Screening for pre-eclampsia--lessons from aneuploidy screening.

BACKGROUND: Antenatal screening for aneuploidy is an established routine clinical practice worldwide. The same statistical methodology, developed and refined over three decades, might be adapted to screening for pre-eclampsia. METHODS: The published literature is reviewed for evidence that the methodology is valid for pre-eclampsia using first trimester maternal serum PP13, PAPP-A, PlGF, ADAM12 and inhibin A, together with MAP and uterine artery Doppler PI. Risk is estimated for both early onset pre-eclampsia, requiring delivery before 34 weeks, or late onset disease. Prior risk from the background prevalence multiplied by likelihood ratios (LRs) for ethnicity, parity, adiposity and family history is multiplied by an LR from the screening marker profile. Markers are expressed in multiples of the gestation-specific median and adjusted for body mass, ethnicity and smoking status as appropriate. A standardized population with a fixed distribution of risk factors and a multi-variate Gaussian model of marker profiles is used to predict performance. RESULTS: There is sufficient published data to estimate individual risks reasonably well. Modeling predicts that using PAPP-A and one other serum marker, together with the physical markers more than two-thirds of early and one-third of late onset cases can be detected by classifying less than 2% of pregnancies as high risk; three-quarters of early case could be detected with a 5% high risk rate. CONCLUSION: Whilst more data on some markers is still required modeling so far suggests that extending first trimester aneuploidy screening programs to include pre-eclampsia screening would yield a high detection. However, prospective studies are needed to verify the model predictions.

First-trimester placental protein 13 and placental growth factor: markers for identification of women destined to develop early-onset pre-eclampsia.

OBJECTIVE: To investigate the predictive value of maternal serum pregnancy-associated plasma protein A (PAPP-A), free ß subunit of human chorionic gonadotrophin (fß-hCG), placental protein 13 (PP13), placental growth factor (PlGF) and a desintegrin and metalloproteinase 12 (ADAM12), for first-trimester identification of early-onset pre-eclampsia. DESIGN: Nested case-control study. SETTING: Routine first-trimester screening for trisomy 21 in the Netherlands. POPULATION: Eighty-eight women who developed pre-eclampsia or haemolysis, elevated liver enzymes, low platelets (HELLP) syndrome before 34 weeks of gestation and 480 controls. METHODS: PP13, PlGF and ADAM12 were measured in stored first-trimester serum, previously tested for PAPP-A and fß-hCG. All marker levels were expressed in multiples of the gestation-specific normal median (MoMs). Model predicted detection rates for fixed false-positive rates were obtained for statistically significant markers alone and in combination. MAIN OUTCOME MEASURES: Development of pre-eclampsia or HELLP syndrome. RESULTS: PP13 and PlGF were reduced in women with pre-eclampsia, with medians 0.68 MoM and 0.73 MoM respectively (P < 0.0001 for both). PAPP-A was reduced (median 0.82 MoM, P < 0.02) whereas ADAM12 and fß-hCG did not differ between control women and those with pre-eclampsia. In pre-eclampsia complicated by a small-for-gestational-age fetus, all markers except fß-hCG had lower values, compared with pregnancies involving fetuses of normal weight. The model-predicted pre-eclampsia detection rate for a combination of PP13 and PlGF was 44% and 54%, respectively, for a fixed 5% and 10% false-positive rate. CONCLUSION: This study demonstrates that PP13 and PlGF in the first-trimester might be promising markers in risk assessment for early pre-eclampsia/HELLP syndrome but for an adequate screening test additional characteristics are necessary.

Placental protein 13 as a first trimester screening marker for aneuploidy.

OBJECTIVE: To determine whether Placental Protein 13 (PP13) could be an additional marker in first trimester screening for aneuploidies. METHODS: To evaluate differences in multiples of the gestation-specific normal median (MoMs), PP13 concentrations were measured in serum samples from Down syndrome, trisomy 18 and 13 affected pregnancies and euploid singleton pregnancies (four for each case matched for duration of storage, maternal weight and age). RESULTS: The PP13 MoM in Down syndrome cases (n = 153) was 0.91 [not statistically significant from controls (n = 853); P = 0.06; Wilcoxon rank sum test, two-tail]. PP13 MoMs were decreased in trisomy 18 (n = 38-median MoM 0.64; P < 0.0001) and trisomy 13 cases (n = 23-median MoM 0.46; P < 0.0001). There was a slight upward trend in MoM values of the Down syndrome cases with gestational weeks. The PP13 MoM was significantly correlated with the pregnancy associated plasma protein-A MoM and the free beta-subunit of human chorion gonadotrophin (fbeta-hCG) MoM. CONCLUSION: PP13 does not seem to be a good marker for Down syndrome. PP13 MoMs are, however, significantly lower in trisomy 18 and 13 pregnancies. The addition of PP13 to the current screening test could be valuable for improving the discrimination of aneuploid from euploid pregnancies.

A novel approach to first-trimester screening for early pre-eclampsia combining serum PP-13 and Doppler ultrasound.

OBJECTIVE: To investigate the value of maternal serum placental protein 13 (PP-13) measurement and uterine artery Doppler during first-trimester screening in the prediction of early pre-eclampsia. METHODS: This was a nested case-control prospective study of pregnancies at 11 + 0 to 13 + 6 weeks of gestation. The pulsatility index (PI) of blood flow in the uterine arteries and the maternal serum concentration of PP-13 were measured in 10 women who went on to develop pre-eclampsia that necessitated delivery before 34 weeks, and in 423 unaffected women. Results were expressed as multiples of the gestation-specific median in controls (MoM). A logistic regression model was used to predict detection and false-positive rates. RESULTS: In the cases that developed pre-eclampsia requiring delivery before 34 weeks, compared with the unaffected pregnancies, the median uterine artery PI was higher (1.43 MoM) and the median serum PP-13 level was lower (0.07 MoM; P < 0.001, Wilcoxon rank sum test for both). Modeling predicted that for a 90% detection rate of pre-eclampsia requiring delivery before 34 weeks, the false-positive rate of screening by PP-13 was 12%, by uterine artery PI was 31% and by a combination of the two methods was 9%. A policy of contingency screening, whereby all women are screened by maternal serum PP-13 and only the 14% at highest risk are then screened by Doppler, achieved a detection rate of 90% with an overall false-positive rate of 6%. CONCLUSION: Effective screening for pre-eclampsia requiring delivery before 34 weeks can potentially be provided by assessment of a combination of maternal serum PP-13 and uterine artery Doppler in the first trimester of pregnancy.

Psychosocial aspects of genetic screening of pregnant women and newborns: a systematic review.

OBJECTIVES: To address five broad questions concerned with knowledge, anxiety, factors associated with participation/non-participation in screening programmes and the long-term sequelae of false-positive, true-positive in newborns and true-negative results. DATA SOURCES: Five electronic databases, two journals and attempts were made to locate unpublished work. REVIEW METHODS: This review started from a substantial literature base that provided the basis for (a) scoping the literature, (b) informing search strategy terms and (c) identifying preliminary article inclusion and exclusion criteria. The main eligibility criteria were: any screening programme aimed at pregnant women or newborn babies that included a 'genetic' target condition, this included chromosomal anomalies; any study that reported psychosocial data collected directly from parents. The data extraction form developed for this study elicited data from the selected studies. The data were entered into a database, which provided a summary of the included papers. RESULTS: A total of 288 candidate publications were identified, 106 of which were eligible: 78 were concerned with antenatal screening and 28 with newborn screening. It was found that levels of knowledge adequate for decision-making were not being achieved despite information leaflets and videos having some effect. Studies that have succeeded in increasing knowledge have not observed a corresponding increase in anxiety, although some anxiety might be an appropriate response and may aid coping and decision-making. Anxiety is clearly raised in women receiving positive screening results, especially young women. However, evidence is lacking of a beneficial (i.e. reassuring) effect of receiving a screen-negative result. Anxiety in screen-positive women falls on receipt of subsequent reassuring results, but some residual anxiety may remain. A minority (perhaps up to 30%) of women receiving a screen-positive result in pregnancy expressed regret about their screening decision. Uptake of neonatal screening has been treated as a 'given' and not as a research topic. CONCLUSIONS: The results of this review have many implications for the work of the National Screening Committee. The most pressing of these, in order of priority, relate to: the inadequacy of current procedures for achieving informed consent; the cost of providing a satisfactory service; the unmet needs of 'false-positives', and the unmet needs of women's partners, particularly in carrier screening. It is suggested that research is conducted on the above four topics in order to fill gaps in the evidence base that relate to screening technologies which have been available for many years. In addition, future screening programmes will create a new list of research questions, based on the same main agenda but applied to new areas, for example, new conditions such as haemoglobinopathies and fragile X syndrome; new client groups such as young women and minority ethnic groups; and new testing modalities such as ultrasound.

Compromise ultrasound dating policy in maternal serum screening for Down syndrome.

Routine ultrasound biometry is the method of choice for gestational dating when screening for Down syndrome. However, it is costly and an alternative policy is to restrict ultrasound to women most likely to have menstrual dating errors. This was evaluated by statistical modelling with parameters from 14,274 women screened between January 1997 and July 2001 using free beta-human chorionic gonadotrophin (free beta-hCG), alpha-fetoprotein (AFP) and unconjugated estriol (uE(3)). A total of 12,711 (89%) women had both ultrasound and menstrual gestations, but in 4101 (29%) women either the last menstrual period (LMP) was uncertain or a pill-withdrawal period, or there were irregular or abnormal length cycles. The LMP was not entered in the test request form for a further 1404 (9.8%) women. Routine ultrasound dating yielded a predicted detection rate higher than for menstrual dating by 3.9-7.1%, depending on the marker combination and cut-off. The false-positive rate was reduced by 0.2-1.1%. Selectively scanning the 39% with unreliable dates increased detection by 2.6-4.6%, and reduced the false-positive rate by 0.04-0.6%. Some centres only use the ultrasound estimate of gestation when it differs from the menstrual estimate by more than 7 days. Such a rule reduces the gain in detection rate to 2.5-4.6% for routine ultrasound and 1.7-3.1% with the compromise policy; the false-positive rate reductions are 0.06-0.6% and 0.0-0.3%, respectively. We conclude that if routine ultrasound is not financially and practically feasible, the compromise policy yields a clinically important improvement in screening performance compared to menstrual dating.

Current awareness in prenatal diagnosis.

In order to keep subscribers up-to-date with the latest developments in their field, John Wiley & Sons are providing a current awareness service in each issue of the journal. The bibliography contains newly published material in the field of prenatal diagnosis. Each bibliography is divided into 17 sections: 1 Books, Reviews & Symposia; 2 General Interest; 3 Normal Fetal Development; 4 Gametogenesis and Pre-implantation Diagnosis; 5 First Trimester Diagnosis; 6 Second Trimester Diagnosis; 7 Fetal Diagnosis by Ultrasound and Other Imaging; 8 Maternal Screening; 9 Screening for Carriers of Genetic Abnormality; 10 Technological Developments; 11 Confined Placental Mosaicism and Uniparental Disomy; 12 Molecular Cytogenetics; 13 Fetal Cells in Maternal Circulation; 14 Fetal Therapy; 15 Psychosocial Aspects; 16 Epidemiology and Environmental Factors; 17 Developmental Pathology. Within each section, articles are listed in alphabetical order with respect to author. If, in the preceding period, no publications are located relevant to any one of these headings, that section will be omitted.

Trends in the incidence of ectopic pregnancy in England and Wales from 1966 to 1996.

OBJECTIVE: To examine the incidence of ectopic pregnancy over the period 1966 to 1996. SETTING: England and Wales. DESIGN: Use of official statistics on hospital discharges, maternities, legal abortions and estimated populations of women aged 15-44 years. MAIN OUTCOME MEASURES: Incidence rates of ectopic pregnancies. RESULTS: Between 1966 to 1970 and 1994 to 1996 the recorded incidence increased 4.5-fold from 3.45 to 15.5 per 1000 maternities, 3.8-fold from 3.25 to 12.4 per 1000 pregnancies and 3.1-fold from 30.2 to 94.8 per 100,000 women aged 15-44. The rate of increase was not uniform. Incidence approximately doubled between 1966 and 1985, when the official data collection system changed. By 1989, when data from the new system became available, there had been a further almost doubling of recorded incidence. Subsequently, the upward trend appears to have continued until 1991 to 1992 and has remained stable in the last four years of the study. The trends were similar in each of three 10-year age groups. CONCLUSIONS: The recorded incidence of ectopic pregnancy has increased markedly over the last three decades. This may be partly due to artefacts of data recording and more sensitive diagnostic tests, but it is likely that the actual incidence has increased, probably due to a sexually transmitted agent.

Co-variables in first trimester maternal serum screening.

The objective of this study was to determined the influence of maternal weight, maternal smoking habits, gravidity, parity and fetal gender on the level of maternal serum marker used in first trimester screening for Down syndrome. A total of 2449 singleton unaffected pregnancies from two centres were studied. Maternal serum free beta-human chorionic gonadotrophin (hCG) and alpha-fetoprotein (AFP) concentrations had been measured in all pregnancies, and pregnancy associated plasma protein (PAPP)-A levels had been measured in 924. All results were expressed as multiples of the gestation specific median (MoM) values after regression, using each centre's own medians. Information on maternal weight was available in 2259 pregnancies, on self-reported current cigarette smoking in 1364 (of whom 117 (8.6%) were smokers), on gravidity in 1371, parity in 1303 and fetal gender in 253. All three markers showed a statistically significant negative association with maternal weight (p<0.0005) and in the subsequent analyses MoM values were weight adjusted using standard methods. The median PAPP-A level in smokers was 0.81 MoM, a significant reduction (p<0.005); free beta-hCG was also reduced (median 0.89 MoM) but not significantly (p=0.17), and AFP was unaltered. The median AFP level in primagravidas was highly significantly greater than that in gravid women (p<0.0005). In PAPP-A the reverse effect was seen but it did not reach statistical significance (p=0.15) and there was no effect for free beta-hCG. Results of a similar magnitude and direction were found for parity. The median level of free beta-hCG was higher (p=0.0005), and the median AFP lower in female pregnancies. Maternal weight and, for PAPP-A, maternal smoking are important first trimester screening co-variables. Gravidity, parity and fetal gender also seem to influence one or more first trimester markers.

Collaborative study of maternal urine beta -core human chorionic gonadotrophin screening for Down syndrome.

Several studies have shown that second-trimester maternal urine beta-core human chorionic gonadotrophin (hCG) levels are raised on average in Down syndrome pregnancies. However, in all but one, testing was retrospective after extended sample storage and so we carried out a large international multicentre prospective study. 16 centres provided 6730 samples from 14-19 week pregnancies: 39 with Down syndrome, 12 with Edwards' syndrome, 42 with other aneuploidies, 52 unaffected twins and 6585 singleton unaffected pregnancies. Samples were from those having routine maternal serum screening in 6 centres and invasive prenatal diagnosis for reasons unrelated to maternal serum screening in 10 centres. Normalized levels of beta-core hCG (nmom/mmol creatinine) were expressed as multiples of the gestation-specific normal median (MoMs). The median beta-core hCG level in Down syndrome was 1.70 MoM (95 per cent confidence interval, 1.26-2.30); 14 (36 per cent) exceeded the normal 90th centile and 9 (23 per cent) the 95th centile. The median level in Edwards' syndrome was 0.23 MoM. On the basis of our results alone it is unlikely that urinary beta-core hCG will be a useful marker in Down syndrome screening practice. But the considerable variability in results between studies means that further research is needed before a reliable conclusion can be drawn.