First Trimester Miscarriage

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Alix Boyle: Hi, this is Alix Boyle reporting for OBGYN.net. I am here at the SMFM meeting in San Francisco, California, and we are speaking to Dr. Errol Norwitz from Yale University. What prompted you to do some research into first trimester miscarriage?

Errol Norwitz, MD, PhD: Miscarriage, especially early miscarriage, is very common. We know that up to 25% of early pregnancies will end in spontaneous miscarriage and the mechanism has never been completely clear to people. Many of these are related to chromosomal abnormalities but there are many other reasons why an apparently healthy pregnancy would end in miscarriage. One of the highest risk factors for miscarriage is bleeding early on in pregnancy. In some of those pregnancies, the bleeding will stop and the pregnancy will continue uneventfully, but in many cases, those women will end up having a miscarriage. I was interested in looking at the mechanism behind early bleeding and miscarriage and people have traditionally felt it was just a mechanical effect that the bleeding causes a disruption at the maternal-fetal interface that leads to insufficient oxygen getting to the baby and ultimately ending up in a miscarriage.

We wondered whether there was perhaps a more complex molecular mechanism underlying it or chemical mechanism underlying it. One of my long-term interests has been in GnRH and GnRH signaling, mainly in the classic endocrine cascade, where we know GnRH pulsatility is important for the onset of puberty and for establishing the menstrual cycle. But we have come to appreciate that there is more than one GnRH molecule. There are at least three and two are biologically active in humans and there is probably more than one GnRH receptor. There are certainly are in low-order animals, including high-order primate species like monkeys, although there is some debate as to whether this GnRH receptor type-2 exists in humans. So I was interested in looking more locally at the maternal-fetal interface and whether GnRH and GnRH receptor signaling is important for the maintenance of early pregnancy. We know, for example, that very early on in pregnancy as the blastocyst is implanting, so traditionally, you ovulate 14 days before your next menstrual cycle.

Fertilization occurs within 24 to 48 hours and the zygote slowly makes its way down the fallopian tube into the uterine cavity by about day 5 after conception. It hangs around for 2 days looking for a nice place to implant and about day 7, it starts to implant into the uterus. By day 10, the blastocyst is completely imbedded in the endometrium, so unlike many other animal species where the blastocyst just sits on top of the endometrium and some very cool animal species, like the pig where the blastocyst can actually move around the uterus during pregnancy, in human pregnancy, the blastocyst actually chooses where in the endometrium and that process is complete by day 10 after conception.

The little blastocyst has to produce human chorionic gonadotropin, HCG, that is the hormone we test for when we look for pregnancy in the mother’s urine or blood, but it actually has to produce that hormone to prevent the corpus luteum from degrading, undergoing epistaxis and it rescues the corpus luteum which then continues to maintain the pregnancy through the production of progesterone. We know that mechanism is critically important until about 7 weeks of gestation because, for example, if you take out the corpus luteum before 7 weeks of gestation, all you give are progesterone receptor antagonists like RU486 and you will end the pregnancy, so that mechanism is really important until about 49 days after conception. After that, the placenta takes over the responsibility of making the progesterone, so that early endocrine loop is very important for maintaining pregnancy and the syncytiotrophoblasts, the blastocysts have to make HCG. We know that production of HCG is regulated by GnRH, so this is work done many years ago by Sam Yen and many other people in the ‘60s and ‘70s which showed that GnRH production by the very, very early pregnancy produces HCG which, in turn, maintains the corpus luteum, produces progesterone, maintains the pregnancy.

So we were wondering if this could be interrupted by first trimester bleeding, so what we looked at was in an in vitro model, we looked at cells at the maternal-fetal interface and whether bleeding or thrombins specifically were able to regulate the expression of GnRH and GnRH receptor isoforms.

Alix Boyle: Interesting. So what were the results of your study?

Errol Norwitz, MD, PhD: What we found was quite interesting, which is that thrombin but not other inflammatory markers that we put into our model to try and determine how robust the model was, so we looked for things like R1 Beta and TNF Alpha and they did not affect the expression of these genes. But thrombins selectively decreased the expression of GnRH receptor genes but not GnRH1 and GnRH2. If, indeed, this is validated in further studies, what it might demonstrate to us is thrombins can suppress GnRH receptor gene expression, thereby decreasing the number of receptors on the cell surface, prevent GnRH from signaling through its receptor and, as such, suppress levels of HCG which would lead to miscarriage. So we think there may be an alternative explanation for early miscarriage, not just a mechanical disruption of the pregnancy, but in fact the bleeding can affect this critical endocrine loop, leading to suppression of HCG production, thereby suppression of circulating progesterone levels and, ultimately, miscarriage.

Alix Boyle: So what does this mean for women who have recurring early miscarriages? Can this study help to figure out why this is happening?

Errol Norwitz, MD, PhD: It might lead to lend some light to the explanation. Certainly, women who are having recurrent bleeding in the first trimester and recurrent miscarriage on the basis of bleeding, it might prompt us to start looking for underlying inherited or quiet bleeding disorders or thrombofilias and if, indeed, these women have it, there might be a way to abrogate this path and prevent the first trimester bleeding and, as such, maintain this critical endocrine loop and maintain the pregnancy. An alternative explanation, a technique a lot of our IVF colleagues use, is to supplement women with progesterone early in pregnancy so in essence all women undergoing reproductive or assisted reproductive technologies get supplemental progesterone early on. In the event that HCG is not sufficiently maintained, the corpus luteum and progesterone production from the corpus luteum, at least they are getting extra or taxonomy progesterone that should be able to maintain the pregnancy.

Alix Boyle: Thank you, Dr. Norwitz.

Errol Norwitz, MD, PhD: Thank you.