Many women with PCOS have metabolic alterations in glycemic control characterized by insulin resistance. This too may be directly or indirectly related to adverse pregnancy outcome, and it may explain increases in the rate of spontaneous pregnancy loss among women with type 2 diabetes mellitus (93). Women with overt insulin-dependent diabetes mellitus (IDDM) appear to exhibit a threshold of pregestational glycemic control above which spontaneous pregnancy loss is increased (94,95). In fact, hyperglycemia has now been directly linked to embryonic damage (96). In cases of advanced IDDM with accompanying vascular complications, compromised blood ﬂow to the uterus may be mechanistically involved in subsequent pregnancy loss.
Patients with thyroid disease often have concomitant reproductive abnormalities, including ovulatory dysfunction and luteal phase defects. In addition, the metabolic demands of early pregnancy mandate an increased requirement for thyroid hormones. It is therefore not surprising that hypothyroidism has been associated with isolated spontaneous pregnancy loss and with recurrent pregnancy loss (97). The definition of hypothyroidism is itself now under scrutiny with many investigators suggesting that cutoff thyroid-stimulating hormone (TSH) values during pregnancy should be less than 2.5 mIU/mL (98). Others have suggested even lower TSH cutoff values (99). Although it has long been debated whether clinically euthyroid patients with antithyroid antibodies have higher rates of miscarriage and recurrent pregnancy loss, thyroid hormone supplementation was shown to reduce miscarriage in infertility patients with positive antithyroid antibodies undergoing IVF (100–106). The mechanism for an association between antithyroid antibody positivity and recurrent pregnancy loss remains unclear; however, these antibodies could be markers of more generalized autoimmunity or may predict an impaired ability of the thyroid gland to respond to the demands of pregnancy.
Two additional endocrinologic abnormalities have been linked with recurrent pregnancy loss, although support for these associations and their mechanistic pathways remains shrouded in controversy. The relationship of hyperprolactinemia with recurrent pregnancy loss continues to be debated. Animal models suggest that elevated prolactin levels may adversely affect corpus luteal function; however, this concept is not well supported in humans (107,108). Some have suggested that elevated prolactin levels may promote pregnancy wastage via direct effects on the endometrium or indirect immunomodulatory mechanisms (88,109). Most recently, attempts have been made to correlate markers of ovarian reserve (day 3 follicle-stimulating hormone, day 3 estradiol, response to the clomiphene challenge test) with recurrent pregnancy loss (89,110,111). At present, no consensus exists concerning this potential association.
Maternal Infection The association of infection with recurrent abortion is among the most controversial and poorly explored of the potential causes for pregnancy loss. Reproductive tract infection with bacterial, viral, parasitic, zoonotic, and fungal organisms have all been linked theoretically to pregnancy loss; however, mycoplasma, ureaplasma, chlamydia, and β-streptococcus are the most commonly studied pathogens (112,113). More recent data have directly addressed the roles of some of these proposed organisms in recurrent pregnancy loss. One prospective comparison trial involving 70 recurrent pregnancy loss patients reported no elevations in any markers for present or past infection with Chlamydia trachomatis when compared with controls (114). In contrast, a very large, prospective trial demonstrated a link between the detection of bacterial vaginosis and a history of second trimester pregnancy loss among 500 recurrent pregnancy loss patients (115). The risk of bacterial vaginosis detection was also positively correlated with cigarette smoking in this study.