A Re-assessment of the Risk:Benefit Analysis of Statin Therapy during Pregnancy: Do Benefits of Treatment Outweigh Putative Reproductive Risks.

An animal model has implicated elevated levels of tissue factor (TF), and resultant hypercoagulability and inflammation, as key factors in recurrent pregnancy loss (RPL) and has demonstrated that pravastatin is effective in treating this condition. In this study, we have re-evaluated the contraindication of statins during pregnancy. Evaluation has shown that while animal testing (at maternally toxic doses) and case reports of birth defects have led to the contraindication of statins during pregnancy, our controlled study, similar to previously published controlled studies, has failed to demonstrate increased fetal risks. As well, we demonstrated that transfer of pravastatin across the placenta is likely limited. While short term suspension of therapy during gestation is considered safe, extended time without therapy is detrimental to cardiovascular health. Coupled with a trend of elevated TF levels in women with RPL, reconsideration of the contraindication of statins is warranted based on appropriate risk: benefit assessment.MAS

Changes in Circulating ProAMH and Total AMH during Healthy Pregnancy and Post-Partum: A Longitudinal Study.

Circulating Anti-Müllerian hormone (AMH) is derived from the gonads, and is a mixture of the prohormone (proAMH), which does not bind to AMH receptors, and receptor-competent AMH. The functions of a hormone are partially defined by the factors that control its levels. Ovarian reserve accounts for 55~75% of the woman-to-woman variation in AMH level, leaving over 25% of the biological variation to be explained. Pregnancy has been reported to decrease circulating AMH levels, but the observations are inconsistent, with the effect of pregnancy on the bioactivity of AMH being unknown. We have therefore undertaken a longitudinal study of circulating proAMH and total AMH during pregnancy. Serum samples were drawn at 6-8 gestational time-points (first trimester to post-partum) from 25 healthy women with prior uneventful pregnancies. The total AMH and proAMH levels were measured at each time-point using ELISA. The level of circulating total AMH progressively decreased during pregnancy, in all women (p<0.001). On average, the percentage decline between the first trimester and 36-39 weeks' gestation was 61.5%, with a standard deviation of 13.0% (range 30.4-81.2%). The percentage decline in total AMH levels associated with maternal age (R = -0.53, p = 0.024), but not with the women's first trimester AMH level. The postpartum total AMH levels showed no consistent relationship to the woman's first trimester values (range 31-273%). This raises the possibility that a fundamental determinant of circulating AMH levels is reset during pregnancy. The ratio of proAMH to total AMH levels exhibited little or no variation during pregnancy, indicating that the control of the cleavage/activation of AMH is distinct from the mechanisms that control the total level of AMH

The influence of maternal age on the pregnancy-associated decline in total AMH level.

<p>The percentage decrease in total AMH levels between the first trimester and the 36–39 week samples is plotted against the women’s ages. The two parameters were significantly correlated, R = -0.53, p = 0.024.</p

The magnitude of pregnancy-related decline was dissociated from a woman’s level of AMH.

<p>Each woman’s level of total AMH during the first trimester is plotted against the extent to which her total AMH levels declined by 36–39 weeks gestation. The two measures showed no significant correlation (R = - 0.04). 1 ng/ml of AMH = 7.14 pmol/L (pM).</p

Change in total AMH levels during gestation.

<p>(A) Each woman’s individual levels are shown. (B) Box and whisker plots (medians, interquartile intervals, range) of AMH levels. (C) Percentage decline. Each woman’s values were normalized to her first trimester (6–11 weeks) sample, using log transformation. The data is the mean ± standard of error of the mean. There is a significant decline with gestational age, p<0.001 (repeated measures, mixed model). LSD post-hoc analysis indicated that all time points were significantly different compared to the 6–11 week samples (p = 0.026 for the 16–19 week time-point and p < 0.001 for the other gestational ages). 1 ng/ml of AMH = 7.14 pmol/L (pM).</p

Change in the proportion of the AMH forms during gestation.

<p>(A) ProAMH levels during pregnancy. Each woman’s values were normalized to her first trimester (6–11 weeks) sample, using log transformation. The data is the mean ± standard of error of the mean. There is a significant decline with gestational age, p<0.001 (repeated measures, mixed model). LSD post-hoc analysis indicated that all gestational time points were significantly different compared to the 6–11 week samples (p < 0.001). (B) API. The ratio of proAMH to total AMH was calculated for each woman at each stage of pregnancy, and normalised to her first trimester (6–11 weeks) sample. The data is the mean ± standard of error of the mean. There was no significant effect of gestational age (repeated measures, mixed model).</p