Record linkage to obtain birth outcomes for the evaluation of screening biomarkers in pregnancy: a feasibility study

<p>Abstract</p> <p>Background</p> <p>Linking population health data to pathology data is a new approach for the evaluation of predictive tests that is potentially more efficient, feasible and efficacious than current methods. Studies evaluating the use of first trimester maternal serum levels as predictors of complications in pregnancy have mostly relied on resource intensive methods such as prospective data collection or retrospective chart review. The aim of this pilot study is to demonstrate that record-linkage between a pathology database and routinely collected population health data sets provides follow-up on patient outcomes that is as effective as more traditional and resource-intensive methods. As a specific example, we evaluate maternal serum levels of PAPP-A and free <it>β</it>-hCG as predictors of adverse pregnancy outcomes, and compare our results with those of prospective studies.</p> <p>Methods</p> <p>Maternal serum levels of PAPP-A and free <it>β</it>-hCG for 1882 women randomly selected from a pathology database in New South Wales (NSW) were linked to routinely collected birth and hospital databases. Crude relative risks were calculated to investigate the association between low levels (multiples of the median ≤ 5^thpercentile) of PAPP-A or free <it>β</it>-hCG and the outcomes of preterm delivery (<37 weeks), small for gestational age (<10^thpercentile), fetal loss and stillbirth.</p> <p>Results</p> <p>Using only full name, sex and date of birth for record linkage, pregnancy outcomes were available for 1681 (89.3%) of women included in the study. Low levels of PAPP-A had a stronger association with adverse pregnancy outcomes than a low level of free <it>β</it>-hCG which is consistent with results in published studies. The relative risk of having a preterm birth with a low maternal serum PAPP-A level was 3.44 (95% CI 1.96–6.10) and a low free <it>β</it>-hCG level was 1.31 (95% CI 0.55–6.16).</p> <p>Conclusion</p> <p>This study provides data to support the use of record linkage for outcome ascertainment in studies evaluating predictive tests. Linkage proportions are likely to increase if more personal identifiers are available. This method of follow-up is a cost-efficient technique and can now be applied to a larger cohort of women.</p

The influence of ethnic origin on first trimester biochemical markers of chromosomal abnormalities

In a first trimester study of 5422 Caucasian women, 752 Afro-Caribbean women and 170 Asian women we have shown that the median maternal serum marker MoMs for free β-hCG and PAPP-A were 19% and 48% higher in Afro-Caribbean women and 19% higher and 35% higher in Asian women, compared to Caucasian women. Correcting for maternal weight made very little difference to the effect in Afro-Caribbeans (21% and 57% higher after weight correction) but reduced the effect in Asians (4% and 17% higher after weight correction). It is estimated that correcting for maternal weight and ethnicity overall would increase the detection rate by a modest 1.4%. However, the effect on an individual's risk could result in as much as a two-fold increase in the patient specific risk for trisomy 21. The impact of ethnic origin seems to be greater than that observed with second trimester biochemical markers and larger studies are required in order to develop robust algorithms for correcting for ethnic origin in the first trimester. Copyright (C) 2000 John Wiley and Sons, Ltd.link_to_subscribed_fulltex

Maternal serum level of placental growth factor in diabetic pregnancies

OBJECTIVE: To determine if maternal serum placental growth factor (PlGF) concentration at 11-14 weeks in pregnancies complicated by diabetes, including those with preexisting diabetes and those that developed gestational diabetes subsequently, differed from that in normal, uncomplicated pregnancies. STUDY DESIGN: PlGF concentration was measured in stored maternal serum samples obtained at 11-14 weeks of gestation from 82 women with diabetic pregnancies, including 32 with pre-existing diabetes and 50 with gestational diabetes, and 400 normal controls. Gestational diabetes mellitus was diagnosed with the 75-g oral glucose tolerance test and by applying World Health Organization criteria. RESULTS: When expressed as the multiple of the median and adjusted for gestation, the log transformed values of PlGF were significantly higher (P<.05) in the diabetic group (mean multiple of the median, [MoM] 1.14; SD 0.11) as compared to the controls (mean MoM, 1.00; SD, 0.11). On further comparison between the diabetic groups with the controls, significant differences were found in the groups with gestational diabetes (mean MoM, 1.15; SD, 0.12) and non-insulin dependent diabetes (mean MoM, 1.16; SD, 0.09) but not in those complicated by insulin-dependent diabetes (mean MoM, 1.09; SD, 0.10). CONCLUSION: These findings suggest that in the first trimester of pregnancy the level of maternal PlGF was already significantly increased not only in pregnancies complicated by non-insulin dependent diabetes but also in those with gestational diabetes. The implications of these findings remain to be explored.link_to_subscribed_fulltex

First-trimester maternal serum activin a in pre-eclampsia and fetal growth restriction

Objective: To investigate whether the reported increase in maternal serum activin A concentration in pre-eclampsia is evident from the first trimester. Design: This was a case-control study carried out in antenatal clinics among singleton pregnancies at 10-14 weeks of gestation. Methods: Activin A concentration was measured in stored maternal serum samples obtained at 11-14 weeks of gestation from 131 women who subsequently developed pre-eclampsia, 77 who developed non-proteinuric pregnancy-induced hypertension, 141 with fetal growth restriction in the absence of hypertensive complications and from 494 normotensive controls. Results: Compared to the median activin A level in the control group (1.00 MoM), the median MoM in the patients who subsequently developed pre-eclampsia and pregnancy-induced hypertension (1.49 MoM and 1.32 MoM, respectively) was significantly increased (p < 0.001), and in patients with fetal growth restriction (1.02 MoM) it was not significantly different (p = 0.57). In the pre-eclampsia group (n = 131) the disease was considered to be sufficiently severe to necessitate iatrogenic delivery before 35 weeks in 25 patients, and in this group the median MoM was 1.92. Conclusion: Maternal serum activin A concentration at 12 weeks of gestation in pregnancies which subsequently develop hypertensive disease is increased, whereas in those complicated by fetal growth restriction it is normal.link_to_subscribed_fulltex

First trimester maternal serum free β human chorionic gonadotrophin and pregnancy associated plasma protein a as predictors of pregnancy complications

Objective. To examine the value of first trimester matemal serum flee β human chorionic gonadotrophin (β hCG) and pregnancy associated plasma protein A (PAPP-A) as predictors of pregnancy complications. Design. Screening study. Setting. Antenatal clinics. Population. Singleton pregnancies at 10-14 weeks of gestation. Methods Maternal serum free β hCG and PAPP-A were measured at 10-14 weeks of gestation in 5584 singleton pregnancies. In the 5297 (94.9%) pregnancies with complete follow up free β hCG and PAPP-A were compared between those with normal outcome and those resulting in miscarriage, spontaneous preterm delivery, pregnancy induced hypertension or fetal growth restriction and in those with pre-existing or gestational diabetes. Results. Maternal serum PAPP-A increased and β hCG decreased with gestation. The multiple of median maternal serum PAPP-A was significantly lower in those pregnancies resulting in miscarriage, pregnancy induced hypertension, growth restriction and in those with pre-existing or gestational diabetes mellitus, but not in those complicated by spontaneous preterm delivery. The level was ≤10th centile of the reference range in about 20% of the pregnancies that subsequently resulted in miscarriage or developed pregnancy induced hypertension or growth restriction, and in 27% of those that developed gestational diabetes. Maternal serum free β hCG was ≤10th centile of the reference range in about 15% of the pregnancies that subsequently resulted in miscarriage or developed pregnancy induced hypertension or growth restriction, and in 20% of those that developed gestational diabetes. Conclusion. Low maternal serum PAPP-A or β hCG at 10-14 weeks of gestation are associated with subsequent development of pregnancy complications.link_to_subscribed_fulltex

Maternal serum levels of total activin-A in first-trimester trisomy 21 pregnancies

Maternal serum total activin-A concentration was measured in 45 pregnancies affected by trisomy 21 and 493 control unaffected pregnancies at 10-14 weeks of gestation. In the trisomy 21 pregnancies total activin-A concentration was significantly higher (1.36 MoM of the unaffected pregnancies) and in 16% of cases the level was above the 95th centile of normal. The log10 SD for the control group and the trisomy 21 group were 0.17 and 0.22, respectively. The median pregnancy associated plasma protein-A (PAPP-A) in this trisomy 21 series was 0.49 and for free β-hCG was 2.05. In the trisomy group there were significant positive associations between total activin-A and PAPP-A (0.6071) and free β-hCG (0.4255). The low median difference and the high overlap in values between trisomic and unaffected pregnancies make total activin-A of little practical use in first-trimester screening for trisomy 21. Copyright © 2001 John Wiley & Sons, Ltd.link_to_subscribed_fulltex

First-trimester maternal serum levels of placenta growth factor as predictor of preeclampsia and fetal growth restriction

OBJECTIVE: To determine whether the reported decrease in maternal serum placenta growth factor concentration in preeclampsia is evident from the first trimester and before clinical onset of the disease. We also examined levels in pregnancies that subsequently resulted in fetal growth restriction (FGR). METHODS: Placenta growth factor concentration was measured in stored maternal serum samples obtained at 11-14 weeks of gestation from 131 women who subsequently developed preeclampsia, 137 women who subsequently developed FGR, and 400 randomly selected controls who did not develop preeclampsia or FGR. Preeclampsia was defined as diastolic blood pressure of 90 mmHg or more on two occasions 4 hours apart, accompanied by proteinuria (more than 300 mg of total protein in a 24-hour urine collection or a positive test for albumin on reagent strip) in women with no pre-existing hypertensive or renal disease. Fetal growth restriction was considered present if a woman subsequently delivered a live infant with a birth weight below the fifth centile for gestation. RESULTS: In the control group, maternal serum placenta growth factor concentration increased with gestation. Compared with the controls (median multiple of the median 0.98, standard deviation [SD] 0.51), levels in the preeclampsia group (median multiple of the median 1.09, SD 0.52) were not significantly different (t=1.83, P=.07), but in the FGR group (median multiple of the median 1.57, SD 0.74), levels were significantly increased (t=10.85, P < .001). CONCLUSION: The previously reported decrease in serum placenta growth factor levels in women with preeclampsia might not precede clinical onset of the disease and is not apparent in the first trimester of pregnancy. Levels are significantly increased in pregnancies resulting in FGR. © 2001 by the American College of Obstetricians and Gynecologists.link_to_subscribed_fulltex

Ethnicity and the need for correction of biochemical and ultrasound markers of chromosomal anomalies in the first trimester: A study of Oriental, Asian and Afro-Caribbean populations

Objectives: To assess whether there is a need to correct first-trimester biochemical markers (free β-hCG and pregnancy-associated plasma protein-A (PAPP-A)) or first-trimester fetal nuchal translucency thickness (NT) in different ethnic groups, when screening for Downs syndrome at 11-14 weeks of gestation. Methods: Free β-hCG, PAPP-A and fetal NT were measured at 11-14 weeks of gestation in a group of women presenting for first-trimester screening in two OSCAR centres. The group comprised 61 219 sets of data from Caucasian women (the reference group); 4835 sets of data from South Asian women; 3450 sets of data from Oriental women and 2727 sets of data from Afro-Caribbean women. The Oriental data set was supplemented with a further 480 cases collected in Hong Kong and the Afro-Caribbean data set was supplemented with 216 cases collected from Kings College. The difference in marker values between the reference group and the other ethnic groups was compared before and after weight correction for the biochemical markers using standard statistical techniques. A correction factor for ethnic origin was applied for all three markers and the screen-positive rate before and after correction was assessed for the various groups. Results: After maternal weight correction, in Afro-Caribbean women, the median PAPP-A was increased by 55% and the free β-hCG increased by 11%. In south Asian women, the PAPP-A was increased by 8% and the free β-hCG decreased by 7.5%. In Oriental women, the PAPP-A was increased by 9% and the free β-hCG by 6%. For delta NT in Afro-Caribbean women, the values were 0.064 mm lower on average than in Caucasian women and for south Asian women 0.045 mm lower. The difference of -0.012 for Oriental women was not significant. Before correcting for ethnic origin, these changes resulted in the screen-positive rates being lower in the Afro-Caribbean group (3.7% vs 5.6%), the south Asian group (4.3% vs 5.6%) and Oriental group (4.9% vs 5.6%). After correction, the screen-positive rates were largely similar in the four groups. Conclusion: Differences in median PAPP-A, free β-hCG and, to a lesser extent, in NT exist in Afro-Caribbean, South Asian and Oriental women. In populations where the medians and delta NT reference ranges are established in predominantly Caucasian populations, some correction for ethnicity is appropriate and can redress differences in screen-positive rates between these different groups. Copyright © 2005 John Wiley & Sons, Ltd.link_to_subscribed_fulltex

Maternal serum activin A and inhibin A in trisomy 18 pregnancies at 10-14 weeks

In 45 cases of trisomy 18 and 493 control pregnancies at 10-14 weeks of gestation, maternal serum inhibin A, total activin A, free β-hCG and PAPP-A were measured. In the trisomy 18 pregnancies the median values were 0.74 MoM for inhibin A, 1.23 MoM for activin A, 0.38 MoM for free β-hCG and 0.16 MoM for PAPP-A. The degree of deviation from normal in the levels of inhibin and activin is small in comparison with free β-hCG and PAPP-A and they are therefore unlikely to be of value in improving the sensitivity of 90% for a 1% false-positive rate achieved by screening with fetal nuchal translucency and maternal serum free β-hCG and PAPP-A. Copyright © 2001 John Wiley & Sons, Ltd.link_to_subscribed_fulltex

The influence of fetal sex in screening for trisomy 21 by fetal nuchal translucency, maternal serum free β-hCG and PAPP-A at 10-14 weeks of gestation

In a study of 2923 normal pregnancies and 203 pregnancies affected by trisomy 21 we have shown a significant difference in the median MoM of the markers: fetal nuchal translucency, maternal serum free β-hCG and PAPP-A in the presence of a female fetus compared with a male fetus. For maternal serum free β-hCG levels are higher by 15% if the fetus is chromosomally normal and by 11% if the fetus has trisomy 21. For maternal serum PAPP-A the levels in chromosomally normal fetuses are 10% higher in the presence of a female fetus and 13%, higher if the fetus has trisomy 21. In contrast, fetal nuchal translucency is 3-4% lower in both chromosomally normal and trisomy 21 female fetuses. The consequence of such changes when screening for trisomy 21 will be a reduction in the detection rate in female fetuses by a factor of 1-2%. Correction of risk algorithms for fetal sex, however, is probably not feasible, since ultrasound detection of fetal sex is only 70-90%, accurate in the 10-14 week period. Copyright (C) 2000 John Wiley and Sons, Ltd.link_to_subscribed_fulltex