Maternal body weight and first trimester screening for chromosomal anomalies

Prenatal risk ratios for Down syndrome adjust for maternal weight because maternal serum 2 biomarker levels decrease with increasing maternal weight. This is accomplished by converting 3 serum biomarker values into a multiple of the expected median (MOM) for women of the same 4 gestational age. Weight is frequently not recorded and the impact of using MOMs not adjusted for 5 weight for calculating risk ratios is unknown. The aim of this study is to examine the effect of 6 missing weight on first trimester Down syndrome risk ratios by comparing risk ratios calculated 7 using weight-unadjusted-and –adjusted MOMs. Findings at the population level indicate that the 8 impact of not adjusting for maternal weight on first trimester screening results for chromosomal 9 anomalies would lead to under-identification of 84 per 10,000 pregnancies.NHMR

Iron deficiency in early pregnancy using serum ferritin and soluble transferrin receptor concentrations are associated with pregnancy and birth outcomes.

Background: There are several biomarkers for measuring iron deficiency (ID) in pregnancy, but evidence of their prevalence in association with inflammation and adverse pregnancy outcomes is inconclusive. Objectives: To describe the prevalence and determinants of ID in women in the first trimester of pregnancy and associations with pregnancy and birth outcomes. Design: A record-linkage cohort study of archived serum samples of women attending first trimester screening and birth and hospital data to ascertain maternal characteristics and pregnancy outcomes. Sera were analysed for iron stores (ferritin; μg/L), tissue iron (soluble transferrin receptor, sTfR; nmol/L) and inflammatory (C-reactive protein, CRP; mg/L) biomarkers. Total body iron (TBI) was calculated from serum ferritin and sTfR concentrations. Multivariate logistic regression analyzed risk factors and pregnancy outcomes associated with ID using the definitions: serum ferritin <12 μg/L, TfR ≥21.0 nmol/L and TBI<0 mg/kg. Results: Of 4,420 women, the prevalence of ID based on ferritin, sTfR and TBI was 19.6%, 15.3% and 15.7%, respectively. Risk factors of ID varied depending on which iron parameter was used and included maternal age <25 years, multiparity, socioeconomic disadvantage, high maternal body weight and inflammation. ID was associated with reduced risk of gestational diabetes (GDM) defined using serum ferritin and TBI, but not sTfR and increased risk of large for gestation age (LGA) infants defined using TBI only. Conclusions: Nearly 1 in 5 Australian women begin pregnancy with ID. Evidence suggests excess maternal weight and inflammation play a role in the relationships between ID and GDM and LGA infants.NHMR

High maternal serum ferritin in early pregnancy and risk of spontaneous preterm birth

Previous studies have reported inconsistent associations between maternal serum ferritin concentrations and risk of preterm birth. The aim of this study was to examine the association between iron biomarkers, including serum ferritin and risk of total, early and moderate-to-late spontaneous preterm birth (sPTB). This cohort study included women with singleton pregnancies who were attending first-trimester screening in New South Wales, Australia. sPTB births included births 75th percentile (≥43 μg/L) (OR: 1.49, 95% CI: 1.06, 2.10) and >90th percentile (≥68 μg/L) (OR: 1.92, 95% CI: 1.25, 2.96). Increased odds of early and moderate-to late sPTB were associated with ferritin levels >90th (OR: 2.50, 95% CI: 1.32, 4.73) and >75th (OR: 1.56, 95% CI: 1.03, 2.37) percentiles, respectively. No association was found between sPTB, and elevated sTfR levels or iron deficiency. In conclusion, elevated early pregnancy maternal serum ferritin levels are associated with increased risk of sPTB from 34 weeks gestation. The usefulness of early pregnancy ferritin levels in identifying women at risk of sPTB warrants further investigation.NHMR

Angiopoietin 1 and 2 serum concentrations in first trimester of pregnancy as biomarkers of adverse pregnancy outcomes

Objective: To assess Ang-1, Ang-2 and the Ang-1/Ang-2 ratio levels in the first trimester of pregnancy, their association with adverse pregnancy outcomes; and their predictive accuracy. Study Design: This cohort study measured serum Ang-1 and Ang-2 levels in 4,785 women with singleton pregnancies attending first trimester screening in New South Wales, Australia. Multivariate logistic regression models were used to assess the association and predictive accuracy of serum biomarkers with subsequent adverse pregnancy outcomes (small for gestational age, preterm birth, preeclampsia, miscarriage >10 weeks and stillbirth). Results: Median (interquartile range) levels for Ang-1, Ang-2 and the Ang-1/Ang-2 ratio for the total population were 19.6 ng/ml (13.6-26.4), 15.5 ng/ml (10.3-22.7) and 1.21 (0.83-1.73), respectively. Maternal age, weight, country of birth and socio-economic status significantly affected Ang-1, Ang-2 and the Ang-1/Ang-2 ratio levels. After adjusting for maternal and clinical risk factors, women with low Ang-2 levels (90th centile) had increased risk of developing most adverse pregnancy outcomes. Compared to the Ang-1/Ang-2 ratio alone, maternal and clinical risk factors had better predictive accuracy for most adverse pregnancy outcomes. The exception was miscarriage [Ang-1/Ang-2 ratio area under ROC curve (AUC) =0.70; maternal risk factors AUC =0.58]. Overall, adding the Ang-1/Ang-2 ratio to maternal risk factors did not improve the ability of the models to predict adverse pregnancy outcomes. Conclusions: Our findings suggest that the Ang-1/Ang-2 ratio in first trimester is associated with most adverse pregnancy outcomes, but do not predict outcomes any better than clinical and maternal risk factor information.Australian National Health and Medical Research Council (NHMRC) Project Grant (#632653)

Evaluation of first trimester serum soluble endothelial cell-specific tyrosine kinase receptor in normal and affected pregnancies

Aims: To assess soluble endothelial cell-specific tyrosine kinase receptor (sTie-2) levels in the first trimester of pregnancy and its association with adverse pregnancy outcomes; and examine the predictive accuracy. Study Design: In this nested case-control study, serum sTie-2 levels were measured in 2,616 women with singleton pregnancies attending first trimester screening in New South Wales, Australia. Multivariate logistic regression models were used to assess the association and predictive accuracy of serum sTie-2 with subsequent adverse pregnancy outcomes. Results: Median (interquartile range) sTie-2 for the total population was 19.6 ng/ml (13.6-26.4). Maternal age, weight, and smoking status significantly affected sTie-2 levels. There was no difference in serum sTie-2 between unaffected and women with adverse pregnancy outcomes. After adjusting maternal and clinical risk factors, low sTie-2 (<25th centile) was associated with preeclampsia (Adjusted odds ratio: 1.61; 95%CI: 1.01-2.57), however, the accuracy of sTie-2 in predicting preeclampsia was not different from chance (AUC=0.54; P=0.08) and does not add valuable predictive information to maternal and clinical risk factors. Conclusions: Our findings suggest that low sTie-2 levels are associated with preeclampsia, however, it does not add valuable information to clinical and maternal risk factor information in predicting preeclampsia or any other adverse pregnancy outcomes.NHMR

High maternal iron status, dietary iron intake and iron supplement use in pregnancy and risk of gestational diabetes mellitus: In-house study and systematic review

Background: High iron measured using dietary and serum biomarkers have been associated with type 2 diabetes; however it is uncertain whether a similar association exists for gestational diabetes mellitus (GDM). Objectives: To conduct a cohort study examining first trimester body iron stores and subsequent risk of GDM and to include these findings in a systematic review of all studies examining the association between maternal iron status, iron intake (dietary and supplemental) and the risk of GDM. Methods: Serum samples for women with first trimester screening were linked to birth and hospital records for data on maternal characteristics and GDM diagnosis. Blood was analysed for ferritin, soluble transferrin receptor (sTfR) and C-reactive protein (CRP). Associations between iron biomarkers and GDM were assessed using multivariate logistic regression. A systematic review and meta-analysis, registered with PROSPERO (CRD42014013663) included all studies published in English from Jan 1995 to March 2014 that examined the association between iron and GDM and included an appropriate comparison group. Results: Of 3, 776 women, 3.4% subsequently developed GDM. Adjusted analyses found increased odds of GDM for ferritin (OR 1.41; 95% CI: 1.11, 1.78) but not for sTfR (OR 1.00, 95% CI: 0.97, 1.03) levels. Two trials of iron supplementation in early pregnancy found no association with GDM. Increased risk of GDM was associated with higher levels of maternal ferritin and serum iron and dietary heme iron intakes. Conclusions: Increased risk of GDM among women with high serum ferritin and iron levels and dietary heme iron intakes warrants further investigation.NHMR

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