Dr. Winifred Mak, MD, PhD, Director of Yale Recurrent Pregnancy Loss Program
Recurrent Pregnancy Loss (RPL), or repeated failed pregnancies, is a medical condition faced by many couples.
RPL is best confronted with a multidisciplinary approach to diagnose and treat any potential underlying cause(s) of the recurrent losses and also to provide the much-needed empathy and emotional support that couples who have experienced RPL require.
The Recurrent Pregnancy Loss Program at Yale provides a team of providers, including reproductive endocrinologists, maternal fetal medicine specialists, a pathologist specializing in fetal loss, genetic counselors, a social worker, a dietitian and a staff of experienced nurses to help couples with RPL navigate through the work-up and treatment of this disorder.
Even when no specific cause for the repeated losses can be identified, very close monitoring and support of a subsequent pregnancy is likely to result in a favorable outcome.
The Yale RPL program offers a comprehensive and individualized approach to the couple with RPL. Dr. Winifred Mak, a Reproductive Endocrinologist and Infertility specialist directs the Early Recurrent Pregnancy Loss Program, while Dr. Michael Paidas, a Maternal Fetal Medicine specialist heads the Late Recurrent Pregnancy Loss Program at Yale. As co-directors, Drs. Kodaman and Paidas confer regularly and provide integrated care to those couples in need of both their services. In addition, the team includes Dorothy Greenfeld, MSW, who has many years of experience assessing and addressing the psychological needs of couples with RPL, while Dr. Harvey Kliman provides detailed histologic reviews of pregnancy loss tissues. The team meets once monthly to discuss the more difficult RPL cases and to brainstorm diagnostic and treatment approaches.
For those couples with RPL in need of fertility treatments, The Yale Fertility Center under the medical directorship of Dr. Pasquale Patrizio, offers the spectrum of ART with excellent success rates, while Dr. Emre Seli heads the also very successful Egg Donation and Gestational Surrogacy services. Dr. Gabor Huszar, director of the Sperm Physiology Lab, facilitates the acquisition and use of donor sperm if required.
Together with well-trained nurses, the physicians at the Yale Center for Reproductive Endocrinology and Infertility provide excellent care to couples with RPL and thereby facilitate their reproductive success. RPL patients are currently being seen in the New Haven, Westport, and Guilford offices. Please call 203-785-4708 (New Haven and Guilford) or (203) 341-8899 (Westport) to schedule a consultation.
While miscarriage affects about 15% of pregnancies in general, only 2% of couples are affected by 2 consecutive losses and even less, about 0.5%, have 3 back to back losses.
Statistically, 2 consecutive losses can happen by chance alone; however, the observed frequency of 3 consecutive losses is greater than that predicted by chance, suggesting that there may be an underlying problem contributing to the reproductive failure.
Recurrent Pregnancy Loss is traditionally defined as the loss of three or more consecutive pregnancies prior to 20 weeks of gestation. While the classic definition is limited to clinically identified pregnancies (those seen by ultrasound or under the microscope), biochemical pregnancies (those identified only by sensitive pregnancy tests) may also be included. Primary RPL refers to repeated miscarriages in the setting of no previous livebirth, and secondary RPL occurs in couples who have previously succeeded in having a child. Early pregnancy loss refers to those in the first trimester (less than 12 weeks), while late or second trimester pregnancy losses occur after 12 weeks. Unexplained RPL reflects to those cases where a specific cause cannot be uncovered.
The American Society for Reproductive Medicine considers two failed pregnancies as RPL and recommends some evaluation after each loss with a more extensive workup after three or more miscarriages. A prompt and thorough evaluation of RPL is especially important in the setting of advancing reproductive age where time is particularly of the essence. It is important to find potentially remediable factors and assist a couple in conceiving again as soon as possible to maximize the chances of a successful outcome as fertility decreases with age, particularly with maternal age, while the chance of miscarriage increases with maternal age.
The most common causes of pregnancy loss include uterine problems, immunologic factors, hormonal disorders, and genetic abnormalities. Lifestyle factors, such as smoking, alcohol consumption, caffeine use, toxic exposures, and obesity may also contribute to RPL. Unfortunately, in at least 50% of cases, a specific cause cannot be found, and the RPL is unexplained.
Uterine factors that can predispose a woman to RPL include congenital uterine anomalies or acquired conditions, such as fibroids, endometrial polyps, and intrauterine adhesions. Of the uterine anomalies, the septate uterus is most commonly associated with RPL and carries a miscarriage risk of up to 60%. In general, an abnormal cavity is thought to impair the ability of the pregnancy (embryo and placenta) to implant and develop normally over time. Poor blood supply, limited space, and increased inflammation in the setting of uterine factors are thought to predispose the pregnancy to eventual loss.
The most common immunologic cause for RPL is the Antiphospholipid Syndrome (APLS). This is an acquired autoimmune condition in which antibodies are made to various components of cell membrane that can lead to pregnancy complications, including recurrent early pregnancy loss, late pregnancy loss, or preeclampsia, as well as to blood clots. While APLS is a well-defined and relatively common immunologic cause of RPL, there are other less understood conditions, such as increased number or activation of uterine natural killer cells, which may also contribute to RPL.
Various hormonal disorders including poorly controlled diabetes, polycystic ovary syndrome (PCOS), undiagnosed or undertreated thyroid disease, elevated prolactin levels, and insufficient progesterone levels (luteal phase defect) can potentially contribute to RPL. At the same time, some of these hormonal disorders may concomitantly make it more difficult for a couple to conceive due to detrimental effects on the menstrual cycle and fertility.
The abnormal number or structural integrity of chromosomes is thought to be the underlying problem in at least 50% of early pregnancy losses. The risk of aneuploidy, or abnormal number of chromosomes in the fetus, increases with advancing maternal age due to damage to the eggs over the course of a woman’s lifetime. The rate of aneuploidy increases dramatically to 40% at age 40 and up to 80% at age 45. In addition, more subtle parental chromosomal rearrangements, known as translocations, occur in 3-5% of couples with RPL. While asymptomatic in the affected parent, such rearrangements can be passed on to the offspring in a manner that is not compatible with survival.
Thrombophilia, the inherited or acquired propensity to form blood clots, is an unlikely cause of early RPL, and routine testing for this is strongly discouraged in the absence of a strong personal or family history of a clotting disorder. On the other hand, thrombophilia can contribute to late (second or third trimester) fetal losses and is investigated more thoroughly in this setting.
Other less well defined causes of RPL may include infections, sperm problems as well as celiac disease , and these are investigated where appropriate based on the presenting factors. In addition, as mentioned above, various lifestyle factors, including alcohol (>3-5 drinks/week), smoking, drug use, caffeine (>3 cups/day) exposure to toxins (pesticides, radiation, secondhand smoke), as well as obesity (BMI > 30 kg/m2), can also contribute to RPL and should be screened for and addressed.
The approach to the couple with RPL involves a thorough and systematic analysis of each loss, such that the timing of the loss, the visualization of developmental milestones prior to the loss (for example, fetal heartbeat on ultrasound), and genetic analysis of the products of conception, if available, are taken in to consideration. In addition, further analysis of the pregnancy loss tissue (products of conception) under the microscope, can sometimes provide additional valuable information with respect to an etiology for the recurrent losses.
Patients with RPL are evaluated initially with a thorough history and physical examination followed by a series of diagnostic tests including bloodwork on both partners and evaluation of the uterus, usually with a specialized ultrasound study (sonohysterogram), to look for anomalies or acquired factors, such as fibroids, scar tissue or polyps, that may compromise implantation. Additional evaluation of couples with RPL is determined on a case by case basis and may include cultures to look for infection, endometrial biopsy to evaluate the endometrium, and detailed analysis of the sperm. Additionally, couples are offered genetic testing for recessive genetic diseases that could impair their reproductive success.
If a specific cause for the prior losses is identified, this is addressed as the first step. For example, uterine factors are surgically rectified where possible, hormonal disturbances are corrected, and women diagnosed with APLS are anticoagulated with heparin and low dose aspirin. Additionally, lifestyle factors that may be contributing to poor reproductive outcome, such as smoking and obesity, are tackled aggressively. In cases of unexplained RPL, there may be a potential benefit of supplemental progesterone administration, though the data supporting this practice are limited.
What is clear is that all couples with RPL can benefit from psychological support and close monitoring of the next pregnancy. There are now multiple studies showing that this practice alone results in an improved outcome for these couples, underscoring the degree of stress and anxiety these couples face after their repeated losses. With the identification of a positive pregnancy test, serial blood testing is initiated every 2-4 days to assess for the adequate rise of the pregnancy hormone (bhCG) levels. Progesterone levels may also be measured. Once the bhCG level reaches a certain threshold (at or beyond 2000 mIU/ml), an ultrasound is performed to visualize the pregnancy. Patients are followed with ultrasound very closely thereafter, usually every 1-2 weeks during the first trimester to evaluate the growth of the embryo and its attainment of certain milestones, such as the development of a fetal heartbeat. It is very important to closely follow the pregnancy beyond the gestational age at which the previous pregnancy loss(es) occurred as once this mark is reached, the odds are improved that the current pregnancy will progress safely.
Even without intervention or with just close monitoring of the next pregnancy, couples with unexplained RPL have a good chance for success. These couples are encouraged to make lifestyle changes to minimize any detrimental effects on a subsequent pregnancy and are often also given supplemental progesterone as mentioned above. In addition, fertility treatments can be offered to these couples to help maximize their chances of getting pregnant in a timely fashion, as such treatments enhance egg production and optimize endometrial receptivity. Such fertility treatments include ovulation induction often combined with intrauterine insemination and if needed, in vitro fertilization (IVF).
IVF with preimplantation genetic screening (PGS) allows for the screening of embryos for chromosomal health prior to transfer to the uterus. While the data on the use of this Assisted Reproductive Technology (ART) for unexplained RPL is limited, it may provide a useful treatment modality for certain couples with RPL, such as those with defined chromosomal conditions resulting in repetitive miscarriage.
Overall livebirth rates are on the order of 70 and 80% after abnormal and normal findings during the RPL workup. The risk of another miscarriage is based on the number of previous miscarriages, such that after 2, 3, and 4+ losses, the recurrent risks are approximately 20, 30 and 40%.