Effect of in vitro fertilization treatment and subsequent pregnancy on the protein C pathway

Thirty-three women who were planned for an in vitro fertilization (IVF) cycle donated blood at four time points during treatment: at baseline, after downregulation, hyperstimulation and luteal support. Levels of progesterone, 17beta-oestradiol and indicators of the protein C pathway, i.e. activated protein C sensitivity ratios (APCsr), protein C, protein C inhibitor and protein S were measured. Compared with baseline, oestradiol decreased twofold at downregulation and increased 40-fold at hyperstimulation. Progesterone was elevated 2.5-fold at hyperstimulation and 40-fold at luteal support. The APCsr increased slightly at downregulation, significantly increased during hyperstimulation and remained high during luteal support. The plasma levels of the anticoagulant proteins did not change or changed moderately during treatment. During downregulation, progesterone correlated negatively with APCsr (r = -0.398, P = 0.024). At hyperstimulation oestradiol correlated with the APCsr (r =0.615, P < 0.0005). Moreover, there was a significant correlation (r = 0.599, P < 0.0005) between the difference in baseline and hyperstimulation values of oestradiol (Delta E2 = 6.6 nmol/l) and the APCsr (Delta APCsr = 0.30). Six women who participated in this study became pregnant. Compared with baseline, the APCsr was increased 1.9-fold (Delta APCsr = 1.48) and free protein S free level decreased 30% at 7 weeks of pregnancy. This study demonstrates that despite the considerable changes in endogenous oestradiol and progesterone during an IVF cycle, changes in plasma levels of anticoagulant proteins are moderate. The significant increase in the APCsr during hyperstimulation indicates that acquired APC resistance observed during sex steroid hormone changes in women is at least partially caused by high oestrogen levels. Our findings demonstrate that IVF treatment is accompanied by the development of a mild prothrombotic condition.