intended to assess the cost-effectiveness of adding unconjugated oestriol (uE3) in maternal serum screening for Down's syndrome in Taiwan, where there is a decreasing birth rate but an increasing trend of old women having pregnancies.

METHODS

We used logistic regressions to estimate the risk of Down's syndrome with maternal age and different combinations of biomarkers. Cost-effectiveness analysis was presented in terms of the average and incremental cost-effectiveness ratios. Sensitivity analyses with different parameters were performed.

RESULTS

Given a cut-off point of 1:270 for the confirmation of Down's syndrome with amniocentesis, the average cost per case averted for maternal age above 35 years only, double test [alpha-fetoprotein (AFP) and human chorionic gonadotrophin (hCG)] and triple test (AFP, hCG and uE3) were estimated as $14,561, $42,367 and $37,424. The additional costs per case averted for double test and triple test (compared with maternal age above 35 years) were $135,950 and $77,394, respectively. The additional cost per case averted for triple test was $15 199 compared with double test.

CONCLUSIONS

The performance of triple test is not only more effective in detecting Down's syndrome cases but also more cost-effective than double test in this study.

OBJECTIVE

To determine the ability of the quadruple Down's syndrome screening test (quad screen) to predict other adverse perinatal outcomes (APO) in a high-risk obstetric population.

METHODS

A tertiary medical centre in West Virginia.

METHODS

We retrospectively reviewed 342 obstetric patients with quad screen data from a single clinic. The quad screen included maternal serum levels of alphafetoprotein (AFP), human chorionic gonadotrophin (hCG), uncongjugated oestriol (uE(3)), and inhibin A. The risk of APO was compared between patients with at least one abnormal marker versus no abnormal markers and>>or=2 abnormal markers versus <2 abnormal markers. Abnormal markers were determined by cut-off values produced by Receiver Operator Characteristic (ROC) curves and the FASTER trial. Unadjusted and adjusted effects were estimated using logistic regression analysis.

RESULTS

The risk of having an APO increased significantly for patients with abnormal markers by about three-fold using ROC and two-fold using FASTER trial thresholds.

CONCLUSIONS

The quad screen shows value in predicting risk of APO in high-risk patients.

Levels of placental protein 14 (PP14), human placental lactogen (hPL) and unconjugated oestriol (E3) were measured in maternal peripheral and umbilical arterial and venous blood obtained from 65 normal pregnancies at term delivery. PP14 levels were one order of magnitude higher in the mother than in the fetus. Neither maternal nor fetal levels of PP14 were related to the birthweight of the fetus. There was a relationship between maternal and umbilical venous levels of PP14, which suggests that fetal PP14 is derived by transfer from the mother, or that there is an independent fetal source with a control mechanism similar to that of the mother. The findings are compatible with earlier observations to the effect that PP14, in contrast to products such as hPL and E3, is not specific to the trophoblast.

A number of biochemical markers in maternal serum have been proposed for first trimester screening for Down's syndrome. The most promising four are pregnancy associated plasma protein A (PAPP-A), the free beta sub-unit of human chorionic gonadotrophin (hCG) (free beta glycoprotein sub-unit), unconjugated oestriol (uE3) and alpha-fetoprotein (AFP). An analysis of the published literature suggests that 70% of affected pregnancies could be detected for a 5% false-positive rate if the four markers are used in combination with maternal age and assumed to be independent measures of risk. This is a level of performance that is similar to second trimester screening. It is, however, a tentative estimate because of the assumption of independence and the possibility that the effect may be exaggerated by publication bias. Further research is needed before such screening is introduced. Other first trimester markers which have been studied include total hCG, free alpha-hCG, CA125, PLAP and SP1 but they either look unpromising or there are too few data available to determine their value. The timing of antenatal diagnosis by means of chorion villus sampling should be delayed until after 10 weeks of pregnancy because of the risk of causing limb defects. Screening need not, therefore, be performed before about 9 or 10 weeks of pregnancy.

The aim of our study was to compare three protocols for second-trimester maternal serum screening for Down's syndrome in the same serum samples, using two triple tests [total human chorionic gonadotrophin (HCG), alpha-fetoprotein, unconjugated oestriol; and free beta-HCG, alpha-fetoprotein, unconjugated oestriol] and a double test (free beta-HCG and alpha-fetoprotein). The three protocols were compared in a series of 23 serum samples from Down's syndrome pregnancies and in a cohort of 2516 pregnant women receiving routine antenatal care between June 1992 and June 1993. Among the 23 affected cases, at a cut-off risk of 1:380, the detection rate of Down's syndrome was comparable with the double test (74%; 17/23) and the triple tests (65%; 15/23) (not significantly different). At the same cut-off risk, in the cohort of 2516 pregnant women screened between 15 and 18 weeks gestation, both protocols using free beta-HCG achieved a significant reduction of the number of false positive cases (P = 0.013 and 0.004 for double and triple tests respectively). We conclude that, compared to total HCG, alpha-fetoprotein and unconjugated oestriol, use of free beta-HCG and alpha-fetoprotein represents a better second-trimester screening test for Down's syndrome, because it significantly decreases the false positive rate at a lower running cost. The addition of unconjugated oestriol to the double test adds no further advantage.

Because of the concern about environmental chemicals with oestrogenic and anti-oestrogenic effects, there is a need to construct biosensors for classifying such chemicals according to their effect on oestrogen receptor conformation. The conformation of the ligand-binding domains (LBD) of oestrogen receptor-alpha and -beta determine their transcription regulation activity. Some ligands, i.e., the natural oestrogen oestradiol, induce an active conformation allowing interaction with co-activators. In contrast, antagonists like ICI 182, 780, because of their bulky side chains, do not allow an alpha-helix 12 positioning compatible with co-activator binding. Another type of oestrogen receptor-ligand interactions, termed "passive antagonism", was first defined by X-ray crystal structure analysis of receptors in complex with the side chain-less 5,11-cis-diethyl-5,6,11,12-tetrahydrochrysene-2,8-diol (THC). We have now used the ability of peptides selected from phage-displayed peptide libraries to bind conformation specifically to oestrogen receptor-alpha and -beta LBDs to analyse conformations induced by THC and a group of chlorinated biphenyls and their aryl-hydroxylated metabolites, suspected of being environmental chemical disruptors. In oestrogen receptor-beta, THC defined a "passive antagonist" peptide recognition pattern, which was also induced by several antagonistic hydroxylated biphenyls, while a clearly different peptide recognition pattern was induced by their chlorinated agonistic counterparts. In oestrogen receptor-alpha, THC induced a conformation similar to that induced by oestriol and other oestrogen receptor-alpha agonists, which, as evaluated by site-directed mutagenesis, have a functionally important interaction with oestrogen receptor-alpha residue His524. We conclude that the peptide recognition pattern can be used to classify suspected environmental endocrine disruptors according the oestrogen receptor-alpha and -beta conformations they induce.

In a successful abdominal pregnancy, urinary oestriol levels were about the fifth centile, but other hormone concentrations suggested that placental function was normal until 32 weeks gestation. After that, plasma oestrogen concentrations levelled off and plasma placental lactogen concentrations declined. Pre-eclampsia developed at 34 weeks and necessitated the delivery at 36 weeks and 2 days of a live normal female infant by laparotomy. The placenta was not removed. All hormone levels fell rapidly during the first weeks of the puerperium and then more slowly during the next six weeks to non-pregnancy levels. Plasma progesterone, urinary pregnanediol, and plasma oestradiol were the slowest to return to non-pregnant levels.

OBJECTIVE

To estimate the detection rates (DRs) and false-positive rates (FPRs) in the incidental identification of trisomy 18 (T18) and trisomy 13 (T13) as part of antenatal screening for Down's syndrome (DS) using the Combined, Quadruple and Integrated test markers.

METHODS

Screening marker levels on 224 T18 and 67 T13 pregnancies screened for DS were evaluated. Estimated means, standard deviations and correlation coefficients were used with published estimates for unaffected pregnancies to derive detection algorithms for the two disorders. DRs and FPRs of the algorithms were estimated using Monte Carlo simulation.

RESULTS

In T18 and T13 pregnancies first trimester nuchal translucency was raised, free β-human chorionic gonadotrophin (hCG) and pregnancy associated plasma protein-A reduced. In T18 pregnancies second trimester alphafetoprotein, unconjugated oestriol and free β-hCG were reduced. In T13 pregnancies second trimester inhibin-A was raised. These markers specified T18 and T13 algorithms. The DS Combined test algorithm detected 42% of T18 and 59% of T13 (2.00% FPR); 88% and 74% by adding the T18 Combined test algorithm (2.17% FPR) and 89% and 75% by further adding the T13 Combined test algorithm (2.19% FPR). The corresponding detection rates for the Quadruple test were: 5% and 21% (2.00% FPR), 59% and 21% (2.16% FPR) and 59% and 24% (2.28% FPR), and for the Integrated test were: 40% and 60% (2.00% FPR), 92% and 68% (2.12% FPR) and 92% and 74% (2.18% FPR).[Corrected]

CONCLUSIONS

Antenatal screening for DS detects about 40% of T18 and about 60% of T13 pregnancies. The addition of a T18 algorithm substantially increases the detection of both trisomies with a small increase in the FPR. The further addition of a T13 algorithm results in a small increase in the detection of T13.

BACKGROUND

Vesico-urethral function may be evaluated in humans and dogs by conventional urodynamic testing (cystometry and urethral pressure profilometry) or by electromyography. These techniques are performed under general anaesthesia in dogs. However, anaesthesia can depress bladder and urethral pressures and inhibit the micturition reflex. The primary objective of this pilot study was to evaluate the use of telemetry for urodynamic investigation in dogs. We also aimed to determine the applicability of telemetry to toxicologic studies by assessing the repeatability of telemetric recordings.

RESULTS

Conventional diuresis cystometry was performed in six continent adult female Beagle dogs prior to surgical implantation of telemetric and electromyographic devices. In the first phase of the telemetric study, continuous recordings were performed over 8 days and nights. Abdominal, intravesical and detrusor threshold pressures (Pdet th), voided volume (Vv), urethral smooth muscle electrical activity and involuntary detrusor contractions (IDC) were measured during the bladder filling phase and during micturition episodes.Vv recorded during telemetry was significantly lower than bladder volume obtained by diuresis cystometry. Repeatability of telemetric measurements was greater for observations recorded at night. IDC frequency and Pdet th were both lower and Vv was higher at night compared to values recorded during daytime.In the second phase of the telemetric study, phenylpropanolamine, oestriol, bethanechol, oxybutynin or duloxetine were administered orally for 15 days. For each drug, continuous recordings were performed overnight for 12 hours on days 0, 1, 8 and 15. Electromyographic urethral activity was significantly increased 8 days after oestriol or duloxetine administration. No significant changes in bladder function were observed at any time point.

CONCLUSIONS

In dogs, the high repeatability of nocturnal telemetric recordings indicates that this technique could provide more informative results for urologic research. Urethral smooth muscle electrical activity appears to be modified by administration of drugs with urethral tropism. In this pilot telemetric study, bladder function was not affected by oral administration of urological drugs at their recommended clinical dosages. Experimental studies, (pharmacokinetic and pharmacodynamic) and clinical studies are warranted to further define the effects of these drugs on vesico-urethral function in dogs.

In a series of 26,209 patiens, the incidence of pre-eclampsia was 9.3%, being significantly higher in primiparae (14.1%) than multiparae (5.7%) (P less than 0.001). In patients with early-onset pre-eclampsia there were highly significant (P less than 0.001) increases in the incidences of proteinuria, severe hypertension, placental abruption, fetal growth retardation, neonatal asphyxia and perinatal mortality. There were no significant differences between the incidences of these complications in primiparae and multiparae. The incidence of subnormal oestriol excretion was increased before the emergence of early-onset pre-eclampsia with equal to significance (P less than 0.001) in primiparae and multiparae. Eclampsia was more common in patients with late-onset pre-eclampsia, but not significantly so.

Maternal serum levels of total oestriol and human placental lactogen (HPL) were measured in 280 normal and 87 pre-eclamptic pregnancies. Normal levels of HPL, but significantly reduced total oestriol values were obtained when pre-eclampsia was present. However, when fetal complications developed, both hormone levels were further significantly reduced. The severity of pre-eclampsia had no effect on the serum levels of oestriol and HPL. An analysis of the 18 pregnancies with significant fetal-placental dysfunction showed that 13 (72%) were predicted by unfavourable levels of total oestriol, nine (50%) by unfavourable levels of HPL, and 14 (78%) by the use of both assays. The present study supports the value of antenatal measurement both of serum total oestriol and of HPL in the management of pre-eclamptic pregnancies.

Orally administered salbutamol (8 mg every six hours) is a simple, acceptable and effective method of inhibiting labour. Of 208 patients, 89.4% had pregnancy prolonged for longer than two days. The pregnancy was prolonged for one week in 77.5%, and for two weeks in 66.8% of patients. Tremor and anxiety occurred in 68.3% of patients, and tachycardia greater than 110 beats per minute in 21.2%, but these proved tolerable if the patient was forwarned. Haemorrhages, both ante partum, and post partum, were apparently reduced. Glycosuria and pre-eclampsia were uncommon. Urinary oestriol levels were not significantly altered. Perinatal mortality was 58 per 1000 live and still births. The babies were active at delivery, but prone to hypothermia. The incidence of respiratory distress syndrome (4.1%) was low, particularly in babies born within four hours of the last salbutamol administration. Low Apgar scores were also uncommon in this group.

In a series of 6,361 consecutive patients, low oestroil excretion late in pregnancy was detected in 871 cases (13-6%) and was associated with significantly increased incidences of still birth (P less than 0-001), neonatal death (P less than 0-001) and intrauterine growth retardation (P less than 0-001). Persistently low oestriol excretion occurred in approximately 3% of patients and two-thirds of these were suitable for conservative treatment with intravenous infusion of dextrose (25%) and fructose (20%) (2 1. of each in 48 hours). In 97 of 147 patients (65%), low oestriol excretion was favourably affected by this regimen, with significantly improved perinatal results (P less than 0-001).