Document Type

Dissertation

Date of Degree

Summer 2014

Degree Name

PhD (Doctor of Philosophy)

Degree In

Epidemiology

First Advisor

Elaine M. Smith

Abstract

When the delicate hormonal balance in early pregnancy is disrupted, the consequences can be significant. We have a poor understanding of the "cross-talk" in the fetal/placental/ovarian axis that occurs throughout pregnancy and is essential for normal fetal development. This lack of knowledge challenges our ability to recognize disruptions in this axis that may be a signal for future disease. As a result, our ability to apply preventive measures against adverse obstetric outcomes, such as preterm birth (PTB), are quite limited.

Attempts to predict PTB using biomarkers of feto-placental health have been largely unsuccessful, but no one has considered the inclusion of ovarian biomarkers in these models. Anti-Mullerian hormone (AMH) is a biomarker of ovarian activity that has recently been found to decline in early pregnancy at a time that corresponds to the involution of the corpus luteum (CL). The signal for CL involution is believed to originate from the placenta; therefore, the AMH levels in pregnancy may reflect the degree of ovarian up or down-regulation based on feto-placental needs. As the major function of the CL in pregnancy is the production of progesterone, which acts as an anti-inflammatory agent in the placental bed, changes in CL-derived progesterone could result in higher or lower degrees of placental inflammation. Therefore, monitoring the changes in AMH levels may provide insight into the inflammatory state of the placenta which could then be used as a signal for possible adverse obstetric outcomes resulting from a pro-inflammatory state, such as PTB.

The first aim of this project was to test the hypothesis of an association between AMH levels in early pregnancy and PTB risk. When the differences in AMH levels between the 1st and 2nd trimesters of pregnancy were stratified by the level of maternal serum alpha-fetoprotein (MSAFP) and controlled for maternal weight gain between trimesters, small or absent decreases in AMH levels were associated with a higher probability of preterm birth. However, when AMH was modeled alone, no significant associations were found. The need for changes in multiple biomarkers in the fetal/placental/ovarian axis suggests that a change is only significant if it can impact multiple axis points. Therefore, models that included two biomarkers from different part of the axis would find stronger associations than two biomarkers from a single point (e.g. two feto-placental biomarkers), and monitoring these changes may help identify women at risk for PTB.

The strategy of the second aim was to determine if the changes in AMH levels in early pregnancy could be used to predict time to delivery. Again, only when the risks of AMH and MSAFP were combined was a significant, dose-dependent relationship found with time to delivery. In women with an MSAFP of >1 multiple of the median (MoM), smaller declines and/or elevations in AMH levels were significantly associated with shorter times to delivery. In fact, 19% of women in the highest risk group delivered prior to 32 weeks gestation compared to 7% in the lowest risk group, and all infants who delivered prior to 24 weeks gestation were in the highest risk category. Thus, the amount of change in the AMH level when MSAFP is elevated may reflect the level of disruption in the fetal/placental/ovarian axis, which can then be used to predict time to delivery.

Finally, the third aim of this study was to determine if AMH levels were associated with a pro-inflammatory placental state other than PTB. The degree of placental inflammation is known to vary by fetal gender, with male placentas having higher levels of inflammation compared to female placentas. When AMH levels were compared between women with male vs. female fetuses in early pregnancy, 1st trimester AMH levels were found to be lower when carrying a male fetus. Further, sexually-dimorphic patterns in AMH levels were seen between genders when stratified by birth outcome (term vs. preterm delivery). The stronger ovarian response seen in women with female fetuses suggests a better survival function and may account for the discrepancies between PTB rates in males and females. This also strengthens our hypothesis that the dynamic changes in AMH levels reflect the degree of placental inflammation and the need for CL-derived progesterone.

This project demonstrates that the changes in AMH levels may be representative of the cross-talk occurring in the fetal/placental/ovarian axis in early pregnancy. Further, changes in AMH levels may be an indication of the amount of inflammation in the placenta and the physiologic need for higher levels of progesterone to control this inflammatory state when considered along with MSAFP. Therefore, the consideration of AMH levels as a biomarker of ovarian activity along with biomarkers of feto-placental health may provide clinically useful information about the development of future diseases such as preterm birth.

Keywords

Anti-Mullerian Hormone, Cox regression, Logistic regression, Pregnancy, Preterm birth, time to delivery

Pages

xii, 86 pages

Bibliography

Includes bibliographical references (pages 79-86).

Copyright

Copyright 2014 Barbara J. Stegmann

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