Reproductive Immunology - More Than Infertility and Recurrent Pregnancy Loss

Posted By Braverman Reproductive Immunology || 22-Jul-2014

The maternal immune system plays an important role over the entire course of pregnancy. Second and third trimester complications of pregnancy including preeclampsia, HELLP syndrome, preterm labor/preterm birth, intrauterine growth restriction (fetal growth restriction), placental abruption, and stillbirth are frequently indications of a pathological maternal immune response to pregnancy. However many of these syndromes are attributed to "one time experiences" and correct diagnostic tests are never performed and treatments never offered to prevent these complications in future pregnancies. Women who experience any of these pregnancy complications should contact us so that we can conduct a complete evaluation to determine the underlying immunologic issues that are responsible. Second and third trimester complications frequently stem from an altered immune response to an embryo at very early stages of pregnancy, and treatment to prevent these complications should be started very early – if possible prior to the initiation of embryo implantation. Monitoring of the immune response throughout the pregnancy by an experienced reproductive immunologist can help to identify those at risk for later complications so that therapies can be initiated to prevent them.

Many Late Pregnancy Complications Are Associated With Immune Dysfunction (Unfortunately Most Obstetricians and Their Patients Are Not Aware)

Reproductive immunology is a field of medicine that deals with the interaction of the maternal immune system with an embryo and later a fetus, and adverse consequences that can result when this interaction is unharmonious. Up to this point in time the clinical application of reproductive immunology has been almost entirely focused on diagnosing and treating women with infertility, recurrent pregnancy loss, and failed IVF cycles (failed implantation) not explained by more traditional diagnostic approaches (genetics, anatomy, endocrinology, thrombophilia). This clinical focus on early stages of pregnancy has been dictated by the knowledge that a failure of the maternal immune system to adequately tolerate an embryo containing "foreign" paternal genetics can lead to these early adverse outcomes.

However, it is now abundantly clear that unfavorable maternal immune responses towards an embryo/fetus can also result in significant complications in the second and third trimesters of pregnancy. These can include intrauterine growth restriction (fetal growth restriction), preeclampsia, HELLP syndrome, preterm labor/preterm birth, placental abruption, and stillbirth. It is also becoming increasingly evident that promotion of a pro-inflammatory in utero environment for a fetus by the maternal immune system can have adverse consequences that persist long after birth of the child. For example, significant evidence now exists that links the development of autism in children (with genetic predisposition) to their exposure as fetuses to inflammatory immune responses in the womb. We have started a new website to provide information on this topic at – this site will be launched in the next few months.

Women with a history of second and third trimester complications are at increased risk for the recurrence of these complications in subsequent pregnancies, as well as for the development of early pregnancy failure (infertility, recurrent pregnancy loss, implantation failure). Therefore, we strongly encourage women with a history of any of these second or third trimester complications or any of the 15 indications listed here to seek a complete immunological evaluation with us. When treatments are required they need to be started prior to embryo implantation (ie, prior to conception in a natural cycle or prior to embryo transfer in an IVF cycle) as these later complications are frequently have their roots in these very early stages of pregnancy.

At Braverman IVF & Reproductive Immunology we define success for our patients as the achievement of an uncomplicated pregnancy and birth of a healthy child, and not merely in terms of the ability to conceive and carry past the first trimester. As such, we closely monitor the status of our patient's immune systems and development of the placental vasculature throughout the pregnancy to determine if they are being adequately treated. We adapt our treatment protocols as needed in response to our monitoring on a highly individualized level.

We are constantly striving to augment and adapt our immunological testing during the first trimester of pregnancy to help us determine when changes to treatment protocols are needed, and to determine those patients that remain at highest risk for later pregnancy complications due to their altered immunological states. For example, we closely follow serum levels of the cytokine interferon gamma-induced protein 10 (IP-10), which has been shown to be predictive for the later development of preeclampsia when present at high levels in the first trimester. We also monitor levels of anti-HLA antibodies in those patients that have species specific for their partner's HLA genetics, as these have been shown to play a role in the development of chronic chorioamnionitis and the induction of spontaneous preterm birth. We are currently working to expand our monitoring panel to include the cytokines sFlt-1 and PlGF. The ratio of these two cytokines present in a patient's blood in the first trimester is currently amongst the most sensitive predictors known for later development of preeclampsia. We are also closely following brand new research just revealed at the recent annual meeting of the American Society for Reproductive Immunology, which Dr. Braverman co-chaired, that shows that levels of a molecule called PD-1 on the surface of regulatory T (Treg) cells may predict the later occurrence of gestational diabetes.

With the recognition that the maternal immune system plays a significant role throughout pregnancy and that inappropriate immune responses can lead not only to early complications (infertility, failed IVF, recurrent miscarriage) but also to later complications of pregnancy (intrauterine growth restriction, preeclampsia, HELLP syndrome, preterm labor/preterm birth, placental abruption, stillbirth), we strongly believe that the field of clinical reproductive immunology should widen its focus to include monitoring and management over the entire course of pregnancy. To this end, we have started to monitor and manage patients into the second trimester that have certain risk factors for the development of later complications.

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