Endocrinology and Recurrent Early Pregnancy Loss

M. Leah Smith, M.D.,1 and Danny J. Schust, M.D.1

ABSTRACT

KEYWORDS: Thyroid autoantibodies, polycystic ovarian syndrome, luteal phase defect, recurrent pregnancy loss

pontaneous 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 dened 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 denition. Using three losses as the criteria for dening 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
1 Department of Obstetrics, Gynecology and Womens Health, University of Missouri School of Medicine, Columbia, Missouri. Address for correspondence and reprint requests: Danny J. Schust, M.D., Department of Obstetrics, Gynecology and Womens Health, University of Missouri School of Medicine, 500 North Keene Street, Suite 203, Columbia, MO 65201 (e-mail: schustd@ health.missouri.edu).

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 dene 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,
Recurrent Early Pregnancy Loss; Guest Editor, Mary D. Stephenson, M.D., M.Sc. Semin Reprod Med 2011;29:482490. Copyright # 2011 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA. Tel: +1(212) 584-4662. DOI: http://dx.doi.org/10.1055/s-0031-1293202. ISSN 1526-8004.

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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 dened hypothyroidism, thyroid autoimmunity, luteal phase defects, obesity, and polycystic ovary syndrome.

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HYPOTHYROIDISM AND THYROID AUTOIMMUNITY Thyroid function changes dramatically in normal pregnancies.14 Accompanying the onset of increased maternal blood volume and the presence of the developing fetus, the rst trimester of pregnancy is characterized by an increase in the distribution space for extrathyroidal thyroxine (T4). As estrogen levels rise during gestation, so too does the serum thyroid binding globulin (TBG) concentration. Increased circulating TBG binds additional circulating thyroid hormone, decreasing the amount of unbound hormone necessary to exert action on end organs. If overall thyroid homeostasis is to be maintained during pregnancy, these changes challenge the thyroid gland to increase its production of thyroid hormone. This increase in thyroid hormone production depends heavily on the availability of adequate dietary iodine, which can be problematic in areas of the world in which sources of iodized salt are limited. Diseased thyroid glands may also be limited in their ability to respond adequately to the challenges of pregnancy. A study of thyroid function and pregnancy outcome in 2009 revealed a positive linear relationship between fetal loss and maternal thyroid-stimulating hormone (TSH) levels, including TSH levels previously dened to be in the normal range.15 Autoimmune thyroid disease is the most common endocrine disorder in women of reproductive age, often going undiagnosed for several years before presentation with overt hyper- or hypothyroidism. With an overall prevalence in women of 10 to 15%, this disorder is up to 10 times more common in women than in men.16 Among pregnant women, autoimmune thyroid disease has a prevalence of 5 to 20%, depending on the population studied.17

Figure 1 Synthesis of triiodothyronine (T3) and thyroxine (T4). Iodide, absorbed from the gastrointestinal tract, is carried to the follicular cells of the thyroid. Through active transport, the iodide passes across the follicular cell into the colloid matrix where it is oxidized by thyroperoxidase (TPO). It is then attached to tyrosine molecules in thyroglobulin (made in the follicular cell), which forms monoiodotyrosine (MIT) and diiodotyrosine (DIT). TPO further links MIT and DIT to form T3 and T4, which remain attached to thyroglobulin. This complex is then resorbed back into the follicular cells where T3 and T4 are ultimately released. MIT and DIT are recycled as T3 and T4 are released into circulation. H2O2, hydrogen peroxide.

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surgical correction of the septate uterus and removal of intrauterine polyps and submucous leiomyomas are associated with the most dramatic improvements in outcome.911 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.

The most commonly targeted thyroid antigens in autoimmune thyroid disease are thyroperoxidase (TPO) and thyroglobulin (Tg). TPO and Tg are integral to the formation of thyroid hormones. In the adult thyroid gland, inorganic dietary iodide is concentrated in the thyroid follicles by active transport across the follicular cell (Fig. 1). The iodode is then trapped in the thyroglobulin colloid within the follicular lumen through a series of steps that include iodide oxidation by thyroid peroxidase and linkage of iodide to tyrosyl molecules in Tg. Mono- and di-iodotyrosines on Tg are again acted on by TPO to form either T4 or triiodothyronine (T3). The third National Health and Nutrition Examination Survey (NHANES III) reported on the prevalence of thyroid antibodies among asymptomatic patients >12 years of age, nding anti-TPO antibodies in 8% of asymptomatic men and 14.6% of asymptomatic women and anti-Tg antibodies in 6.9% of asymptomatic men and 13.8% of asymptomatic women.18 The enigma of the fetal allograft was rst posed by Billingham et al in 1953.19 Their report stimulated nearly 70 years of investigations aimed at explaining the

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incongruent presence of the fetal semiallograft in an immunocompetent maternal host. This conundrum remains incompletely answered. During this time, several investigators have described increased pregnancy wastage among women with autoimmune diseases, including APS12 and, most recently, celiac disease.20 StagnaroGreen et al21 were the rst to link thyroid autoimmunity to RPL in a 1990 report showing elevated levels of thyroid autoantibodies among women with repeated pregnancy losses. Since that time, the literature has been replete with correlative studies suggesting an association between antithyroid antibodies (ATAs) and RPL, with most,2126 but not all,27,28 showing a positive correlation between the presence of ATA and the occurrence of RPL.29 Of those that include such data, most have not shown an association between autoantibody titers and RPL, giving rise to a debate over whether this is actually a causal relationship. The exact mechanism of how thyroid autoantibodies lead to RPL is unknown.29,30 It is hypothesized that the thyroid antibodies could be makers of more generalized autoimmunity that results in early pregnancy loss. Others postulate that thyroid autoantibody-mediated disease alters thyroid reserve to such an extent that the thyroid gland is unable to respond adequately to the demands of pregnancy. Still others believe that women with ATA are merely older when they become pregnant and that advanced maternal age is their primary risk factor for miscarriage.29,30 Interestingly, in mice immunized with TPO, anti-TPO antibodies bound to preimplantation embryos, although the effect of such binding on later embryo development has not been studied.31 Mice immunized with thyroglobulin also demonstrate an increase in spontaneous fetal loss.32,33 The effect of thyroid autoimmunity on pregnancy has recently been reexamined because of recommendations by several national and international groups, including The Endocrine Society,34 to revisit normal serum TSH cutoff values, particularly among pregnant women. Within just the past year, two important clinical papers were published that may help guide clinical care for all pregnant women. Negro et al35 reported that early pregnancy loss rates were increased among ATA-negative women with TSH levels between 2.5 mIU/mL and 5.0 mIU/mL, a level previously considered to lie within the normal range in most clinical laboratories. De Vivo et al36 demonstrated that subclinical hypothyroidism and ATA are independently associated with early pregnancy loss; many of these losses occurred very early in gestation (i.e., before 6 weeks of gestation). Such early occurrence of ATA-associated pregnancy losses may not be surprising because maternal ATA levels are known to decrease over the course of gestation.37 Several studies are now available demonstrating that therapeutic intervention using levothyroxine in women with hypothyroidism38 or in euthyroid women

with ATA3941 improves pregnancy outcomes. Three of these reports, like much of the recent data on thyroid function and pregnancy outcome, have addressed spontaneous pregnancy loss but not RPL. However, given that thyroid autoimmunity may be present for many years before the onset of overt thyroid disease, it is likely that a proportion of women with REPL and REM are suffering from undiagnosed thyroid autoimmunity. The rather small and nonrandomized study by Vaquero et al41 supports this concept by demonstrating that women with REPL and ATA who received thyroxine therapy had improved pregnancy outcomes when compared with those treated with immunosuppressive agents. This suggests that the etiology of the failed pregnancy is hormonal rather than immunological. A recent Cochrane database review of interventions for clinical and subclinical hypothyroidism in pregnancy has determined that it may prove worthwhile to treat women with subclinical hypothyroidism and ATA in an attempt to decrease their chance for adverse pregnancy outcomes, including miscarriage.42 We agree with these authors and extend this recommendation to promote the evaluation of TSH and thyroid autoantibodies (anti-TPO and anti-Tg) in patients with RPL. For women found to be overtly hypothyroid or hyperthyroid, standard therapies are appropriate. There are no clear recommendations for euthyroid women with thyroid autoantibodies and limited data concerning how much thyroid replacement to use. Among women with a history of REPL or REM, we suggest that those with thyroid autoantibodies but a TSH < 2.0 to 2.5 mIU/L need no therapy. Close clinical follow-up during early gestation is essential because the increased thyroid demands in pregnancy may manifest as early as 4 to 8 weeks of gestation.43 For women with ATA and TSH values between 2.5 and 4 mIU/L, we agree with others that levothyroxine replacement is indicated and should be tailored to the TSH level.17,44,45 All patients with thyroid autoantibodies should have thyroid function checked later in pregnancy regardless of treatment status because the average increase in the amount of thyroid replacement necessary to maintain homeostasis over the course of pregnancy approaches 30 to 50%.46

LUTEAL PHASE DEFECT The luteal phase begins at the onset of the luteinizing hormone (LH) surge, typically dened as menstrual cycle day 14. This surge in LH, accompanied by a smaller but important surge in follicle-stimulating hormone, directs the oocyte within the dominant follicle to complete its rst meiotic division and the dominant follicle to release its resident ovum. Oocyte release generally occurs within 36 hours of the LH surge. The granulosa cells of the ovulating follicle begin to luteinize

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and produce progesterone. Like the late follicular phase, the luteal phase of the menstrual cycle is characterized by relatively high levels of circulating estrogens. Changes in the follicular phase affect the health of the uterine decidua, with estrogen supporting endometrial glandular development.47 Unique to the luteal phase of the cycle is a dramatic increase in circulating progesterone, which rises rapidly beginning at approximately day 14 of a standard 28-day cycle and peaks during the window of implantation (approximately days 19 to 23 of the cycle). Progesterone exerts its primary effects in the endometrial stroma,47 promoting decidualization and readiness for embryo implantation. The implanting embryo produces chorionic gonadotropin that sustains progesterone production by the ovarian corpus luteum. The corpus luteum continues to produces progesterone, supporting the pregnancy until 7 to 9 weeks gestation, when the developing placenta takes over progesterone support of the pregnancy. If the corpus luteum is removed before week 8 of gestation, the pregnancy will fail.48 Normal luteal phases are characterized by adequate hormone production by the corpus luteum and adequate endometrial response to these hormones. Theories for luteal phase defect (also knows as luteal phase insufciency or luteal phase deciency) include poor follicular development, decreased progesterone production by the corpus luteum, and dysfunctional endometrial response to secreted progesterone.49 Other primary etiologies that have been suggested include hyperprolactinemia, stress, exercise, and weight loss.50 RPL has long been associated with luteal phase defects, although the methods used to dene LPD in most of the published investigations have used tools now known to have signicant limitations (see later). In 1977, Horta et al51 demonstrated that serial luteal phase serum progesterone levels in nonconception cycles were lower among women with a history of three or more spontaneous pregnancy losses when compared with healthy nonpregnant controls. Others have used timed endometrial biopsies to show similar outcomes.52 In the best studies available to date, the incidence of LPD among women with RPL was between 17.4% and 28%.53,54 Finding consistent, accessible, and reliable diagnostic criteria for dening LPD has been challenging, and a single modality for the diagnosis of luteal phase defect is still not universally accepted. Luteal phase length < 10 to 11 days as measured by basal body temperature elevations can be difcult to document consistently and reliably. Luteal phase serum hormone levels uctuate throughout the day; predictive testing of luteal phase progesterone levels requires intravenous catheter placement or multiple blood draws over a 12- to 24-hour period and complicated calculations of area under the curve. Serial serum progesterone measurements over the course of the luteal phase have also been promoted.51 For many years, the timed endometrial biopsy was routinely

POLYCYSTIC OVARY SYNDROME It is estimated that 40% of pregnancies in women with PCOS will result in spontaneous loss.67 PCOS is a complex disorder involving abnormalities in interactions between the pancreas, the hypothalamus/pituitary, the ovaries, the liver, and adipose tissues. As illustrated in Fig. 2 women with PCOS commonly display irregular menses, obesity, and laboratory evidence of elevated androgens, elevated levels of LH, insulin resistance, and hyperinsulinemia. Not all women with PCOS display all of these abnormalities, and the phenotype of the disorder likely results from variable combinations of etiologies and abnormalities. Interestingly, women with PCOS have a threefold higher prevalence of thyroid autoimmunity when compared with healthy age-matched controls.68

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used to determine the adequacy of endometrial development during the luteal phase. Denition of LPD using endometrial biopsies required that two biopsies be abnormal in subsequent menstrual cycles. Documentation of abnormality for this invasive procedure was dened as endometrial histology, as dened by Noyes et al,55 that lagged  2 days behind menstrual dating. Few clinicians continue to use timed endometrial biopsies in the evaluation of RPL patients because of poor reproducibility secondary to interobserver56,57 and intraobserver variation.58,59 It has been estimated that diagnosis would change in between 20% and 40% of biopsies if read by two different pathologists.60,61 That said, despite their report on the poor positive predictive value of the timed luteal phase biopsy for predicting fertility, Coutifaris et al62 showed the usefulness was slightly improved among women with a history of RPL. Treatment options for women with RPL and LPD have varied widely and included ovulation induction,63 luteal phase supplementation with human chorionic gonadotropin,64,65 and luteal phase progesterone supplementation. All remain somewhat contentious, although the most commonly used is luteal phase progesterone supplementation. A recent Cochrane Review of 15 trials and 2118 women showed that progesterone supplementation did not appear to prevent isolated spontaneous pregnancy loss (odds ratio [OR]: 0.98; 95% condence interval [CI], 0.78 to 1.24) but was useful in women with a history of three or more consecutive pregnancy losses (OR; 0.38; 95% CI, 0.2 to 0.7).66 The authors of this meta-analysis do not provide guidance on progesterone preparation, dosage, route of delivery, timing of initiation, or timing of cessation of supplementation. We recommend vaginal progesterone delivery, 100 mg twice a day, beginning 2 to 3 days postovulation and ending after completion of the lutealplacental shift in all women with REM; we consider similar treatment for women with REPL.

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Figure 2 Diagnostic criteria for the polycystic ovary syndrome (PCOS). When applied to similar populations, application of the two most commonly used criteria for diagnosing PCOS92,93 can result in markedly different estimates of disease prevalence. The Rotterdam criteria allow women with regular menses to be diagnosed with PCOS. DHEAS, dehydroepiandrosterone sulfate; NIH/NICHD, National Institutes of Health/National Institute of Child Health and Human Development.

There is signicant clinical overlap among women with type 2 diabetes mellitus and PCOS. Although it is well established that glycemic control during early pregnancy in overt diabetics is associated with increased rates of early pregnancy loss,69,70 nding a clear association between PCOS and RPL is hindered by variability in disease etiologies and diagnostic criteria. Still, several of the abnormalities seen in PCOS patients have been independently associated with RPL, including insulin resistance, hyperinsulinemia, hyperandrogenemia, and obesity. Hyperinsulinemia and insulin resistance may be independent risk factors for RPL,71 but studies on their association with early pregnancy loss do not always adequately discriminate the two. There is a higher prevalence of insulin resistance among women with RPL when compared with matched controls (27% versus 9.5%; OR: 3.55; 95% CI, 1.4 to 9.0),72 and treatment of insulin-resistant infertility, REPL and REPM patients with insulin-sensitizing agents (metformin) was shown to decrease rates of early pregnancy loss in a series of small studies.67,7375 The benets of insulin-sensitizing agents (metformin) were also demonstrated in women with RPL and an abnormal preconceptional glucose tolerance test.76 To date, the best designed and largest

investigations on the effects of metformin on isolated spontaneous pregnancy losses in infertility patients have demonstrated no decrease in subsequent pregnancy loss rates.77,78 Patients in these studies stopped metformin use with the diagnosis of pregnancy. It remains unclear whether the extended use of metformin during early pregnancy would have altered study outcomes and whether the results of these studies can be extrapolated to women with PCOS and RPL. In addition to its effects on insulin resistance, metformin lowers circulating levels of plasminogen activator inhibitor (PAI).79 PAI inhibits brinolysis and is elevated in women with PCOS. Elevated levels of PAI have been reported to be an independent risk factor for early spontaneous pregnancy loss.80 Metformin use during pregnancy does not appear to be linked to teratogenicity or developmental disorders among exposed children studied during their rst 18 months of life.81 Hyperinsulinemia and hyperandrogenemia are tightly associated,82 but the presence of an independent link between hyperandrogenemia and RPL remains contentious.71 Elevated androgens in the local microenvironment of the developing follicles impair follicular development and cause anovulation in PCOS patients. This, in turn, leads to the characteristic ultrasonographic

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CONCLUSION Endocrine etiologies, including thyroid disorders, luteal phase defect, and PCOS, may be found in as many as 1 in 5 women with RPL; many of these women may experience REPL or REM. Hypothyroidism and hyperthyroidism can have negative effects on fetal development. Recent studies have focused on the role of antithyroid antibodies and of previously normal (2.5 to 5 mIU/ml) TSH levels in early pregnancy loss and in RPL, although the mechanisms that cause adverse pregnancy outcomes remain unclear. Inadequate thyroid reserve during early pregnancy may be critically involved. This theory is supported by positive outcomes among women with antithyroid antibodies and isolated or repeated pregnancy losses who are treated with levothyroxine during early pregnancy. The usual tight control of the endometrium by the corpus luteum in early pregnancy may become inadequate for pregnancy support in women with REPL and REM. This may be caused by limited progesterone secretion by the corpus luteum and/ or diminished endometrial response to normal amounts of progesterone. Diagnostic testing for LPD remains poorly predictive of pregnancy outcomes. However, patients with RPL have improved outcomes when given progesterone during early pregnancy. This is possibly secondary to correction of LPD, although other or additional mechanisms have been proposed. Finally, women with PCOS have multiple metabolic and endocrine abnormalities, including hyperandrogenism, obesity, hyperinsulinemia, and insulin resistance. These abnormalities have been associated with as much as a 40% risk of pregnancy loss. Many studies have suggested that weight loss and the use of insulin-sensitizing agents reduce the rate of spontaneous loss in PCOS patients,

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appearance of the PCOS ovary. The presence of ultrasonographic evidence of PCOS, however, does not independently predict pregnancy outcomes.83,84 Elevated androgen levels85 and elevated insulin levels72 have detrimental effects on endometrial development. Elevated androgen levels decrease oocyte quality and embryo viability.86 Obesity has adverse effects on pregnancy maintenance that are independent of those associated with PCOS.87 Women with a body mass index (BMI) >30 kg/m2 increase their odds for isolated rst trimester pregnancy loss by a factor of 1.2 and their odds of RPL by a factor of 3.5.88 Several studies have shown that among women with PCOS, increased BMI and the incidence of RPL are positively correlated,89,90 possibly secondary to the metabolic disturbances associated with obesity, including hyperinsulinemia, insulin resistance, and hyperandrogenemia. Weight loss among women with elevated BMI is associated with decreased pregnancy loss rates.91

although the latter investigations continue to be actively contested. Based on the available data, we recommend measuring TSH, antithyroglobulin, and antithyroperoxidase antibody levels in the evaluation of patients with RPL. In the absence of an easy, inexpensive, and reliable test for LPD, we offer REM and most REPL patients empirical progesterone therapy beginning in the luteal phase of cycles during which they are actively attempting to conceive. We encourage weight loss in women with obesity and REPL/REM, including those with concurrent PCOS. We also offer insulin-sensitizing agents to women with PCOS, particularly those with elevated insulin and androgen levels. Both weight loss and insulin-sensitizing agents have been shown to decrease circulating insulin and androgen levels among women with PCOS. We look forward to future developments in diagnostic testing and treatment of endocrine disorders among patients with RPL. These will undoubtedly ow from improvements in the denition of RPL and the standardization of inclusion and exclusion criteria in studies involving testing and therapeutic interventions.

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