IVF Linked to Increased Risk for Pulmonary Embolism

Yael Waknine

January 18, 2013

In vitro fertilization (IVF) pregnancies are linked to an increased risk for first-trimester blood clots and pulmonary embolism (PE) compared with natural pregnancies, according to a Swedish registry study published online January 15 in the British Medical Journal.

Researchers led by Peter Henriksson, MD, professor of internal medicine at the Karolinska Institutet in Stockholm, Sweden, found that the odds of venous thromboembolism (VTE), although still low, were quadrupled in the first trimester in IVF pregnancies compared with natural pregnancies. The risk for PE increased 7-fold.

Although the increased risk for embolism translates to only 2 or 3 additional cases per 10,000 IVF pregnancies, the authors caution that PE is an "elusive" condition that is difficult to diagnose and a leading cause of maternal death.

"Doctors should be aware of these increased risks because the symptoms of [PE] can be insidious and the condition is potentially fatal," the authors write. They suggest further efforts should be made to identify women at risk for VTE, including consideration of prophylactic anticoagulation in women planning to undergo IVF.

Well-Established Risk

According to the authors, VTE is already a well-established risk of normal pregnancies, with an incidence rate slightly higher than 0.1%. Some case reports have suggested a heightened risk in IVF pregnancies, but no studies have been performed to determine its magnitude or the incidence of PE.

In the current study, Dr. Henriksson's team analyzed Swedish registry data for 23,498 women who had undergone IVF between 1990 and 2008, comparing them with 116,960 age-matched and delivery year–matched women with normal pregnancies; they took into account the increased risk for VTE observed in Sweden during the last decade.

Median age in both groups was 33 years (range, 31 - 36 years), and VTE risk did not differ between groups before pregnancy (HR, 0.85; 95% CI, 0.66 - 1.10) and during the year after delivery (HR, 1.29; 95% CI, 0.82 - 2.02).

However, IVF pregnancies were associated with a significantly increased risk for VTE relative to natural pregnancies (HR, 1.77; 95% CI, 1.41 - 2.23, P < .001). The association remained unchanged after adjusting for calendar period, parity, single or multiple births, smoking, education, maternal age, country of birth, and marital status in multivariate analysis (adjusted HR, 4.22; 95% CI, 2.46 - 7.26).

Further analysis revealed that the relative risk for VTE in IVF pregnancies was particularly high during the first trimester compared with that of natural pregnancies (HR, 4.05; 95% CI, 2.54 - 6.46). A similar pattern was observed for the relative risk for PE, which was heightened overall (HR, 1.42; 95% CI, 0.86 - 2.36) but dramatically increased in the first trimester, relative to natural pregnancies (HR, 6.97; 95% CI, 2.21 - 21.96).

The authors emphasize, however, that the absolute risk for clotting complications in IVF pregnancies remains low, with 0.42% (4.2/1000; n = 99) of women diagnosed with VTE and 0.08% diagnosed with PE (8.1/10,000; n = 19) compared with 0.25% (2.5/1000; n = 291) and 0.06% (6.0/10,000; n = 70) of women with natural pregnancies.

According to the authors, the increased first-trimester PE risk in IVF pregnancies points to changes induced by the procedure itself, as natural pregnancies carry the highest risk for PE in the postpartum period.

"A plausible initiator of adverse mechanisms could be the noticeable [10- to 100-fold] increase in endogenous estrogen levels during the stimulation phase of treatment before the actual procedure," they write. They note that exogenous estrogens have long been linked to an increased risk for VTE regardless of their reason for use.

The study was supported by a regional agreement on medical training and clinical research between Stockholm County Council and the Karolinska Institutet, by the Swedish Research Council, and by the Karolinska Institutet. The authors have disclosed no relevant financial relationships.

BMJ. Published online January 15, 2013. Full text