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DOI: 10.1055/s-0031-1293202
Endocrinology and Recurrent Early Pregnancy Loss
Publikationsverlauf
Publikationsdatum:
08. Dezember 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.
KEYWORDS
Thyroid autoantibodies - polycystic ovarian syndrome - luteal phase defect - recurrent pregnancy loss
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
MissingFormLabel
- 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
MissingFormLabel
- 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
MissingFormLabel
- 4
Rai R, Regan L.
Recurrent miscarriage.
Lancet.
2006;
368
(9535)
601-611
MissingFormLabel
- 5
Suzumori N, Sugiura-Ogasawara M.
Genetic factors as a cause of miscarriage.
Curr Med Chem.
2010;
17
(29)
3431-3437
MissingFormLabel
- 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
MissingFormLabel
- 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
MissingFormLabel
- 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
MissingFormLabel
- 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
MissingFormLabel
- 10
Propst A M, Hill III J A.
Anatomic factors associated with recurrent pregnancy loss.
Semin Reprod Med.
2000;
18
(4)
341-350
MissingFormLabel
- 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
MissingFormLabel
- 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
MissingFormLabel
- 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
MissingFormLabel
- 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
MissingFormLabel
- 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
MissingFormLabel
- 16
Poppe K, Velkeniers B, Glinoer D.
Thyroid disease and female reproduction.
Clin Endocrinol (Oxf).
2007;
66
(3)
309-321
MissingFormLabel
- 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
MissingFormLabel
- 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
MissingFormLabel
- 19
Billingham R E, Brent L, Medawar P B.
Actively acquired tolerance of foreign cells.
Nature.
1953;
172
(4379)
603-606
MissingFormLabel
- 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
MissingFormLabel
- 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
MissingFormLabel
- 22
Bussen S, Steck T.
Thyroid autoantibodies in euthyroid non-pregnant women with recurrent spontaneous
abortions.
Hum Reprod.
1995;
10
(11)
2938-2940
MissingFormLabel
- 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
MissingFormLabel
- 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
MissingFormLabel
- 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
MissingFormLabel
- 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
MissingFormLabel
- 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
MissingFormLabel
- 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
MissingFormLabel
- 29
Kaprara A, Krassas G E.
Thyroid autoimmunity and miscarriage.
Hormones (Athens).
2008;
7
(4)
294-302
MissingFormLabel
- 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
MissingFormLabel
- 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
MissingFormLabel
- 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
MissingFormLabel
- 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
MissingFormLabel
- 34
Krassas G E, Poppe K, Glinoer D.
Thyroid function and human reproductive health.
Endocr Rev.
2010;
31
(5)
702-755
MissingFormLabel
- 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
MissingFormLabel
- 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
MissingFormLabel
- 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
MissingFormLabel
- 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
MissingFormLabel
- 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
MissingFormLabel
- 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
MissingFormLabel
- 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
MissingFormLabel
- 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
MissingFormLabel
- 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
MissingFormLabel
- 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
MissingFormLabel
- 45
Glinoer D, Delange F.
The potential repercussions of maternal, fetal, and neonatal hypothyroxinemia on the
progeny.
Thyroid.
2000;
10
(10)
871-887
MissingFormLabel
- 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
MissingFormLabel
- 47
Valbuena D, Jasper M, Remohí J, Pellicer A, Simón C.
Ovarian stimulation and endometrial receptivity.
Hum Reprod.
1999;
14
(Suppl 2)
107-111
MissingFormLabel
- 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
MissingFormLabel
- 49
Jones G S.
The luteal phase defect.
Fertil Steril.
1976;
27
(4)
351-356
MissingFormLabel
- 50
Arredondo F, Noble L S.
Endocrinology of recurrent pregnancy loss.
Semin Reprod Med.
2006;
24
(1)
33-39
MissingFormLabel
- 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
MissingFormLabel
- 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
MissingFormLabel
- 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
MissingFormLabel
- 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
MissingFormLabel
- 55
Noyes R W, Hertig A T, Rock J.
Dating the endometrial biopsy.
Am J Obstet Gynecol.
1975;
122
(2)
262-263
MissingFormLabel
- 56
Duggan M A, Brashert P, Ostor A et al..
The accuracy and interobserver reproducibility of endometrial dating.
Pathology.
2001;
33
(3)
292-297
MissingFormLabel
- 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
MissingFormLabel
- 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
MissingFormLabel
- 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
MissingFormLabel
- 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
MissingFormLabel
- 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
MissingFormLabel
- 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
MissingFormLabel
- 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
MissingFormLabel
- 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
MissingFormLabel
- 65
Li T C, Tuckerman E M, Laird S M.
Endometrial factors in recurrent miscarriage.
Hum Reprod Update.
2002;
8
(1)
43-52
MissingFormLabel
- 66
Haas D M, Ramsey P S.
Progestogen for preventing miscarriage.
Cochrane Database Syst Rev.
2008;
(2)
CD003511
MissingFormLabel
- 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
MissingFormLabel
- 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
MissingFormLabel
- 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
MissingFormLabel
- 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
MissingFormLabel
- 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
MissingFormLabel
- 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
MissingFormLabel
- 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
MissingFormLabel
- 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
MissingFormLabel
- 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
MissingFormLabel
- 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
MissingFormLabel
- 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
MissingFormLabel
- 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
MissingFormLabel
- 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
MissingFormLabel
- 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
MissingFormLabel
- 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
MissingFormLabel
- 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
MissingFormLabel
- 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
MissingFormLabel
- 84
Rai R, Backos M, Rushworth F, Regan L.
Polycystic ovaries and recurrent miscarriage—a reappraisal.
Hum Reprod.
2000;
15
(3)
612-615
MissingFormLabel
- 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
MissingFormLabel
- 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
MissingFormLabel
- 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
MissingFormLabel
- 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
MissingFormLabel
- 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
MissingFormLabel
- 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
MissingFormLabel
- 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
MissingFormLabel
- 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
MissingFormLabel
- 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
MissingFormLabel
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