Antenatal screening for Down syndrome using serum placental growth factor with the combined, quadruple, serum integrated and integrated tests.

OBJECTIVE: To estimate the value of first or second trimester placental growth factor (PlGF) as an additional antenatal screening marker for Down syndrome. DESIGN: Nested case-control study. SETTING: Antenatal screening service. POPULATION OR SAMPLE: 532 Down syndrome pregnancies and 1,155 matched unaffected pregnancies. METHODS: Stored maternal serum samples (-40°C) were assayed for PlGF. Monte Carlo simulation was used to estimate the screening performance of PlGF with the Combined, Quadruple, serum Integrated and Integrated tests. MAIN OUTCOME MEASURES: Median PlGF levels in affected and unaffected pregnancies and screening performance (detection rates [DR] for specified false-positive rates [FPR] and vice versa). RESULTS: First trimester median PlGF was 15%, 28% and 39% lower in Down syndrome than unaffected pregnancies at 11, 12 and 13 completed weeks' gestation respectively (all p<0.001). Second trimester median PlGF was 31% lower at 14 weeks (p<0.001), and the difference decreased (6% lower at 17 weeks). At a 90% DR with first trimester markers measured at 13 weeks, adding PlGF decreased the FPR from 11.1 to 5.1% using the Combined test, 9.3% to 4.5% using the serum Integrated test, and 3.4% to 1.5% using the Integrated test (or 1.5 to 1.4% with first trimester markers measured at 11 weeks). Adding PlGF to the Quadruple test (measured at 15 weeks) decreased the FPR from 10.0% to 9.6% at a 90% DR. CONCLUSIONS: First trimester PlGF measurements improve the performance of antenatal screening for Down syndrome using the Combined, serum Integrated and Integrated tests. Second trimester PlGF measurements are of limited value.

Screening for pre-eclampsia using serum placental growth factor and endoglin with Down's syndrome Quadruple test markers.

OBJECTIVE: To estimate the pre-eclampsia screening performance of placental growth factor (PlGF) and endoglin with second-trimester Quadruple test markers used for antenatal Down's syndrome screening. METHODS: A nested case-control study of 88 pregnant women with known early second-trimester Down's syndrome Quadruple test marker levels who subsequently developed pre-eclampsia and 275 unaffected controls. Frozen maternal serum samples were thawed and assayed for PlGF and endoglin. Monte Carlo simulation was used to estimate the pre-eclampsia screening performance of a pre-eclampsia detection algorithm using the Quadruple test markers with or without the addition of PlGF and/or endoglin. RESULTS: Median PlGF was 33% lower (95% confidence interval 24-41%) and endoglin 31% (20-43%) higher in pre-eclampsia than in unaffected pregnancies. Adding PlGF to the Quadruple test markers increased the pre-eclampsia detection rate from 34% to 45% at a 5% false-positive rate - it increased it to 43% with endoglin and to 50% with both. The corresponding estimates for early pre-eclampsia (before 36 weeks' gestation) were a few percentage points higher (48%, 48% and 55% respectively). Including information on parity, pre-eclampsia in a previous pregnancy, family history (woman's mother) and assuming a pre-eclampsia prevalence of 2%, the detection rates for a 5% false-positive rate were 39% with the Quadruple test markers, 48% with addition of endoglin, 49% with addition of PlGF, and 54% with addition of both. CONCLUSIONS: Adding PlGF to the Quadruple test Down's syndrome screening markers improves pre-eclampsia screening performance. There is a modest extra benefit in also adding the measurement of endoglin.

The value of early second trimester PAPP-A and ADAM12 in screening for pre-eclampsia.

OBJECTIVE: To estimate the pre-eclampsia screening performance of PAPP-A (pregnancy-associated plasma protein-A) and ADAM12 (A Disintegrin And Metalloprotease 12) in the early second trimester of pregnancy. METHODS: Stored frozen serum samples from a previously published nested case-control study comprising 77 women who developed pre-eclampsia and 224 unaffected controls were thawed and assayed for PAPP-A and ADAM12. Levels were converted into multiple of the unaffected median (MoM) values. RESULTS: Neither PAPP-A or ADAM12 were significantly different in women who developed pre-eclamspia compared with unaffected controls (PAPP-A: 0.97 MoM [95% confidence interval 0.73 to 1.25], ADAM12: 1.01 MoM [0.91 to 1.13]). CONCLUSION: Our results do not support the use of PAPP-A or ADAM12 in early second trimester antenatal screening for pre-eclampsia.

Antenatal thyroid screening and childhood cognitive function.

BACKGROUND: Children born to women with low thyroid hormone levels have been reported to have decreased cognitive function. METHODS: We conducted a randomized trial in which pregnant women at a gestation of 15 weeks 6 days or less provided blood samples for measurement of thyrotropin and free thyroxine (T(4)). Women were assigned to a screening group (in which measurements were obtained immediately) or a control group (in which serum was stored and measurements were obtained shortly after delivery). Thyrotropin levels above the 97.5th percentile, free T(4) levels below the 2.5th percentile, or both were considered a positive screening result. Women with positive findings in the screening group were assigned to 150 µg of levothyroxine per day. The primary outcome was IQ at 3 years of age in children of women with positive results, as measured by psychologists who were unaware of the group assignments. RESULTS: Of 21,846 women who provided blood samples (at a median gestational age of 12 weeks 3 days), 390 women in the screening group and 404 in the control group tested positive. The median gestational age at the start of levothyroxine treatment was 13 weeks 3 days; treatment was adjusted as needed to achieve a target thyrotropin level of 0.1 to 1.0 mIU per liter. Among the children of women with positive results, the mean IQ scores were 99.2 and 100.0 in the screening and control groups, respectively (difference, 0.8; 95% confidence interval [CI], -1.1 to 2.6; P=0.40 by intention-to-treat analysis); the proportions of children with an IQ of less than 85 were 12.1% in the screening group and 14.1% in the control group (difference, 2.1 percentage points; 95% CI, -2.6 to 6.7; P=0.39). An on-treatment analysis showed similar results. CONCLUSIONS: Antenatal screening (at a median gestational age of 12 weeks 3 days) and maternal treatment for hypothyroidism did not result in improved cognitive function in children at 3 years of age. (Funded by the Wellcome Trust UK and Compagnia di San Paulo, Turin; Current Controlled Trials number, ISRCTN46178175.).

Screening in early pregnancy for pre-eclampsia using Down syndrome quadruple test markers.

OBJECTIVES: To estimate the screening performance of early second-trimester prenatal serum markers for Down syndrome, in screening for the development of pre-eclampsia, and analyse the uncertainty over its screening performance. METHODS: A nested case-control study was carried out on 96 women with pre-eclampsia and 5 controls for each case from among the women attending three hospitals in London for their prenatal care. Record linkage between computerized obstetric and screening databases identified women with pre-eclampsia and unaffected control women. The stored frozen serum samples collected from these pregnancies between 15 and 22 weeks' gestation were retrieved and assayed for alpha-fetoprotein (AFP), unconjugated estriol (uE(3)), total human chorionic gonadotrophin (hCG), free beta-hCG and inhibin-A. RESULTS: Pre-eclampsia was identified from the computerized obstetric records and confirmed by examination of the medical notes. In the pregnancies that went on to develop pre-eclampsia, early second trimester inhibin-A and hCG values were significantly raised and uE(3) values were significantly lowered, while AFP values were not significantly altered. Using the Quadruple test markers (AFP, uE(3), hCG (total or free beta) and inhibin-A), an estimated 34% of pregnancies that developed pre-eclampsia were detected at a 5% false-positive rate. If all the women who had pre-eclampsia in a previous pregnancy (assuming a pre-eclampsia prevalence of 4%) are considered as screen positive and the serum test is applied to the remaining women, then around 42% of pre-eclamptic pregnancies would be detected at a 6.5% false-positive rate. Pre-eclampsia screening performance using the Quadruple test markers was materially better than that using the Triple test markers. CONCLUSION: Adding screening for pre-eclampsia to an existing Down syndrome screening programme using the Quadruple test markers is simple and worthwhile. It will detect over 40% of pregnancies with pre-eclampsia at an acceptable false-positive rate (about 6%) and with minimal additional costs.