David A. Aitken

Reliability of self reported smoking status by pregnant women for estimating smoking prevalence: a retrospective, cross sectional study

Objective To determine what impact reliance on self reported smoking status during pregnancy has on both the accuracy of smoking prevalence figures and access to smoking cessation services for pregnant women in Scotland. Design Retrospective, cross sectional study of cotinine measurements in stored blood samples. Participants Random sample (n=3475) of the 21 029 pregnant women in the West of Scotland who opted for second trimester prenatal screening over a one year period. Main outcome measure Smoking status validated with cotinine measurement by maternal area deprivation category (Scottish Index of Multiple Deprivation). Results Reliance on self reported smoking status underestimated true smoking by 25% (1046/3475 (30%) from cotinine measurement v 839/3475 (24%) from self reporting, z score 8.27, P<0.001). Projected figures suggest that in Scotland more than 2400 pregnant smokers go undetected each year. A greater proportion of smokers in the least deprived areas (deprivation categories 1+2) did not report their smoking (39%) compared with women in the most deprived areas (22% in deprivation categories 4+5), but, because smoking was far more common in the most deprived areas (706 (40%) in deprived areas compared with 142 (14%) in affluent areas), projected figures for Scotland suggest that twice as many women in the most deprived areas are undetected (n=1196) than in the least deprived areas (n=642). Conclusion Reliance on self reporting to identify pregnant smokers significantly underestimates the number of pregnant smokers in Scotland and results in a failure to detect over 2400 smokers each year who are therefore not offered smoking cessation services.

Circulating angiogenic factors in early pregnancy and the risk of preeclampsia, intrauterine growth restriction, spontaneous preterm birth, and stillbirth

OBJECTIVE: To estimate the relationship between maternal serum levels of placental growth factor (PlGF) and soluble fms-like tyrosine kinase-1 (sFlt-1) in early pregnancy with the risk of subsequent adverse outcome. METHODS: A nested, case–control study was performed within a prospective cohort study of Down syndrome screening. Maternal serum levels of sFlt-1 and PlGF at 10–14 weeks of gestation were compared between 939 women with complicated pregnancies and 937 controls. Associations were quantified as the odds ratio for a one decile increase in the corrected level of the analyte. RESULTS: Higher levels of sFlt-1 were not associated with the risk of preeclampsia but were associated with a reduced risk of delivery of a small for gestational age infant (odds ratio [OR] 0.92, 95% confidence interval [CI] 0.88–0.96), extreme (24–32 weeks) spontaneous preterm birth (OR 0.90, 95% CI 0.83–0.99), moderate (33–36 weeks) spontaneous preterm birth (OR 0.93, 95% CI 0.88–0.98), and stillbirth associated with abruption or growth restriction (OR 0.77, 95% CI 0.61–0.95). Higher levels of PlGF were associated with a reduced risk of preeclampsia (OR 0.95, 95% CI 0.90–0.99) and delivery of a small for gestational age infant (OR 0.95, 95% CI 0.91–0.99). Associations were minimally affected by adjustment for maternal characteristics. CONCLUSION: Higher early pregnancy levels of sFlt-1 and PlGF were associated with a decreased risk of adverse perinatal outcome. LEVEL OF EVIDENCE: II

DIMERIC INHIBIN A AS A MARKER FOR DOWN'S SYNDROME IN EARLY PREGNANCY

BACKGROUND In screening for Downs syndrome in the second trimester of pregnancy, the concentrations of alpha-fetoprotein, the beta subunit of human chorionic gonadotropin, and intact human chorionic gonadotropin in material serum are widely used markers. We investigated a new marker, dimeric inhibin A, and compared its predictive value with that of the established markers. METHODS Serum samples were obtained at 7 to 18 weeks of gestation from 58 women whose fetuses were known to be affected by Downs syndrome, 32 whose fetuses were affected by trisomy 18, and 438 whose fetuses were normal, and the samples were analyzed for each marker. Individual serum concentrations of each marker were converted to multiples of the median value at the appropriate length of gestation in the women with normal pregnancies, and rates of detection of Downs syndrome by screening for inhibin A in various combinations with the other markers were estimated by multivariate analysis. RESULTS In the women with fetuses affected by Downs syndrome, the serum inhibin A concentrations were 2.06 times the median value in the women with normal pregnancies (P < 0.001). This compared with 2.00 times the median for the beta subunit of human chorionic gonadotropin, 1.82 times the median for intact human chorionic gonadotropin, and 0.72 for alpha-fetoprotein. The serum concentrations of inhibin A in the women with fetuses affected by Downs syndrome did not appear to be significantly elevated above normal until the end of the first trimester and were not significantly different from normal in the women with fetuses affected by trisomy 18 (P = 0.17). The rate of detection of Downs syndrome was 53 percent and the false positive rate was 5 percent when alpha-fetoprotein, the beta subunit of human chorionic gonadotropin, the maternal age were used together as predictors. The detection rate increased to 75 percent when inhibin A was added (P = 0.002). CONCLUSIONS In the second trimester of pregnancy, measuring inhibin A in maternal serum, in combination with measurements of alpha-fetoprotein and beta subunit of human chorionic gonadotropin, significantly improved the rate of detection of Downs syndrome.

Combined ultrasound and biochemical screening for Down's Syndrome in the first trimester: a Scottish multicentre study

Objective To evaluate the use of ultrasound measurements of fetal nuchal translucency (NT) obtained in a routine antenatal clinic setting in combination with appropriate biochemical markers as a first trimester screening test for Downs Syndrome.

Pregnancy-associated plasma protein A and alpha-fetoprotein and prediction of adverse perinatal outcome.

OBJECTIVE: To describe the association between pregnancy associated plasma protein A (PAPP-A), alpha-fetoprotein (AFP) and adverse perinatal outcome. METHODS: We conducted a multicenter prospective cohort study of 8,483 women attending for prenatal care in southern Scotland between 1998 and 2000. The risk of delivering a small for gestational age infant, delivering preterm, and stillbirth were related to maternal serum levels of PAPP-A and AFP. RESULTS: Women with a low PAPP-A were not more likely to have elevated levels of AFP. Compared with women with a normal PAPP-A and a normal AFP, the odds ratio for delivering a small for gestational age infant for women with a high AFP was 0.9 (95% confidence interval [CI] 0.5–1.6), for women with a low PAPP-A was 2.8 (95% CI 2.0–4.0), and for women with both a high AFP and a low PAPP-A was 8.5 (95% CI 3.6–20.0). The odds ratio for delivering preterm for women with a high AFP was 1.8 (95% CI 1.3–2.7), for women with a low PAPP-A was 1.9 (95% CI 1.3–2.7), and for women with both a low PAPP-A and a high AFP was 9.9 (95% CI 4.4–22.0). These interactions were statistically significant for both outcomes (P = .03 and .04, respectively). There was a nonsignificant trend toward a similar interaction in relation to stillbirth risk. Of the women with the combination of a low PAPP-A and high AFP, 32.1% (95% CI 15.9–52.4) delivered a low birth weight infant. CONCLUSION: Low maternal serum levels of PAPP-A between 10 and 14 weeks and high levels of AFP between 15 and 21 weeks gestation are synergistically associated with adverse perinatal outcome. LEVEL OF EVIDENCE: II-2

Screening for Down's syndrome: changes in marker levels and detection rates between first and second trimesters

Objective To monitor changes with gestation in levels of alpha‐fetoprotein (AFP), free beta human chorionic gonadotrophin (FβhCG) and pregnancy associated plasma protein‐A (PAPP‐A) in Downs syndrome pregnancies and to compare risks estimated in the first trimester with those obtained by routine screening in the second trimester for the same pregnancies.

First trimester biochemical screening for trisomy 21: the role of free beta hCG, alpha fetoprotein and pregnancy associated plasma protein A.

The potential efficacy of screening for trisomy 21 in the first trimester, using maternal serum markers α fetoprotein, free β human chorionic gonadotropin, unconjugated oestriol and pregnancy associated plasma protein A, was studied in an unselected population of women between the seventh and fourteenth week of gestation. Using a combination of α fetoprotein and free β human chorionic gonadotropin, 53% of affected pregnancies could be identified at a false positive rate of 5%. Unconjugated oestriol and pregnancy associated plasma protein A levels were lower in cases of trisomy 21, but their inclusion with other markers did not significantly improve detection rate. Monitoring the same pregnancies also in the second trimester showed that screening in the first trimester identified the same cases as in the second. We conclude that first trimester screening using free β human chorionic gonadotropin and α fetoprotein, is a viable possibility and will lead to detection rates in excess of 50%. Prospective studies are needed to confirm these observations.

URINE FREE BETA hCG AND BETA CORE IN PREGNANCIES AFFECTED BY DOWN'S SYNDROME

Urine beta core was shown in recent studies to be markedly elevated in pregnancies affected by Downs syndrome in the late second trimester. Free beta human chorionic gonadotropin (hCG) has also been shown to be the most discriminatory maternal serum marker of Downs syndrome. Since free beta hCG is rapidly cleared from the maternal circulation, we have carried out a study to evaluate whether free beta hCG is elevated in the urine of pregnancies affected by Downs syndrome and to investigate whether urine beta core or urine free beta hCG may be used as possible screening markers. Urine samples from 29 cases of Downs syndrome, three cases of trisomy 18, and 400 control pregnancies were analysed for the two prospective markers. Results were corrected for urine concentration by expressing marker concentrations at a fixed creatinine concentration and then expressing the results as multiples of the median for unaffected pregnancies of the same gestation. The median value of beta core in the Downs syndrome pregnancies was 2·35 compared with 2·47 for free beta hCG. Free beta hCG distributions were closely similar to those in maternal serum. Using free beta hCG, we predict Downs syndrome detection rates of 58 per cent at a 5 per cent false‐positive rate. Using beta core, however, this rate fell to 41 per cent. Measurement of free beta hCG in urine may present a feasible route for screening pregnant populations, particularly where community‐based obstetric care is the norm and/or if early first‐trimester screening becomes a reality.

Is maternal serum total hCG a marker of trisomy 21 in the first trimester of pregnancy

In a study of 130 first trimester cases of trisomy 21 and 959 controls we have shown that the median MoM for alpha‐fetoprotein (AFP) is lower (0.82) and that for total human chorionic gonadotrophin (hCG) is higher (1.31) than in the control group. For AFP 15.3% of cases were below the 5th centile and for total hCG 19.8% were above the 95th centile. The median shift observed for AFP and total hCG is poorer than that for pregnancy associated plasma protein‐A (PAPP‐A) or free β‐hCG and together with maternal age, AFP and total hCG could only be expected to detect 40% of cases. In combination with PAPP‐A, total hCG would identify 52% of cases, somewhat less than the 67% observed with free β‐hCG and PAPP‐A. However, we have demonstrated for total hCG a significant temporal change in median MoM with gestational age. Before 70 days the median MoM was less than 0.5, between 70 and 83 days this increased to 1.13, and between 84 and 97 days this increased to 1.52. This median shift has significant implications for interpreting previous studies and even more significant implications for detection rates. When population parameters specific to the gestational age in question are used, detection rates with total hCG and PAPP‐A increase from 47% at 70–83 days to 60% at 84–97 days. This observation explains much of the confusion around total hCG in the first trimester and shows the importance of selecting analyte pairs and population parameters appropriate to the time in gestation when screening is performed. Copyright

Impact of a Regional Screening Programme Using Maternal Serum a Fetoprotein (AFP) and Human Chorionic Gonadotrophin (hCG) on the Birth Incidence of Down's Syndrome in the West of Scotland

Objectives – To evaluate the impact of a large scale population screening programme on the birth incidence of Downs syndrome in the west of Scotland over a 12 month period. Methods – Biochemical screening for Downs syndrome using maternal serum α fetoprotein, chorionic gonadotrophin, and maternal age was offered to a pregnant population of 37 226 women in the west of Scotland between 1991 and 1992. The combined risk of Downs syndrome pregnancy was reported for each of the 30 084 women who opted for screening. Results — When a threshold risk of 1:220 was used 1523 women (5.1% of the screened population) were assigned to the high risk group, of whom 1070 (70%) proceeded to diagnostic ammiocentesis or midtrimester chorionic villus sampling. When multiple sources of ascertainment were used 37 Downs syndrome pregnancies were identified within the screened population, 26 (70%) of which were within the high risk group and 21 (57%) of which were prenatally diagnosed. In addition, three Downs syndrome pregnancies were diagnosed by first trimester chorionic villus sampling before biochemical screening. A further 10 Downs syndrome pregnancies were identified at birth, eight to women who had not had a screening test and two to women who had moved into the area, making a total of 50 Downs syndrome pregnancies in the whole pregnant population of 37 226. Thus the potential prenatal detection rate in the screened population was 70% (26/37), the actual prenatal detection rate in the screened population was 57% (21/37), and the overall prenatal detection rate in the total (screened and unscreened) population was 48% (24/50). Conclusion- Biochemical screening for Downs syndrome is practical and effective in routine clinical practice, enabling women to make an informed choice about prenatal diagnosis and providing better use of scarce resources when a suitable protocol is applied to the whole pregnant population. Its maximum potential for the reduction of the birth incidence of Downs syndrome is limited by incomplete uptake of screening and compliance with diagnostic testing in the high risk group.