Semin Reprod Med 2011; 29(6): 482-490
DOI: 10.1055/s-0031-1293202
© Thieme Medical Publishers

Endocrinology and Recurrent Early Pregnancy Loss

M. Leah Smith1 , Danny J. Schust1
  • 1Department of Obstetrics, Gynecology and Women's Health, University of Missouri School of Medicine, Columbia, Missouri
Further Information

Publication History

Publication Date:
08 December 2011 (online)

ABSTRACT

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.

REFERENCES

  • 1 Boklage C E. Survival probability of human conceptions from fertilization to term.  Int J Fertil. 1990;  35 (2) 75, 79-80, 81–94
  • 2 Wilcox A J, Weinberg C R, O'Connor J F et al.. Incidence of early loss of pregnancy.  N Engl J Med. 1988;  319 (4) 189-194
  • 3 Edmonds D K, Lindsay K S, Miller J F, Williamson E, Wood P J. Early embryonic mortality in women.  Fertil Steril. 1982;  38 (4) 447-453
  • 4 Rai R, Regan L. Recurrent miscarriage.  Lancet. 2006;  368 (9535) 601-611
  • 5 Suzumori N, Sugiura-Ogasawara M. Genetic factors as a cause of miscarriage.  Curr Med Chem. 2010;  17 (29) 3431-3437
  • 6 Alberman E. The epidemiology of repeated abortion. In: Beard R W, Sharp F, eds. Early Pregnancy Loss: Mechanisms and Treatment. New York, NY: Springer-Verlag; 1988: 9-17
  • 7 Fryns J P, Van Buggenhout G. Structural chromosome rearrangements in couples with recurrent fetal wastage.  Eur J Obstet Gynecol Reprod Biol. 1998;  81 (2) 171-176
  • 8 Jaslow C R, Carney J L, Kutteh W H. Diagnostic factors identified in 1020 women with two versus three or more recurrent pregnancy losses.  Fertil Steril. 2010;  93 (4) 1234-1243
  • 9 Proctor J A, Haney A F. Recurrent first trimester pregnancy loss is associated with uterine septum but not with bicornuate uterus.  Fertil Steril. 2003;  80 (5) 1212-1215
  • 10 Propst A M, Hill III J A. Anatomic factors associated with recurrent pregnancy loss.  Semin Reprod Med. 2000;  18 (4) 341-350
  • 11 Homer H A, Li T C, Cooke I D. The septate uterus: a review of management and reproductive outcome.  Fertil Steril. 2000;  73 (1) 1-14
  • 12 Miyakis S, Lockshin M D, Atsumi T et al.. International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome (APS).  J Thromb Haemost. 2006;  4 (2) 295-306
  • 13 Ziakas P D, Pavlou M, Voulgarelis M. Heparin treatment in antiphospholipid syndrome with recurrent pregnancy loss: a systematic review and meta-analysis.  Obstet Gynecol. 2010;  115 (6) 1256-1262
  • 14 Glinoer D. The regulation of thyroid function in pregnancy: pathways of endocrine adaptation from physiology to pathology.  Endocr Rev. 1997;  18 (3) 404-433
  • 15 Benhadi N, Wiersinga W M, Reitsma J B, Vrijkotte T G, Bonsel G J. Higher maternal TSH levels in pregnancy are associated with increased risk for miscarriage, fetal or neonatal death.  Eur J Endocrinol. 2009;  160 (6) 985-991
  • 16 Poppe K, Velkeniers B, Glinoer D. Thyroid disease and female reproduction.  Clin Endocrinol (Oxf). 2007;  66 (3) 309-321
  • 17 Glinoer D. Thyroidal and immune adaptation to pregnancy: focus on maternal hypo- and hyperthyroidism. In: Lazarus J Pirags V Butz S eds. The Thyroid and Reproduction. New York, NY: Thieme; 2009: 46-58
  • 18 Hollowell J G, Staehling N W, Flanders W D et al.. Serum TSH, T(4), and thyroid antibodies in the United States population (1988 to 1994): National Health and Nutrition Examination Survey (NHANES III).  J Clin Endocrinol Metab. 2002;  87 (2) 489-499
  • 19 Billingham R E, Brent L, Medawar P B. Actively acquired tolerance of foreign cells.  Nature. 1953;  172 (4379) 603-606
  • 20 Anjum N, Baker P N, Robinson N J, Aplin J D. Maternal celiac disease autoantibodies bind directly to syncytiotrophoblast and inhibit placental tissue transglutaminase activity.  Reprod Biol Endocrinol. 2009;  7 16
  • 21 Stagnaro-Green A, Roman S H, Cobin R H, el-Harazy E, Alvarez-Marfany M, Davies T F. Detection of at-risk pregnancy by means of highly sensitive assays for thyroid autoantibodies.  JAMA. 1990;  264 (11) 1422-1425
  • 22 Bussen S, Steck T. Thyroid autoantibodies in euthyroid non-pregnant women with recurrent spontaneous abortions.  Hum Reprod. 1995;  10 (11) 2938-2940
  • 23 Glinoer D, Soto M F, Bourdoux P et al.. Pregnancy in patients with mild thyroid abnormalities: maternal and neonatal repercussions.  J Clin Endocrinol Metab. 1991;  73 (2) 421-427
  • 24 Kutteh W H, Yetman D L, Carr A C, Beck L A, Scott Jr R T. Increased prevalence of antithyroid antibodies identified in women with recurrent pregnancy loss but not in women undergoing assisted reproduction.  Fertil Steril. 1999;  71 (5) 843-848
  • 25 Pratt D, Novotny M, Kaberlein G, Dudkiewicz A, Gleicher N. Antithyroid antibodies and the association with non-organ-specific antibodies in recurrent pregnancy loss.  Am J Obstet Gynecol. 1993;  168 (3 Pt 1) 837-841
  • 26 Singh A, Dantas Z N, Stone S C, Asch R H. Presence of thyroid antibodies in early reproductive failure: biochemical versus clinical pregnancies.  Fertil Steril. 1995;  63 (2) 277-281
  • 27 Esplin M S, Branch D W, Silver R, Stagnaro-Green A. Thyroid autoantibodies are not associated with recurrent pregnancy loss.  Am J Obstet Gynecol. 1998;  179 (6 Pt 1) 1583-1586
  • 28 Rushworth F H, Backos M, Rai R, Chilcott I T, Baxter N, Regan L. Prospective pregnancy outcome in untreated recurrent miscarriers with thyroid autoantibodies.  Hum Reprod. 2000;  15 (7) 1637-1639
  • 29 Kaprara A, Krassas G E. Thyroid autoimmunity and miscarriage.  Hormones (Athens). 2008;  7 (4) 294-302
  • 30 Matalon S T, Blank M, Ornoy A, Shoenfeld Y. The association between anti-thyroid antibodies and pregnancy loss.  Am J Reprod Immunol. 2001;  45 (2) 72-77
  • 31 Lee Y L, Ng H P, Lau K S et al.. Increased fetal abortion rate in autoimmune thyroid disease is related to circulating TPO autoantibodies in an autoimmune thyroiditis animal model.  Fertil Steril. 2009;  91 (5, Suppl) 2104-2109
  • 32 Imaizumi M, Pritsker A, Kita M, Ahmad L, Unger P, Davies T F. Non-MHC driven exacerbation of experimental thyroiditis in the postpartum period.  Autoimmunity. 2001;  34 (2) 95-105
  • 33 Iijima T, Tada H, Hidaka Y, Mitsuda N, Murata Y, Amino N. Effects of autoantibodies on the course of pregnancy and fetal growth.  Obstet Gynecol. 1997;  90 (3) 364-369
  • 34 Krassas G E, Poppe K, Glinoer D. Thyroid function and human reproductive health.  Endocr Rev. 2010;  31 (5) 702-755
  • 35 Negro R, Schwartz A, Gismondi R, Tinelli A, Mangieri T, Stagnaro-Green A. Increased pregnancy loss rate in thyroid antibody negative women with TSH levels between 2.5 and 5.0 in the first trimester of pregnancy.  J Clin Endocrinol Metab. 2010;  95 (9) E44-E48
  • 36 De Vivo A, Mancuso A, Giacobbe A et al.. Thyroid function in women found to have early pregnancy loss.  Thyroid. 2010;  20 (6) 633-637
  • 37 Smyth P P, Wijeyaratne C N, Kaluarachi W N et al.. Sequential studies on thyroid antibodies during pregnancy.  Thyroid. 2005;  15 (5) 474-477
  • 38 Abalovich M, Gutierrez S, Alcaraz G, Maccallini G, Garcia A, Levalle O. Overt and subclinical hypothyroidism complicating pregnancy.  Thyroid. 2002;  12 (1) 63-68
  • 39 Bussen S, Steck T, Dietl J. Increased prevalence of thyroid antibodies in euthyroid women with a history of recurrent in-vitro fertilization failure.  Hum Reprod. 2000;  15 (3) 545-548
  • 40 Negro R, Formoso G, Mangieri T, Pezzarossa A, Dazzi D, Hassan H. Levothyroxine treatment in euthyroid pregnant women with autoimmune thyroid disease: effects on obstetrical complications.  J Clin Endocrinol Metab. 2006;  91 (7) 2587-2591
  • 41 Vaquero E, Lazzarin N, De Carolis C, Valensise H, Moretti C, Ramanini C. Mild thyroid abnormalities and recurrent spontaneous abortion: diagnostic and therapeutical approach.  Am J Reprod Immunol. 2000;  43 (4) 204-208
  • 42 Reid S M, Middleton P, Cossich M C, Crowther C A. Interventions for clinical and subclinical hypothyroidism in pregnancy.  Cochrane Database Syst Rev. 2010;  (7) CD007752
  • 43 Alexander E K, Marqusee E, Lawrence J, Jarolim P, Fischer G A, Larsen P R. Timing and magnitude of increases in levothyroxine requirements during pregnancy in women with hypothyroidism.  N Engl J Med. 2004;  351 (3) 241-249
  • 44 Glinoer D. Thyroid immunity, thyroid dysfunction, and the risk of miscarriage: à propos article by Vaquero et al. Mild thyroid abnormalities and recurrent spontaneous abortion: diagnostic and therapeutical approach.  Am J Reprod Immunol. 2000;  43 (4) 202-203
  • 45 Glinoer D, Delange F. The potential repercussions of maternal, fetal, and neonatal hypothyroxinemia on the progeny.  Thyroid. 2000;  10 (10) 871-887
  • 46 Mandel S J, Larsen P R, Seely E W, Brent G A. Increased need for thyroxine during pregnancy in women with primary hypothyroidism.  N Engl J Med. 1990;  323 (2) 91-96
  • 47 Valbuena D, Jasper M, Remohí J, Pellicer A, Simón C. Ovarian stimulation and endometrial receptivity.  Hum Reprod. 1999;  14 (Suppl 2) 107-111
  • 48 Csapo A I, Pulkkinen M O, Wiest W G. Effects of luteectomy and progesterone replacement therapy in early pregnant patients.  Am J Obstet Gynecol. 1973;  115 (6) 759-765
  • 49 Jones G S. The luteal phase defect.  Fertil Steril. 1976;  27 (4) 351-356
  • 50 Arredondo F, Noble L S. Endocrinology of recurrent pregnancy loss.  Semin Reprod Med. 2006;  24 (1) 33-39
  • 51 Horta J L, Fernández J G, de León B S, Cortés-Gallegos V. Direct evidence of luteal insufficiency in women with habitual abortion.  Obstet Gynecol. 1977;  49 (6) 705-708
  • 52 Serle E, Aplin J D, Li T C et al.. Endometrial differentiation in the peri-implantation phase of women with recurrent miscarriage: a morphological and immunohistochemical study.  Fertil Steril. 1994;  62 (5) 989-996
  • 53 Li T C, Spuijbroek M D, Tuckerman E, Anstie B, Loxley M, Laird S. Endocrinological and endometrial factors in recurrent miscarriage.  BJOG. 2000;  107 (12) 1471-1479
  • 54 Tulppala M, Björses U M, Stenman U H, Wahlström T, Ylikorkala O. Luteal phase defect in habitual abortion: progesterone in saliva.  Fertil Steril. 1991;  56 (1) 41-44
  • 55 Noyes R W, Hertig A T, Rock J. Dating the endometrial biopsy.  Am J Obstet Gynecol. 1975;  122 (2) 262-263
  • 56 Duggan M A, Brashert P, Ostor A et al.. The accuracy and interobserver reproducibility of endometrial dating.  Pathology. 2001;  33 (3) 292-297
  • 57 Scott R T, Snyder R R, Strickland D M et al.. The effect of interobserver variation in dating endometrial histology on the diagnosis of luteal phase defects.  Fertil Steril. 1988;  50 (6) 888-892
  • 58 Daya S. Efficacy of progesterone support for pregnancy in women with recurrent miscarriage. A meta-analysis of controlled trials.  Br J Obstet Gynaecol. 1989;  96 (3) 275-280
  • 59 Scott R T, Snyder R R, Bagnall J W, Reed K D, Adair C F, Hensley S D. Evaluation of the impact of intraobserver variability on endometrial dating and the diagnosis of luteal phase defects.  Fertil Steril. 1993;  60 (4) 652-657
  • 60 Gibson M, Badger G J, Byrn F, Lee K R, Korson R, Trainer T D. Error in histologic dating of secretory endometrium: variance component analysis.  Fertil Steril. 1991;  56 (2) 242-247
  • 61 Smith S, Hosid S, Scott L. Endometrial biopsy dating. Interobserver variation and its impact on clinical practice.  J Reprod Med. 1995;  40 (1) 1-3
  • 62 Coutifaris C, Myers E R, Guzick D S NICHD National Cooperative Reproductive Medicine Network et al. Histological dating of timed endometrial biopsy tissue is not related to fertility status.  Fertil Steril. 2004;  82 (5) 1264-1272
  • 63 Sherman B M, Korenman S G. Measurement of plasma LH, FSH, estradiol and progesterone in disorders of the human menstrual cycle: the short luteal phase.  J Clin Endocrinol Metab. 1974;  38 (1) 89-93
  • 64 Harrison R F. Human chorionic gonadotrophin (hCG) in the management of recurrent abortion; results of a multi-centre placebo-controlled study.  Eur J Obstet Gynecol Reprod Biol. 1992;  47 (3) 175-179
  • 65 Li T C, Tuckerman E M, Laird S M. Endometrial factors in recurrent miscarriage.  Hum Reprod Update. 2002;  8 (1) 43-52
  • 66 Haas D M, Ramsey P S. Progestogen for preventing miscarriage.  Cochrane Database Syst Rev. 2008;  (2) CD003511
  • 67 Glueck C J, Wang P, Goldenberg N, Sieve-Smith L. Pregnancy outcomes among women with polycystic ovary syndrome treated with metformin.  Hum Reprod. 2002;  17 (11) 2858-2864
  • 68 Janssen O E, Mehlmauer N, Hahn S, Offner A H, Gärtner R. High prevalence of autoimmune thyroiditis in patients with polycystic ovary syndrome.  Eur J Endocrinol. 2004;  150 (3) 363-369
  • 69 Dorman J S, Burke J P, McCarthy B J et al.. Temporal trends in spontaneous abortion associated with type 1 diabetes.  Diabetes Res Clin Pract. 1999;  43 (1) 41-47
  • 70 Mills J L, Simpson J L, Driscoll S G et al.. Incidence of spontaneous abortion among normal women and insulin-dependent diabetic women whose pregnancies were identified within 21 days of conception.  N Engl J Med. 1988;  319 (25) 1617-1623
  • 71 Cocksedge K A, Li T C, Saravelos S H, Metwally M. A reappraisal of the role of polycystic ovary syndrome in recurrent miscarriage.  Reprod Biomed Online. 2008;  17 (1) 151-160
  • 72 Craig L B, Ke R W, Kutteh W H. Increased prevalence of insulin resistance in women with a history of recurrent pregnancy loss.  Fertil Steril. 2002;  78 (3) 487-490
  • 73 Glueck C J, Phillips H, Cameron D, Sieve-Smith L, Wang P. Continuing metformin throughout pregnancy in women with polycystic ovary syndrome appears to safely reduce first-trimester spontaneous abortion: a pilot study.  Fertil Steril. 2001;  75 (1) 46-52
  • 74 Jakubowicz D J, Iuorno M J, Jakubowicz S, Roberts K A, Nestler J E. Effects of metformin on early pregnancy loss in the polycystic ovary syndrome.  J Clin Endocrinol Metab. 2002;  87 (2) 524-529
  • 75 Sills E S, Perloe M, Palermo G D. Correction of hyperinsulinemia in oligoovulatory women with clomiphene-resistant polycystic ovary syndrome: a review of therapeutic rationale and reproductive outcomes.  Eur J Obstet Gynecol Reprod Biol. 2000;  91 (2) 135-141
  • 76 Zolghadri J, Tavana Z, Kazerooni T, Soveid M, Taghieh M. Relationship between abnormal glucose tolerance test and history of previous recurrent miscarriages, and beneficial effect of metformin in these patients: a prospective clinical study.  Fertil Steril. 2008;  90 (3) 727-730
  • 77 Legro R S, Barnhart H X, Schlaff W D Cooperative Multicenter Reproductive Medicine Network et al. Clomiphene, metformin, or both for infertility in the polycystic ovary syndrome.  N Engl J Med. 2007;  356 (6) 551-566
  • 78 Moll E, Bossuyt P M, Korevaar J C, Lambalk C B, van der Veen F. Effect of clomifene citrate plus metformin and clomifene citrate plus placebo on induction of ovulation in women with newly diagnosed polycystic ovary syndrome: randomised double blind clinical trial.  BMJ. 2006;  332 (7556) 1485
  • 79 Palomba S, Orio Jr F, Falbo A, Russo T, Tolino A, Zullo F. Plasminogen activator inhibitor 1 and miscarriage after metformin treatment and laparoscopic ovarian drilling in patients with polycystic ovary syndrome.  Fertil Steril. 2005;  84 (3) 761-765
  • 80 Glueck C J, Wang P, Fontaine R N, Sieve-Smith L, Tracy T, Moore S K. Plasminogen activator inhibitor activity: an independent risk factor for the high miscarriage rate during pregnancy in women with polycystic ovary syndrome.  Metabolism. 1999;  48 (12) 1589-1595
  • 81 Glueck C J, Goldenberg N, Pranikoff J, Loftspring M, Sieve L, Wang P. Height, weight, and motor-social development during the first 18 months of life in 126 infants born to 109 mothers with polycystic ovary syndrome who conceived on and continued metformin through pregnancy.  Hum Reprod. 2004;  19 (6) 1323-1330
  • 82 Conway G S, Jacobs H S, Holly J M, Wass J A. Effects of luteinizing hormone, insulin, insulin-like growth factor-I and insulin-like growth factor small binding protein 1 in the polycystic ovary syndrome.  Clin Endocrinol (Oxf). 1990;  33 (5) 593-603
  • 83 Liddell H S, Sowden K, Farquhar C M. Recurrent miscarriage: screening for polycystic ovaries and subsequent pregnancy outcome.  Aust N Z J Obstet Gynaecol. 1997;  37 (4) 402-406
  • 84 Rai R, Backos M, Rushworth F, Regan L. Polycystic ovaries and recurrent miscarriage—a reappraisal.  Hum Reprod. 2000;  15 (3) 612-615
  • 85 Okon M A, Laird S M, Tuckerman E M, Li T C. Serum androgen levels in women who have recurrent miscarriages and their correlation with markers of endometrial function.  Fertil Steril. 1998;  69 (4) 682-690
  • 86 van Wely M, Bayram N, van der Veen F, Bossuyt P M. Predicting ongoing pregnancy following ovulation induction with recombinant FSH in women with polycystic ovary syndrome.  Hum Reprod. 2005;  20 (7) 1827-1832
  • 87 Metwally M, Ong K J, Ledger W L, Li T C. Does high body mass index increase the risk of miscarriage after spontaneous and assisted conception? A meta-analysis of the evidence.  Fertil Steril. 2008;  90 (3) 714-726
  • 88 Lashen H, Fear K, Sturdee D W. Obesity is associated with increased risk of first trimester and recurrent miscarriage: matched case-control study.  Hum Reprod. 2004;  19 (7) 1644-1646
  • 89 Al-Azemi M, Omu F E, Omu A E. The effect of obesity on the outcome of infertility management in women with polycystic ovary syndrome.  Arch Gynecol Obstet. 2004;  270 (4) 205-210
  • 90 Hamilton-Fairley D, Kiddy D, Watson H, Paterson C, Franks S. Association of moderate obesity with a poor pregnancy outcome in women with polycystic ovary syndrome treated with low dose gonadotrophin.  Br J Obstet Gynaecol. 1992;  99 (2) 128-131
  • 91 Clark A M, Ledger W, Galletly C et al.. Weight loss results in significant improvement in pregnancy and ovulation rates in anovulatory obese women.  Hum Reprod. 1995;  10 (10) 2705-2712
  • 92 Rotterdam ESHRE/ASRM-Sponsored PCOS Consensus Workshop Group . Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome.  Fertil Steril. 2004;  81 (1) 19-25
  • 93 Zawadski J K, Dunaif A. Diagnostic criteria for polycystic ovary syndrome: towards a rational approach. In:, Dunaif A, Givens J R, Haseltine F P, Merriam G R, eds. Polycystic Ovary Syndrome. Boston, MA: Blackwell Scientific; 1992: 377-384

Danny J. SchustM.D. 

Department of Obstetrics, Gynecology and Women's Health, University of Missouri School of Medicine

500 North Keene Street, Suite 203, Columbia, MO 65201

Email: schustd@health.missouri.edu

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