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Recurrent Pregnancy Loss

At Reproductive Medicine Institute (RMI), we strive to offer our referring community and our shared patients the most current information on Assisted Reproductive Technologies (ART). In this blog we discuss Recurrent Pregnancy Loss (RPL).


Recurrent Pregnancy Loss

Nasir Rana, MD, MPH


While most miscarriages are sporadic and not repetitive, there is a subset of couples that suffer recurrent miscarriage. Recurrent miscarriage affects around 1% of couples, at least 50% of whom without any obvious pathology noted.  In the past, the definition of recurrent pregnancy loss was considered to be 3 or more miscarriages. A short time ago, the American Society for Reproductive Medicine published a change of definition of recurrent pregnancy loss: “Recurrent pregnancy loss is a disease distinct from infertility, defined by 2 or more failed pregnancies”.

Historically, the cause of recurrent pregnancy loss was unknown in most couples. More recently, however, much progress has been made in understanding the mechanisms involved. Two major reasons for recurrent pregnancy loss exist. One is that there is a problem with the pregnancy itself that prohibits the pregnancy from growing properly. The other reason is a problem within the uterine environment that does not allow an otherwise normal embryo to grow properly.


Problems with the pregnancy are usually characterized by the presence of an abnormal chromosome of the conceptus. Around 40% of miscarriages in recurrent miscarriage patients are chromosomally abnormal highlighting the importance of embryonic aneuploidy in this population. However, not all of conceptions from women experiencing recurrent pregnancy loss display chromosomal abnormalities. This leaves some seemingly unaccounted for, but it’s not. Collectively combined parental and embryonic factors provide an explanation more than 90% of recurrent miscarriage patients.


Problems within the uterine environment have been classified as anatomic, hormonalimmunologic and thrombophilic. While anatomic and hormonal abnormalities have been associated with pre-implantation pregnancy losses, their roles in post-implantation pregnancy loss have been controversial. Thrombophilias are inherited or acquired conditions that predispose an individual to blood clotting. The most common thrombophilia is acquired and is manifested by elevated circulating antiphospholipid antibodies. While the association of antiphospholipid antibodies and recurrent pregnancy loss has been well accepted, the role of inherited thrombophilia recently come into question especially among women with no previous history of blood clotting problems.


The most frequently studied risk factors to identify an immunologic cause of reproductive failure have included the not only the presence of antiphospholipid antibodies but also elevated natural killer (NK) cells. Women with reproductive failures have significantly elevated numbers of peripheral NK cells compared with normal fertile controls. Thus, detection of elevation of circulating CD56+ (NK) cells has been shown to be helpful in identifying individuals at risk for losing chromosomally normal pregnancies. Not all individuals experiencing reproductive failure display markers circulating in the blood.


The good news is, despite the complexity of the issue(s), effective treatment for reproductive failure is available, albeit dependent on the cause of the failure.


  • Heparin and aspirin are successful in the treatment of elevated APA among women with recurrent miscarriage but not with recurrent implantation failure.
  • Treatment with intralipid with steroids or granulocyte colony stimulating factor (G-CSF) have been shown to enhance live births among women displaying hyper-active endometrium by EIP.
  • Immunotherapy for treatment of reproductive failure enhances live birth but only in those women displaying abnormal immunologic risk factors.

It is widely accepted that emotional and physical trauma of losing a pregnancy requires psychological support and dedicated follow-up complemented with weekly ultrasound scanning. Patients should be advised that modifiable factors such as obesity, coffee, alcohol, smoking, and cocaine use have linked to increased miscarriage risk.  Eliminating smoking and alcohol and optimizing body mass index would benefit not only miscarriage but also risk profile for later pregnancy. Increased semen abnormalities such as DNA fragmentation and aneuploidy have been found in recurrent miscarriage couples, but at this stage, such abnormalities cannot be considered predictive of increased risk of recurrent miscarriage.


While the pain of loss is the same, not all pregnancies fail for the same reason. Before effective treatment for reproductive failure can be instituted, the cause of the failure must be determined. Only patients experiencing reproductive failure with an immunologic cause would be expected to respond to immunotherapy and obstetrical history alone cannot be used to determine whether immunotherapy will be useful. A consult with a Reproductive Endocrinologist and Infertility (REI) physician who specializes in Recurrent Pregnancy Loss is the first step in ending the cycle.