Prenatal biochemical screening and long term risk of maternal cardiovascular disease: population based cohort study

Abstract Objective To examine whether abnormal prenatal biochemical screening results are associated with an increased risk of premature cardiovascular disease after pregnancy. Design Population based cohort study. Setting The entire province of Ontario, Canada, where healthcare is universally available. Participants Women aged 12-55 years, without pre-existing cardiovascular disease, who underwent prenatal screening between 1993 and 2011. One pregnancy per woman was randomly selected. Exposures Low (≤5th centile multiple of the median) serum total chorionic gonadotropin, unconjugated estriol, and pregnancy associated plasma protein A and high (≥95th centile multiple of the median) alphafetoprotein and dimeric inhibin-A. Main outcome measures Composite of hospital admission or revascularisation for coronary artery, cerebrovascular, or peripheral arterial disease or hospital admission for heart failure or dysrhythmia at least 365 days after pregnancy. Results Among 855 536 pregnancies, and after a median of 11.4 (interquartile range 6.8-17.5) years of follow-up, 6209 women developed the main cardiovascular disease outcome. Abnormal results for each of the five prenatal biochemical screening analytes, especially dimeric inhibin-A, were associated with a higher risk of cardiovascular disease. Women with an abnormally high dimeric inhibin-A (≥95th centile) had the highest rate of cardiovascular disease (30 events or 8.3 per 10 000 person years versus 251 events or 3.8 per 10 000 person years for those <95th centile; multivariable adjusted hazard ratio 2.0, 95% confidence interval 1.4 to 3.0). Compared with women without any abnormal biochemical measure, the hazard ratio for the cardiovascular disease composite outcome was 1.2-1.3 times higher with one abnormal analyte and 1.5-2.0 times higher with two or more abnormal analytes. Conclusions Women with abnormal prenatal biochemical screening results, especially for dimeric inhibin-A, may be at higher risk of cardiovascular disease. If these findings are replicated elsewhere, a massive amount of data exists that could aid in identifying women at higher risk of premature cardiovascular disease and that could be conveyed to them or their healthcare providers.

Supplementary file 2. Variables used to define cohort entry and exclusion criteria, study exposures, outcomes and adjustment variables.  Supplementary file 3. Fractional polynomial derived best fitting plots of the continuous relation between the multiple of the median (MoM) for serum alphafetoprotein (AFP) (a), unconjugated estriol (uE3) (b), total human chorionic gonadotropin (hCG) (c), pregnancy-associated plasma protein A (PAPP-A) (d) and dimeric inhibin-A (DIA) (e), and the respective hazard for the cardiovascular disease (CVD) composite outcome of any hospitalization or revascularization for coronary artery, cerebrovascular or peripheral arterial disease, heart failure or dysrhythmia. The 1 st , 5 th , 95 th and 99 th percentile cut-points for each analyte are shown by vertical dashed lines.

. Flow chart of inclusion and exclusions
Supplementary file 5 (Additional analysis 1). Risk of the primary cardiovascular disease composite outcome of any hospitalization or revascularization for coronary artery, cerebrovascular or peripheral arterial disease, heart failure or dysrhythmia, arising ≥ 365 days after the start of the index pregnancy, in association with an abnormal cut-point of the 5 th or 95 th percentile of the multiple of the median (MoM) for a given serum analyte. This analysis further adjusts for maternal weight at the time of prenatal biochemical screening, in a sub-set of all pregnancies.

Cardiovascular disease composite outcome
Abnormal serum analyte Cut-points used to define normal and abnormal Supplementary file 6. Risk of the primary cardiovascular disease composite outcome of any hospitalization or revascularization for coronary artery, cerebrovascular or peripheral arterial disease, heart failure or dysrhythmia, arising ≥ 365 days after the start of the index pregnancy, in association with an abnormal cut-point of the 5 th or 95 th percentile of the multiple of the median (MoM) for a given serum analyte. This analysis further excludes women with pre-existing renal disease, chronic hypertension or dyslipidemia within 365 days preceding the start of the index pregnancy, and up to and including 365 days after the start of the index pregnancy (i.e., time zero).

Cardiovascular disease composite outcome
Abnormal serum analyte Cut-points used to define normal and abnormal a Adjusted for maternal age (continuous), gravidity (1, 2+, missing), neighborhood income quintile (1, 2, 3, 4, 5, missing), rural residence (rural, urban, missing), ethnicity (Asian, Black Caucasian, Hispanic, Oriental, other, missing) and gestational age (continuous) -each at the time of prenatal biochemical screening -as well as maternal diabetes mellitus and tobacco/drug use within 365 days preceding the start of the index pregnancy, up to and including 365 days after the start of the index pregnancy (i.e., time zero Supplementary file 10 (Additional analysis 5). Risk of the primary cardiovascular disease composite outcome of any hospitalization or revascularization for coronary artery, cerebrovascular or peripheral arterial disease, heart failure or dysrhythmia, arising ≥ 365 days after the start of the index pregnancy, in association with an abnormal cut-point of the 5 th or 95 th percentile of the multiple of the median (MoM) for a given serum analyte. This analysis also adjusts for the number of prior pregnancies with a given abnormal serum analyte, as described in column c of Supplementary file 9.

Cardiovascular disease composite outcome
Abnormal serum analyte Cut-points used to define normal and abnormal Adjusted for maternal age (continuous), gravidity (1, 2+, missing), neighbourhood income quintile (1, 2, 3, 4, 5, missing), rural residence (rural, urban, missing), ethnicity (Asian, Black Caucasian, Hispanic, Oriental, other, missing) and gestational age (continuous) -each at the time of the woman's last prenatal biochemical screening -as well as maternal diabetes mellitus, chronic hypertension, renal disease, tobacco/drug use and dyslipidemia within 365 days preceding the start of the woman's last pregnancy, up to and including 365 days after the start of the woman's last pregnancy. Also adjusted for the number of prior pregnancies with a given abnormal serum analyte.