Subfertility/infertility and assisted reproductive conception are independent risk factors for pre‐eclampsia

Pregnancies achieved by assisted reproductive technology (ART) are at increased risk for pre-eclampsia, compared with those with spontaneous conception. This increased risk could be related to certain maternal risk factors that are associated with ART, such as advanced maternal age, obesity, change of partner, longer interval between births, reduced smoking, pre-existing infertility and etiology of infertility, to male factors such as azospermia, to female factors such as polycystic ovary syndrome (PCOS), or to factors related to the ART technique itself [in vitro fertilisation (IVF), intracytoplasmic sperm injection (ICSI), or frozen embryo]. Previous pregnancy loss (spontaneous or induced) or a healthy pregnancy with the same partner is associated with a reduced risk of pre-eclampsia (protective effect with previous exposure to fetal antigens). Tandberg et al. conducted a population-based cohort study from the Medical Registry of Norway to compare risk of pre-eclampsia in ART singleton pregnancies, compared with spontaneously conceived singleton pregnancies, and to evaluate whether the observed risk could be explained by differences in maternal age, inter-birth intervals, partner change, or smoking. The study included 501 766 women with first singleton pregnancies (8549 ART), 418 782 with second singleton Mini Commentarypregnancies (3466 ART), and 188 976 with third singleton pregnancies (425 ART). They found that ART was associated with an increased risk of pre-eclampsia, and that risk increased by parity, particularly in those with previous normotensive pregnancy, suggesting that previous exposure to fetal antigens is not protective against pre-eclampsia in women conceiving by ART. In addition, they found that the association between ART pregnancies and pre-eclampsia is partially explained by advanced maternal age and by a long inter-birth interval, but not by change in partner or smoking. The association between ART and pre-eclampsia in second and third pregnancies was largely explained by inter-birth interval. Finally, they found that the associations remained present after all adjustments and exclusions of confounding risk factors in a third pregnancy, where the rate of pre-eclampsia was similar to that in a first pregnancy, suggesting that the risk may be related to the ART procedure itself. The study by Tandberg et al. provides insight regarding the importance of inter-birth duration and advanced maternal age as risk factors for pre-eclampsia in ART pregnancies. A major weakness of the study relates to the diagnosis of pre-eclampsia using the criteria of threshold increases in systolic or diastolic blood pressure for the diagnosis of hypertension. These criteria are no longer used because more than 50% of women who met the criteria never developed pre-eclampsia. In addition, there was lack of data on recurrent miscarriages, as only pregnancies beyond 16 weeks of gestation were included in the registry. This is important as recurrent miscarriage, obesity, and PCOS are known risk factors for pre-eclampsia. Failure to adjust for the above factors could have overestimated the associations between inter-birth interval and pre-eclampsia. What is the plausible biological explanation for the association between prolonged birth interval and pre-eclampsia in ART pregnancies? One explanation could be that prolonged inter-pregnancy interval indicates a female infertility problem. The authors report that the percentage of women requiring ART to conceive in second and third pregnancies increased steeply with increased inter-birth interval. Another explanation could be that the ART procedure itself may have adverse effects on placentation in inadequate trophoblast invasion/migration. This adverse effect may be related to the use of various medications that affect the uterine milieu, or may be related to the laboratory methods used to achieve conception with ART. Based on the results of the current study and other reports, it is now clear that both subfertility/infertility and the need for ART should be considered as independent risk factors for pre-eclampsia. This information should be used in counselling women receiving ART. The author reports no conflicts of interest.