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

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

doi:10.1590/S0004-28032014000200014

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

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

Autoria SCIMAGO INSTITUTIONS RANKINGS

Resumo

Contexto A doença celíaca é uma doença auto imune do intestino delgado associada a manifestações extra-intestinais, tais como distúrbios reprodutivos. A relação entre a doença celíaca e a infertilidade foi previamente avaliada, com resultados conflitantes.

Objetivos Procuramos determinar a relação entre a doença celíaca e a infertilidade.

Métodos Utilizou-se dados extraídos de estudos de projeto de caso-controle ou coorte de 1966 à dezembro de 2013 utilizando o MEDLINE-Pubmed, EMBASE, LILACS e Cochrane Library. Foram analisados dois tipos de ensaios: os que avaliam o risco de infertilidade em pacientes com doença celíaca já diagnosticados e, os que avaliam a prevalência da doença celíaca não diagnosticada em indivíduos com diagnóstico de infertilidade.

Resultados A busca resultou em 413 estudos potencialmente relevantes para a revisão, 12 dos quais foram finalmente incluídos para análise. Foi encontrada uma associação significativa entre as mulheres com diagnóstico de infertilidade e doença celíaca não diagnosticada [TR 3,09 (IC 95% 1,74-5,49)]. Ao considerar esses estudos avaliando a ocorrência de infertilidade em pacientes com doença celíaca já diagnosticada, não foi encontrada diferença entre os pacientes com doença celíaca e controles [TR 0,99 (0,86-1,13)].

Conclusões A falta de diagnóstico para a doença celíaca é um fator de risco para a infertilidade. As mulheres que procuram o conselho médico para esta condição particular, devem ser examinados para a doença celíaca. A adoção de uma dieta sem glúten pode ter um impacto positivo sobre a fertilidade neste grupo de pacientes.

Doença celíaca; Infertilidade feminina; Dieta livre de glúten

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

CASE-CONTROL AND CROSS SECTIONAL STUDIES

Molteni et al.⁽²¹⁾	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.⁽²⁴⁾	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.⁽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.⁽¹⁵⁾	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.⁽²³⁾	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.⁽²⁹⁾	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.⁽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.⁽¹⁶⁾	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.⁽¹⁴⁾	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.⁽¹²⁾	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.⁽²⁸⁾	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.⁽³⁰⁾	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.⁽²¹⁾	Yes	Consecutive series	Hospital and community controls	No history of disease	Sex, age and origin adjustment	Questionnaire	Yes	Not stated
Sher et al.⁽²⁴⁾	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.⁽⁴⁾	Yes	Consecutive series	Hospital controls	No history of disease	No adjustment	Laboratory+ biopsy when + ve screening	Yes	Not stated
Kohlo et al.⁽¹⁵⁾	Yes	Consecutive series	Hospital controls	No history of disease	No adjustment	Laboratory	Yes	Not stated
Shamaly et al.⁽²³⁾	Yes	Consecutive series	Hospital controls	No history of disease	Age and sex adjustment	Laboratory+ biopsy when + ve screening	Yes	Not stated
Tiboni et al.⁽²⁹⁾	Yes	Consecutive series	Hospital controls	No history of disease	No adjustment	Laboratory+ biopsy when + ve screening	Yes	Not stated
da Silva Martins et al.⁽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.⁽¹⁶⁾	Yes	Consecutive series	Hospital controls	No history of disease	No adjustment	Laboratory	Yes	Not stated
Khoshbaten et al.⁽¹⁴⁾	Yes	Consecutive series	Hospital controls	No history of disease	No adjustment	Laboratory+ biopsy when + ve screening	Yes	Not stated
Hogen Ersch et al.⁽¹²⁾	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.⁽²⁸⁾	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.⁽³⁰⁾	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.⁽⁴⁾	4	150	0	150	3.9%	9.25 [0.49, 173.25]	1996
Collin et al.⁽⁴⁾	4	150	0	150	3.9%	9.25 [0.49, 173.25]	1996
Kohlo et al.⁽¹⁵⁾	1	129	1	51	4.2%	0.39 [0.02, 6.37]	1999
Shamaly et al.⁽²³⁾	5	192	1	210	7.1%	5.59 [0.65, 48.27]	2004
da Silva Martins et al.⁽⁶⁾	3	200	0	400	3.8%	14.19 [0.73, 276.16]	2006
Tiboni et al.⁽²⁹⁾	5	200	2	200	12.1%	2.54 [0.49, 13.24]	2006
Kumar et al.⁽¹⁶⁾	13	230	4	305	25.7%	4.51 [1.45, 14.01]	2010
Hogen Esch et al.⁽¹²⁾	6	1038	2	716	12.9%	2.08 [0.42, 10.31]	2011
Khoshbaten et al.⁽¹⁴⁾	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.⁽¹²⁾	4	1038	3	716	44.4%	0.92 [0.21, 4.12]	2011
Khoshbaten et al.⁽¹⁴⁾	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.⁽²¹⁾	4	38	3	38	0.8%	1.37 [029, 6.59]	1990
Sher et al.⁽²⁴⁾	11	68	1	68	0.4%	12.93 [1.62, 103.22]	1994
Tata et al.⁽²⁸⁾	1001	1521	5124	7732	44.0%	0.98 [0.87, 1.10]	2005
Zugna et al.⁽³⁰⁾	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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[TFN01t01] IBS: Irritable bowel syndrome, AE: Anti-endomysium, GFD: Gluten-free diet, AtTG: Anti-transglutaminase, CD: Celiac disease, HLA: Human leukocyte antigen, AG: Anti-gliadin, GPRD: General practice research database, UI: Unexplained infertility, HR: Hazard ratio