RISK OF INFERTILITY IN PATIENTS WITH CELIAC DISEASE: a meta-analysis of observational studies

LASA, Juan Sebastian; ZUBIAURRE, Ignacio; SOIFER, Luis Oscar

doi:10.1590/S0004-28032014000200014

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Original Articles • Arq. Gastroenterol. 51 (2) • Apr-Jun 2014 • https://doi.org/10.1590/S0004-28032014000200014 copy

RISK OF INFERTILITY IN PATIENTS WITH CELIAC DISEASE: a meta-analysis of observational studies

Risco de infertilidade em pacientes com doença celíaca: uma meta-análise de estudos observacionais

Authorship SCIMAGO INSTITUTIONS RANKINGS

Context

Celiac disease is an autoimmune disorder of the small intestine associated with several extra-intestinal features, such as reproductive disorders. The relationship between celiac disease and infertility has been previously assessed, with conflicting results.

Objectives

We seek to determine the relationship between celiac disease and infertility.

Methods

Data was extracted from case-control or cohort design studies from 1966 to December 2013 using the MEDLINE-Pubmed, EMBASE, LILACS and Cochrane Library databases. We analyzed two kinds of trials: those assessing the risk of infertility in subjects with already diagnosed celiac disease, and those evaluating the prevalence of undiagnosed celiac disease in subjects with a diagnosis of infertility.

Results

The search yielded 413 potentially relevant studies for revision, 12 of which were finally included for analysis. A significant association was found between women with a diagnosis of infertility and undiagnosed celiac disease [OR 3.09 (95% CI 1.74-5.49)]. When considering those studies assessing the occurrence of infertility in subjects with already-diagnosed celiac disease, no difference was found between celiac disease patients and control subjects [OR 0.99 (0.86-1.13)].

Conclusions

Undiagnosed celiac disease is a risk factor for infertility. Women seeking medical advice for this particular condition should be screened for celiac disease. Adoption of a gluten-free diet could have a positive impact on fertility in this group of patients.

Celiac disease; Infertility female; Diet gluten-free

Author	Location	Subjects	Controls	Type of infertility assessed	Celiac disease definition	Outcomes

CASE-CONTROL AND CROSS SECTIONAL STUDIES

Molteni et al.⁽²¹21. Molteni N, Bardella MT, Bianchi PA. Obstetric and gynecological problems in women with untreated celiac sprue. J Clin Gastroenterol. 1990;12:37-9.⁾	Italy	38 newly diagnosed celiac disease women with normal sexual life without contraceptive method	38 women from hospital staff or IBS outpatients, matched for age, origin and sexual behavior	Not clearly stated	Jejunal biopsy and GFD response	Infertility in CD Group = 4/38 (10.52%); Infertility in control Group = 3/38 (7.89%)
Sher et al.⁽²⁴24. Shamaly H, Mahameed A, Sharony A, Shamir R. Infertility and celiac disease: do we need more than one serological marker? Acta Obstet Gynecol Scand. 2004;83:1184-8.⁾	United Kingdom	68 celiac disease women from previously performed epidemiologic study	68 sex and age- matched, healthy individuals from the same community (one described source= patients’ relatives)	Not clearly stated	Not clearly stated	Infertility in CD Group = 11/68 (16.17%); Infertility in control Group = 1/68 (1.47%) (subject to recall bias)
Collin et al.⁽⁴4. Collin P, Vilska S, Heinonen PK, Hallstrom O, Pikkarainen P. Infertility and coeliac disease. Gut. 1996;39:382-4.⁾	Finland	150 women evaluated for infertility; 50 women with ≥2 abortions [mean age 31 (22-42)]	150 women w/normal obstetric history undergoing sterilization	All kind;98 (65.3%) unexplained (UI)	Screening w/IgA AG+antireticulin; confirmed by biopsy	CD in infertility Group = 4/150 (2.7%); 4/4 UI (4.1%); CD in control Group = 0/150
Kohlo et al.⁽¹⁵15. Kolho KL, Tiitinen A, Tulppala M, Unkila-Kallio L, Savilahti E. Screening for coeliac disease in women with a history of recurrent miscarriage or infertility. Br J Obst Gynaecol. 1999;106:171-3.⁾	Finland	129 women evaluated at the department of obstetrics and gynecology	51 apparently healthy women working at hospital	All kind; 47 (36.43%) UI	IgA AE (not confirmed by biopsy)	CD in infertility Group = 1/129 (0.77%); 1/1 UI (1/47=2.12%); CD in control Group = 1/51 (1.96%)
Shamaly et al.⁽²³23. Reilly NR, Fasano A, Green PH. Presentation of celiac disease. Gastrointest Endosc Clin N Am. 2012;22:613-21.⁾	Israel	192 women attending infertility clinic (age range 18-44)	210 women attending pediatric clinic (age range 18-44)	UI	IgA AtTG; IgA AE; confirmation by biopsy	CD in infertility Group = 5/192 (2.6%); CD in control Group = 1/210 (0.48%)
Tiboni et al.⁽²⁹29. Tata LJ, Card TR, Logan RFA, Hubbard RB, Smith CJP, West J. Fertility and pregnancy-related events in women with celiac disease: a population-based cohort study. Gastroenterology. 2005;128:849-55.⁾	Italy	200 women undergoing ART (mean age 35±5)	200 apparent healthy women with at least 1 child	All kind; 26.5% UI	Screening w/IgA AtTG+ IgA AE; confirmation by biopsy	CD in infertility Group = 5/200 (2.5%); 0/5 UI. CD in control Group = 2/200 (1%)
da Silva Martins et al.⁽⁶6. Da Silva Martins CL, Gandolfi L, Tauil PL, de Almeida Rocha Picanco M, Galvao de Araujo MO, Pratesi R. Celiac disease and female infertility: a frequently neglected association. Rev Bras Ginecol Obstet. 2006;28:601-6.⁾	Brazil	200 women attending hospital due to infertility	400 women attending hospital for other reason than infertility	All kind	Screening w/ IgA AE; confirmation by biopsy	CD in infertility Group = 3/200 (1.5%); CD in control Group = 0/400
Kumar et al.⁽¹⁶16. Kumar A, Meena M, Begum N, Kumar N, Gupta RK, Agarwal S, et al. Latent celiac disease in reproductive perfomance of women. Fertil Steril. 2011;95:922-7.⁾	India	230 women attending infertility clinic (mean age 29.7±4)	305 women w/ normal obstetric history	UI	IgA/IgG AG; IgA AtTG+ IgA AE	CD in infertility Group = 13/230 (5.6%); CD in control Group = 4/305 (1.3%)
Khoshbaten et al.⁽¹⁴14. Khoshbaten M, Nejad MR, Farzady L, Sharifi N, Hashemi SH, Rostami K. Fertility disorder associated with celiac disease in males and females: fact or fiction? J Obstet Gynael Res. 2011;37:1308-12.⁾	Azerbaijan	100 women attending infertility clinic (w/male Partners) (mean age 29±6)	200 apparently healthy couples with at least 1 birth	UI	IgA AtTG (confirmed by biopsy)	CD in infertility Group = 8/100 (8%); CD in control Group = 7/200 (3.5%); CD in male Partners = 5/100 (5%); CD in male controls = 4/200 (2%)
Hogen Ersch et al.⁽¹²12. Hogen Esch CE, Van Rijssen MJL, Roos A, Koning F, Dekker FW, Mearin ML, et al. Screening for unrecognized coeliac disease in subfertile couples. Scand J Gastroenterol. 2011;46:1423-8.⁾	Netherlands	1038 women attending to infertility clinic (mean age 32.3; range20-45) (w/male Partners)	1432 healthy community adults (716 female)	All kind; 34% UI	IgA AtTG; IgA AE (endoscopy not offered)	CD in infertility Group = 6/1038 (0.58%); CD in UI = 2/351 (0.57%); CD in control. Group = 2/716 (0.28%); CD in male Partners = 4/1038 (0.39%); CD in male controls = 3/716 (0.42%)

COHORT STUDIES

Tata et al.⁽²⁸28. Stroup DF, Berlin JA, Morton SC, Olkin I, Williamson GD, Rennie D, et al. Meta-analysis of observational studies in epidemiology: a proposal for reporting. JAMA. 2000;283:2008-12.⁾	United Kingdom	1521 celiac women in fertile age (18-44 y)between 1987-2002	7732 women without CD matched by age, sex, general practice and follow-up time	Not applicable	Records from GPRD (criteria not specified)	Births in CD Group = 341 (median follow-up = 4.3y); births in control Group = 1903 (median follow-up = 4.9y); HR 1.01 (95% CI0.91-1.14)
Zugna et al.⁽³⁰30. Tiboni GM, de Vita MG, Faricelli R, Giampietro F, Liberati M. Serological testing for celiac diseasein women undergoingassisted reproduction techniques. Hum Reprod. 2006;21:376-9.⁾	Sweden	11495 celiac women born between 1920-1990	51109 women without CD matched by age, sex, calendar period and county of residence	Not applicable	Swedish regional biopsy data	Births in CD Group = 6870; HR 1.04 (95%CI 1.01-1.07)

Author	Case definition adequate?	Representativeness of cases	Selection of controls	Definition of controls	Comparability of cases and controls	Ascertainment of exposure	Same method of ascertainment	Non-response rate

CASE-CONTROL AND CROSS SECTIONAL STUDIES

Molteni et al.⁽²¹21. Molteni N, Bardella MT, Bianchi PA. Obstetric and gynecological problems in women with untreated celiac sprue. J Clin Gastroenterol. 1990;12:37-9.⁾	Yes	Consecutive series	Hospital and community controls	No history of disease	Sex, age and origin adjustment	Questionnaire	Yes	Not stated
Sher et al.⁽²⁴24. Shamaly H, Mahameed A, Sharony A, Shamir R. Infertility and celiac disease: do we need more than one serological marker? Acta Obstet Gynecol Scand. 2004;83:1184-8.⁾	Not clear	Consecutive series	Community (cases’ friends or relatives enrolled)	No history of disease	Sex and age adjustment	Questionnaire	Yes	67% response rate in cases; 66% in controls
Collin et al.⁽⁴4. Collin P, Vilska S, Heinonen PK, Hallstrom O, Pikkarainen P. Infertility and coeliac disease. Gut. 1996;39:382-4.⁾	Yes	Consecutive series	Hospital controls	No history of disease	No adjustment	Laboratory+ biopsy when + ve screening	Yes	Not stated
Kohlo et al.⁽¹⁵15. Kolho KL, Tiitinen A, Tulppala M, Unkila-Kallio L, Savilahti E. Screening for coeliac disease in women with a history of recurrent miscarriage or infertility. Br J Obst Gynaecol. 1999;106:171-3.⁾	Yes	Consecutive series	Hospital controls	No history of disease	No adjustment	Laboratory	Yes	Not stated
Shamaly et al.⁽²³23. Reilly NR, Fasano A, Green PH. Presentation of celiac disease. Gastrointest Endosc Clin N Am. 2012;22:613-21.⁾	Yes	Consecutive series	Hospital controls	No history of disease	Age and sex adjustment	Laboratory+ biopsy when + ve screening	Yes	Not stated
Tiboni et al.⁽²⁹29. Tata LJ, Card TR, Logan RFA, Hubbard RB, Smith CJP, West J. Fertility and pregnancy-related events in women with celiac disease: a population-based cohort study. Gastroenterology. 2005;128:849-55.⁾	Yes	Consecutive series	Hospital controls	No history of disease	No adjustment	Laboratory+ biopsy when + ve screening	Yes	Not stated
da Silva Martins et al.⁽⁶6. Da Silva Martins CL, Gandolfi L, Tauil PL, de Almeida Rocha Picanco M, Galvao de Araujo MO, Pratesi R. Celiac disease and female infertility: a frequently neglected association. Rev Bras Ginecol Obstet. 2006;28:601-6.⁾	Yes	Consecutive series	Hospital controls	No history of disease	Age and sex adjustment	Laboratory + biopsy when + ve screening	Yes	Not stated
Kumar et al.⁽¹⁶16. Kumar A, Meena M, Begum N, Kumar N, Gupta RK, Agarwal S, et al. Latent celiac disease in reproductive perfomance of women. Fertil Steril. 2011;95:922-7.⁾	Yes	Consecutive series	Hospital controls	No history of disease	No adjustment	Laboratory	Yes	Not stated
Khoshbaten et al.⁽¹⁴17. Machado AP, Silva LR, Zausner B, Oliveira J de A, Diniz DR, de Oliveira J. Undiagnosed celiac disease in women with infertility. J Reprod Med. 2013;58:61-6.⁾	Yes	Consecutive series	Hospital controls	No history of disease	No adjustment	Laboratory+ biopsy when + ve screening	Yes	Not stated
Hogen Ersch et al.⁽¹²12. Hogen Esch CE, Van Rijssen MJL, Roos A, Koning F, Dekker FW, Mearin ML, et al. Screening for unrecognized coeliac disease in subfertile couples. Scand J Gastroenterol. 2011;46:1423-8.⁾	Yes	Consecutive series	Community	Not stated	No adjustment	Laboratory	Yes	Not stated

COHORT STUDIES

	Representativeness of exposed cohort	Unexposed cohort	Ascertainment of exposure	Demonstration that outcome was not present at the start of study	Comparability of cohorts	Assessment of outcome	Was follow-up long enough?	Adequacy of follow-up
Tata et al.⁽²⁸28. Stroup DF, Berlin JA, Morton SC, Olkin I, Williamson GD, Rennie D, et al. Meta-analysis of observational studies in epidemiology: a proposal for reporting. JAMA. 2000;283:2008-12.⁾	Representative	Same community	Not clear if biopsy was required	Yes	Adjusted for age, sex, general practice and follow-up time	Record linkage	Yes	Not applicable
Zugna et al.⁽³⁰30. Tiboni GM, de Vita MG, Faricelli R, Giampietro F, Liberati M. Serological testing for celiac diseasein women undergoingassisted reproduction techniques. Hum Reprod. 2006;21:376-9.⁾	Representative	Same community	Adequate (biopsy database)	Yes	Adjusted for age, sex, calendar period and county of residence	Record linkage	Yes	Not applicable

	Infertility		Control			Odds Ratio		Odds Ratio
Study or Subgroup	Events	Total	Events	Total	Weight	M-H, Random, 95% CI	Year	M-H, Random, 95% CI
Collin et al.⁽⁴4. Collin P, Vilska S, Heinonen PK, Hallstrom O, Pikkarainen P. Infertility and coeliac disease. Gut. 1996;39:382-4.⁾	4	150	0	150	3.9%	9.25 [0.49, 173.25]	1996
Collin et al.⁽⁴4. Collin P, Vilska S, Heinonen PK, Hallstrom O, Pikkarainen P. Infertility and coeliac disease. Gut. 1996;39:382-4.⁾	4	150	0	150	3.9%	9.25 [0.49, 173.25]	1996
Kohlo et al.⁽¹⁵15. Kolho KL, Tiitinen A, Tulppala M, Unkila-Kallio L, Savilahti E. Screening for coeliac disease in women with a history of recurrent miscarriage or infertility. Br J Obst Gynaecol. 1999;106:171-3.⁾	1	129	1	51	4.2%	0.39 [0.02, 6.37]	1999
Shamaly et al.⁽²³23. Reilly NR, Fasano A, Green PH. Presentation of celiac disease. Gastrointest Endosc Clin N Am. 2012;22:613-21.⁾	5	192	1	210	7.1%	5.59 [0.65, 48.27]	2004
da Silva Martins et al.⁽⁶6. Da Silva Martins CL, Gandolfi L, Tauil PL, de Almeida Rocha Picanco M, Galvao de Araujo MO, Pratesi R. Celiac disease and female infertility: a frequently neglected association. Rev Bras Ginecol Obstet. 2006;28:601-6.⁾	3	200	0	400	3.8%	14.19 [0.73, 276.16]	2006
Tiboni et al.⁽²⁹29. Tata LJ, Card TR, Logan RFA, Hubbard RB, Smith CJP, West J. Fertility and pregnancy-related events in women with celiac disease: a population-based cohort study. Gastroenterology. 2005;128:849-55.⁾	5	200	2	200	12.1%	2.54 [0.49, 13.24]	2006
Kumar et al.⁽¹⁶16. Kumar A, Meena M, Begum N, Kumar N, Gupta RK, Agarwal S, et al. Latent celiac disease in reproductive perfomance of women. Fertil Steril. 2011;95:922-7.⁾	13	230	4	305	25.7%	4.51 [1.45, 14.01]	2010
Hogen Esch et al.⁽¹²12. Hogen Esch CE, Van Rijssen MJL, Roos A, Koning F, Dekker FW, Mearin ML, et al. Screening for unrecognized coeliac disease in subfertile couples. Scand J Gastroenterol. 2011;46:1423-8.⁾	6	1038	2	716	12.9%	2.08 [0.42, 10.31]	2011
Khoshbaten et al.⁽¹⁴14. Khoshbaten M, Nejad MR, Farzady L, Sharifi N, Hashemi SH, Rostami K. Fertility disorder associated with celiac disease in males and females: fact or fiction? J Obstet Gynael Res. 2011;37:1308-12.⁾	8	100	7	200	30.3%	2.40 [0.84, 6.81]	2011

Total (95% CI)		2239		2232	100.0%	3.09 [1.74, 5.49]
Total events	45		17
Test for overall effect: Z = 3.84 (P = 0.0001)

	Infertility		Control			Odds Ratio		Odds Ratio
Study or Subgroup	Events	Total	Events	Total	Weight	M-H, Random, 95% CI	Year	M-H, Random, 95% CI
Hogen Esch et al.⁽¹²12. Hogen Esch CE, Van Rijssen MJL, Roos A, Koning F, Dekker FW, Mearin ML, et al. Screening for unrecognized coeliac disease in subfertile couples. Scand J Gastroenterol. 2011;46:1423-8.⁾	4	1038	3	716	44.4%	0.92 [0.21, 4.12]	2011
Khoshbaten et al.⁽¹⁴14. Khoshbaten M, Nejad MR, Farzady L, Sharifi N, Hashemi SH, Rostami K. Fertility disorder associated with celiac disease in males and females: fact or fiction? J Obstet Gynael Res. 2011;37:1308-12.⁾	5	100	4	200	55.6%	2.58 [0.68, 9.82]	2011

Total (95% CI)		1138		915	100.0%	1.63 [0.60, 4.46]
Total events	9		7
Heterogeneity: Tau2 = 0.01; Chi2 = 1.01, df = 1 (P = 0.31); I2 = 1%
Test for overall effect: Z = 0.96 (P = 0.34)

	Celiac Disease		Control			Odds Ratio		Odds Ratio
Study or Subgroup	Events	Total	Events	Total	Weight	M-H, Random, 95% CI	Year	M-H, Random, 95% CI
Molteni et al.⁽²¹21. Molteni N, Bardella MT, Bianchi PA. Obstetric and gynecological problems in women with untreated celiac sprue. J Clin Gastroenterol. 1990;12:37-9.⁾	4	38	3	38	0.8%	1.37 [029, 6.59]	1990
Sher et al.⁽²⁴24. Shamaly H, Mahameed A, Sharony A, Shamir R. Infertility and celiac disease: do we need more than one serological marker? Acta Obstet Gynecol Scand. 2004;83:1184-8.⁾	11	68	1	68	0.4%	12.93 [1.62, 103.22]	1994
Tata et al.⁽²⁸28. Stroup DF, Berlin JA, Morton SC, Olkin I, Williamson GD, Rennie D, et al. Meta-analysis of observational studies in epidemiology: a proposal for reporting. JAMA. 2000;283:2008-12.⁾	1001	1521	5124	7732	44.0%	0.98 [0.87, 1.10]	2005
Zugna et al.⁽³⁰30. Tiboni GM, de Vita MG, Faricelli R, Giampietro F, Liberati M. Serological testing for celiac diseasein women undergoingassisted reproduction techniques. Hum Reprod. 2006;21:376-9.⁾	1296	4466	5842	19705	54.8%	0.97 [0.90, 1.04]	2010

Total (95% CI)		6093		27543	100.0%	0.99 [0.86, 1.13]
Total events	45		17
Heterogeneity: Tau² = 0.01; Chi² = 6.16, df = 3 (P = 0.10); I² = 51%
Test for overall effect: Z = 0.17 (P = 0.86)

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[1] Correspondence: Juan Sebastian Lasa. 1958 Austria St. Buenos Aires, Argentina - ZIP Code 1425. Email:juanselasa@gmail.com