Infertility, defined as the inability to become pregnant ...



Supplemental Material:

Long Term Cardiovascular Risk in Women Prescribed Fertility Therapy

Appendix Figure 1. Cumulative incidence of the primary outcome per 1000 person-years with or without fertility therapy stratified by age.

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Kaplan-Meier cumulative incidence curves for the primary outcome (composite cardiovascular endpoint of death, non-fatal coronary ischemia, stroke, transient ischemic attack, thromboembolism, and heart failure) among women giving birth according to fertility therapy status and age group; a) age younger than 30 years; b) age 30-35 years; c) age 35-40 years; d) older than 40 years.

Appendix Figure 2. Adjusted hazard ratios for the primary outcome associated with fertility therapy stratified by baseline income category.

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Legend: Adjusted hazard ratio (HR) for the primary outcome (composite cardiovascular endpoint of death, non-fatal coronary ischemia, stroke, transient ischemic attack, thromboembolism, and heart failure) among women giving birth according to fertility therapy status and income group. The area of each square is proportional to the amount of statistical information in that particular category; a larger square reflects more patient years and events of study. Diamonds represent the synthesis of data. Diamonds and squares to the left of the solid line of unity indicate lower risk with fertility therapy. The effect is statistically significant if the diamond or horizontal lines (confidence intervals [CI]) do not cross the solid line. Square horizontal lines and diamond represent a 95% CI. Income groups were stratified by neighborhood quintile. The test for interaction between the effect of fertility therapy associated with the primary outcome by income group was not significant (p-interaction = 0.67). *Risk adjusted for age, calendar year, geographic residence, neighborhood income, prior physician visits, antenatal visits to an obstetrician, prior medical history (including hypertension, hyperlipidemia, diabetes [including gestational diabetes], neoplasm, alcoholism, female infertility, endometriosis, polycystic ovarian syndrome, sexually transmitted infections, pelvic inflammatory disease, other genital tract disorders, prior ovarian hyperstimulation syndrome, prior vaginal delivery, prior Cesarean delivery, prior multiple gestation, and prior abnormal pregnancy), length of stay and obstetrical characteristics for the index delivery (including number of gestations, number of complicated gestations, Cesarean delivery, operative delivery, assisted labor procedures, disproportion, abnormality of pelvic organs, suspected fetal problems, amniotic fluid and uterine cavity abnormalities, and other serious obstetrical complications) and an interaction term for fertility status x income group.

Appendix Table 1. Long-term Cardiovascular Outcomes

|Outcome |Event Rate by Fertility Therapy |Hazard Ratio (95% CI) |

| |(per 100,000 person-years) | |

|Major cardiovascular events |Absent |Present |Unadjusted |Age-adjusted |Fully-adjusted* |

| |(N=1,179,774) |(N=6,979) | | | |

|Death or cardiovascular event |117 |102.6 |0.96 (0.72-1.29) |0.79 (0.59-1.07) |0.55 (0.41-0.74) |

|Death | |53.8 |41.9 |0.94 (0.59-1.50) |0.72 (0.45-1.15) |0.50 (0.31-0.80) |

|Cardiac ischemia |16.7 |14 |1.23 (0.55-2.74) |0.73 (0.33-1.63) |0.56 (0.25-1.25) |

|Heart failure | |14.6 |18.6 |1.13 (0.56-2.26) |1.12 (0.56-2.26) |0.60 (0.30-1.22) |

|Venothromboembolic events |28 |16.3 |0.54 (0.26-1.13) |0.59 (0.28-1.24) |0.45 (0.21-0.94) |

|Cerebrovascular events |8.5 |16.3 |2.14 (1.02-4.50) |1.63 (0.77-3.43) |1.14 (0.54-2.44) |

|Emergent cardiovascular risk factors† |Absent |Present |Unadjusted |Age-adjusted |Fully-adjusted‡ |

| |(N=1,108,322) |(N=6,394) | | | |

|Any of hypertension, diabetes mellitus, or |3,831 |5,907 |1.53 (1.46-1.60) |1.20 (1.15-1.26) |0.86 (0.82-0.90) |

|hyperlipidemia | | | | | |

|Hypertension | |1,985 |2,945 |1.52 (1.43-1.61) |1.17 (1.10-1.24) |0.88 (0.83-0.94) |

|Diabetes mellitus |1,046 |1,816 |1.68 (1.56-1.81) |1.41 (1.31-1.52) |0.93 (0.86-1.00) |

|Hyperlipidaemia |1,393 |2,094 |1.63 (1.52-1.75) |1.16 (1.09-1.25) |0.85 (0.79-0.91) |

Hazard ratios represent the risk among women with fertility compared with women without fertility therapy (reference). *Risk adjusted for age, calendar year, geographic residence, neighborhood income, prior physician visits, antenatal visits to an obstetrician, prior medical history (including hypertension, hyperlipidemia, diabetes [including gestational diabetes], neoplasm, alcoholism, female infertility, endometriosis, polycystic ovarian syndrome, sexually transmitted infections, pelvic inflammatory disease, other genital tract disorders, prior ovarian hyperstimulation syndrome, prior vaginal delivery, prior Cesarean delivery, prior multiple gestation, and prior abnormal pregnancy), length of stay and obstetrical characteristics for the index delivery (including number of gestations, number of complicated gestations, Cesarean delivery, operative delivery, assisted labor procedures, disproportion, abnormality of pelvic organs, suspected fetal problems, amniotic fluid and uterine cavity abnormalities, and other serious obstetrical complications). †Analyses restricted to patients without history of prior cardiovascular disease, hypertension, diabetes (including gestational diabetes), or hyperlipidemia at baseline. ‡Risk adjusted for all variables listed above except hypertension, diabetes (including gestational diabetes), and hyperlipidemia.

Appendix Table 2. Long-term Risk of Other Serious Events

|Outcome |Events Rate by Fertility Therapy (per 100,000 |Hazard Ratios (95% CI) |

| |person-years) | |

| |Absent |Present |Unadjusted |Age-adjusted |Fully-adjusted* |

| |(N=1,179,774) |(N=6,979) | | | |

|Malignancies | | | | | |

| Breast |33.1 |39.6 |1.42 (0.88-2.28) |0.78 (0.48-1.25) |0.74 (0.45-1.19) |

| Ovarian |5.6 |9.3 |2.04 (0.76-5.46) |1.27 (0.47-3.39) |1.12 (0.41-3.05) |

| Melanoma |0.9 |2.3 |2.85 (0.40-20.5) |2.10 (0.29-15.1) |1.80 (0.24-13.7) |

|Pneumonia |49.5 |49.0 |1.00 (0.65-1.54) |1.03 (0.67-1.59) |0.73 (0.47-1.13) |

|Nephrolithiasis |40.7 |32.6 |0.75 (0.45-1.27) |0.84 (0.50-1.42) |0.71 (0.42-1.21) |

|Alcoholism |164.7 |84.2 |0.53 (0.38-0.73) |0.65 (0.48-0.89) |0.48 (0.35-0.67) |

|Sexually transmitted infections |538.2 |351.0 |0.63 (0.54-0.74) |1.06 (0.91-1.24) |0.64 (0.55-0.76) |

|Motor vehicle collisions |37.1 |16.3 |0.44 (0.21-0.92) |0.57 (0.27-1.19) |0.51 (0.24-1.07) |

|Depression |76 |26 |0.32 (0.18-0.58) |0.41 (0.23-0.74) |0.33 (0.18-0.59) |

|Self-Harm |48.1 |4.7 |0.09 (0.02-0.35) |0.16 (0.04-0.65) |0.15 (0.04-0.62) |

Hazard ratios represent the risk among women with fertility compared with women without fertility therapy (reference). *Risk adjusted for age, calendar year, geographic residence, neighborhood income, prior physician visits, antenatal visits to an obstetrician, prior medical history (including hypertension, hyperlipidemia, diabetes [including gestational diabetes], neoplasm, alcoholism, female infertility, endometriosis, polycystic ovarian syndrome, sexually transmitted infections, pelvic inflammatory disease, other genital tract disorders, prior ovarian hyperstimulation syndrome, prior vaginal delivery, prior Cesarean delivery, prior multiple gestation, and prior abnormal pregnancy), length of stay and obstetrical characteristics for the index delivery (including number of gestations, number of complicated gestations, Cesarean delivery, operative delivery, assisted labor procedures, disproportion, abnormality of pelvic organs, suspected fetal problems, amniotic fluid and uterine cavity abnormalities, and other serious obstetrical complications).

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