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    Recurrent pregnancy loss


    Immune causes

    Many studies have attempted to describe the role of maternal and paternal immunity in establishment of pregnancy and in RPL.25 However, despite some initial small positive studies demonstrating various associations, attempts at immune suppression with steroids or IVIG have not yielded any improvement in the live birth rate.26

    One immunologic process that can lead to recurrent pregnancy loss involves infiltration of the placenta by various types of maternal white blood cells.27,28 The resulting inflammatory process, known variously as chronic intervillositis, hystiocytic intervillositis, or villitis of unknown etiology, has been associated with recurrent fetal loss as well as severe fetal growth restriction and stillbirth in pregnancies that extend beyond the early fetal period.27,28 Although this is a rare condition (severe forms are seen in less than 1% of first-trimester placental specimens),28 evaluation of products of conception from pregnancy loss by an experienced pathologist may yield important diagnostic information.

    Endocrine-related causes

    Many endocrine-mediated diseases including overt hypothyroidism, polycystic ovary syndrome (PCOS), poorly controlled diabetes, and luteal phase defects have been implicated in RPL. Thyroid hormone is involved in trophoblast function. Similarly, progesterone is a critical component of the support of early pregnancy.

    Treatment of subclinical hypothyroidism (ie, euthyroid women with thyroid peroxidase antibodies) to reduce rates of miscarriage was evaluated in a Cochrane review published in 2010.29 That analysis showed a nonsignificant trend toward fewer miscarriages with thyroid replacement therapy.

    A meta-analysis of progesterone therapy among women with RPL (ie, 3 or more consecutive miscarriages; 4 trials, 225 women), demonstrated a statistically significant decrease in the rate of miscarriage in women treated with progesterone compared to placebo or no treatment (OR 0.39; 95% CI 0.21–0.72).30 However, these 4 studies were considered to be of low methodological quality. A recent multicenter, double-blind, placebo-controlled, randomized trial of high-dose (400 mg per day) vaginal progesterone therapy among women with unexplained recurrent miscarriage from around 6 weeks’ through 12 weeks’ gestation showed no significant increase in live birth rates (RR of 1.04; 95% CI: 0.94–1.15).31 Progesterone supplementation, therefore, does not appear to be beneficial after 5 weeks’ gestation, however, the data are insufficient to rule out a benefit of luteal phase therapy and treatment up to 6 weeks.

    PCOS has been studied as a risk factor for RPL, with conflicting results.32,33 Newer data make this relationship less certain, particularly because the use of metformin in these patients does not reduce rates of pregnancy loss.34 Obesity has been independently associated with RPL,35,36 as has diabetes.32 Thus, common sense would suggest that these patients should optimize their body mass index and glucose control before conceiving to improve their likelihood of subsequent live birth.

    Diagnostic workup

    The most important component of the workup is a thorough history and physical exam, which may uncover clues to previously undiagnosed underlying disease. Following that, the workup should include the components listed in Table 2.

    Charles J. Lockwood, MD, MHCM
    Dr. Lockwood, Editor-in-Chief, is Dean of the Morsani College of Medicine and Senior Vice President of USF Health, University of South ...


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