Endocrinology and Recurrent Early Pregnancy Loss

M. Leah Smith, M.D.; Danny J. Schust, M.D.


Semin Reprod Med. 2011;29(6):482-490. 

In This Article

Abstract and Introduction


Endocrine disorders have been frequently linked to recurrent pregnancy loss (RPL). Because embryo attachment and early implantation are exquisitely controlled by the local hormonal milieu, endocrine-related pregnancy failures are likely to occur early in gestation. Thyroid disorders, luteal phase defects, and polycystic ovary syndrome are the endocrine abnormalities most commonly associated with RPL. In this review we discuss new concepts in the pathophysiology and treatment of these diseases with the ultimate goal of improving pregnancy maintenance. We have also included our recommendations on testing and treatment of women with isolated and repeated pregnancy failure that is believed to be at least partially mediated by newly defined hypothyroidism, thyroid autoimmunity, luteal phase defects, obesity, and polycystic ovary syndrome.


Spontaneous pregnancy loss in humans is remarkably high. Up to 75% of fertilized ova and at least 15% of clinically recognized pregnancies never survive to birth.[1,2] Most spontaneous losses occur early; approximately half occur before or just after a missed menses.[3] Most of the remaining losses occur before 8 to 10 completed weeks of gestation, and it is thought that the overwhelming majority of losses in both groups are the result of spontaneous aneuploidy or polyploidy.[4,5] Recurrent pregnancy loss (RPL) has been defined as two or three or more spontaneous pregnancy losses before 20 completed weeks of gestation; research on the disorder has been hampered by lack of a consistent definition. Using three losses as the criteria for defining RPL, the disorder is thought to occur in ~1 in 300 couples.[2] We limit our discussions to early pregnancy losses (<10 completed weeks of gestation) and use the term recurrent early pregnancy loss (REPL) for couples who have experienced two or more spontaneous losses before 10 weeks of gestation and recurrent early miscarriage (REM) for couples who have experienced three or more spontaneous pregnancy losses at <10 weeks of gestation. REPL is diagnosed in at least 1% of couples attempting conception.[6]

The diagnosis and treatment of RPL is decidedly hindered by a lack of consensus on how to define the disorder and inconsistent patient inclusion and exclusion criteria in published studies. That said, proposed etiologies for RPL include parental karyotypic abnormalities, uterine anatomical abnormalities, and hormonal, infectious, immune, and thrombophilic disorders. The least controversial of these etiologies, parental karyotypic abnormalities, is also the least prevalent, occurring in ~3.5 to 5% of studied couples.[7,8] Uterine anatomical abnormalities are found in ~18% of couples experiencing RPL.[9,10] Of these, surgical correction of the septate uterus and removal of intrauterine polyps and submucous leiomyomas are associated with the most dramatic improvements in outcome.[9–11] A connection between the antiphospholipid syndrome (APS) and RPL is also widely accepted,[12] and treatment of the disorder with aspirin and heparin during pregnancy is both common and effective.[13] The relative prevalence of hormonal, infectious, and heritable thrombophilic causes for RPL largely depends on the criteria used for study inclusion and practitioner referral patterns; diagnostic and treatment paradigms for these disorders remain controversial. In this article, we review the most commonly studied hormonal causes of RPL: thyroid disease, luteal phase defect (LPD), and polycystic ovary syndrome (PCOS). Among the proposed etiologies of RPL, most hormonal abnormalities are likely to have effects very early in pregnancy and should be most closely associated with REPL and REM.


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