Fertility and pregnancy-related events in women with celiac disease: A population-based cohort study
2005; Elsevier BV; Volume: 128; Issue: 4 Linguagem: Inglês
10.1053/j.gastro.2005.02.017
ISSN1528-0012
AutoresLaila J. Tata, Tim Card, Richard F. Logan, Richard Hubbard, Christopher J. Smith, Joe West,
Tópico(s)Intestinal Malrotation and Obstruction Disorders
ResumoBackground & Aims: Previous studies have raised concern about reduced fertility and increased adverse pregnancy-related events in women with celiac disease, but none has estimated overall fertility compared with the general female population. Methods: We compared computerized primary care data for 1521 women with celiac disease with data for 7732 age- and practice-matched women without celiac disease. We estimated population-based rates of fertility and adverse pregnancy outcomes. Results: Crude fertility rates were 48.2 and 47.7 live births per 1000 person-years for women with and without celiac disease, respectively (rate ratio, 1.01; 95% confidence interval, 0.90–1.14). Age-specific fertility rates showed that women with celiac disease had lower fertility when younger but higher fertility when older compared with women without celiac disease. This increase in relative fertility with increasing age held whether women had treated or untreated celiac disease. Risks of cesarean section (odds ratio, 1.33; 95% confidence interval, 1.03–1.70) and miscarriage (rate ratio, 1.31; 95% confidence interval, 1.06–1.61) were moderately higher in women with celiac disease, but risks of assisted birth, breech birth, preeclampsia, postpartum hemorrhage, ectopic pregnancy, stillbirth, and termination were similar. Conclusions: Overall, women with celiac disease have fertility similar to that of the general female population, but they have their babies at an older age. Although our findings may reflect a disease effect, the age shift in fertility rates and the increase in cesarean section risk is consistent with socioeconomic or educational advantages of women with celiac disease. Background & Aims: Previous studies have raised concern about reduced fertility and increased adverse pregnancy-related events in women with celiac disease, but none has estimated overall fertility compared with the general female population. Methods: We compared computerized primary care data for 1521 women with celiac disease with data for 7732 age- and practice-matched women without celiac disease. We estimated population-based rates of fertility and adverse pregnancy outcomes. Results: Crude fertility rates were 48.2 and 47.7 live births per 1000 person-years for women with and without celiac disease, respectively (rate ratio, 1.01; 95% confidence interval, 0.90–1.14). Age-specific fertility rates showed that women with celiac disease had lower fertility when younger but higher fertility when older compared with women without celiac disease. This increase in relative fertility with increasing age held whether women had treated or untreated celiac disease. Risks of cesarean section (odds ratio, 1.33; 95% confidence interval, 1.03–1.70) and miscarriage (rate ratio, 1.31; 95% confidence interval, 1.06–1.61) were moderately higher in women with celiac disease, but risks of assisted birth, breech birth, preeclampsia, postpartum hemorrhage, ectopic pregnancy, stillbirth, and termination were similar. Conclusions: Overall, women with celiac disease have fertility similar to that of the general female population, but they have their babies at an older age. Although our findings may reflect a disease effect, the age shift in fertility rates and the increase in cesarean section risk is consistent with socioeconomic or educational advantages of women with celiac disease. Celiac disease affects as much as 1% of the female population in Western Europe and North America, and a large proportion of people with active disease are undiagnosed. Previous research has suggested that celiac disease, along with other chronic inflammatory diseases, may be associated with reduced fertility and an increased risk of adverse pregnancy-related events.1Alstead E.M. Nelson-Piercy C. Inflammatory bowel disease in pregnancy.Gut. 2003; 52: 159-161Crossref PubMed Scopus (86) Google Scholar, 2Rostami K. Steegers E.A. Wong W.Y. Braat D.D. Steegers-Theunissen R.P. Coeliac disease and reproductive disorders a neglected association.Eur J Obstet Gynecol Reprod Biol. 2001; 96: 146-149Abstract Full Text Full Text PDF PubMed Scopus (93) Google Scholar, 3Wood S.L. Jick H. Sauve R. The risk of stillbirth in pregnancies before and after the onset of diabetes.Diabet Med. 2003; 20: 703-707Crossref PubMed Scopus (41) Google Scholar, 4Dominitz J.A. Young J.C. Boyko E.J. Outcomes of infants born to mothers with inflammatory bowel disease a population-based cohort study.Am J Gastroenterol. 2002; 97: 641-648Crossref PubMed Google Scholar, 5Buchel E. Van Steenbergen W. Nevens F. Fevery J. Improvement of autoimmune hepatitis during pregnancy followed by flare-up after delivery.Am J Gastroenterol. 2002; 97: 3160-3165Crossref PubMed Google Scholar Some have accepted that infertility is indeed a complication of celiac disease.6Green P.H. Jabri B. Coeliac disease.Lancet. 2003; 362: 383-391Abstract Full Text Full Text PDF PubMed Scopus (797) Google Scholar Reported associations between celiac disease and a higher incidence of termination, miscarriage, and having babies with low birth weight or intrauterine growth retardation have also raised concern; however, most studies have used small, selected populations; have been limited in their ability to adjust for potential confounding factors; and have been unable to estimate fertility rates.2Rostami K. Steegers E.A. Wong W.Y. Braat D.D. Steegers-Theunissen R.P. Coeliac disease and reproductive disorders a neglected association.Eur J Obstet Gynecol Reprod Biol. 2001; 96: 146-149Abstract Full Text Full Text PDF PubMed Scopus (93) Google Scholar, 7Smecuol E. Maurino E. Vazquez H. et al.Gynaecological and obstetric disorders in coeliac disease frequent clinical onset during pregnancy or the puerperium.Eur J Gastroenterol Hepatol. 1996; 8: 63-89Crossref PubMed Scopus (95) Google Scholar, 8Norgard B. Fonager K. Sorensen H.T. Olsen J. Birth outcomes of women with celiac disease a nationwide historical cohort study.Am J Gastroenterol. 1999; 94: 2435-2440Crossref PubMed Google Scholar, 9Ciacci C. Cirillo M. Auriemma G. Di Dato G. Sabbatini F. Mazzacca G. Celiac disease and pregnancy outcome.Am J Gastroenterol. 1996; 91: 718-722PubMed Google Scholar, 10Sher K.S. Mayberry J.F. Female fertility, obstetric and gynaecological history in coeliac disease a case control study.Acta Paediatr Suppl. 1996; 412: 76-77Crossref PubMed Google Scholar, 11Meloni G.F. Dessole S. Vargiu N. Tomasi P.A. Musumeci S. The prevalence of coeliac disease in infertility.Hum Reprod. 1999; 14: 2759-2761Crossref PubMed Scopus (123) Google Scholar, 12Martinelli P. Troncone R. Paparo F. et al.Coeliac disease and unfavourable outcome of pregnancy.Gut. 2000; 46: 332-335Crossref PubMed Scopus (171) Google Scholar Definitive explanations for these associations have not been proposed. Nevertheless, women with celiac disease tend to have a shorter reproductive period, with slightly later menarche and earlier menopause.7Smecuol E. Maurino E. Vazquez H. et al.Gynaecological and obstetric disorders in coeliac disease frequent clinical onset during pregnancy or the puerperium.Eur J Gastroenterol Hepatol. 1996; 8: 63-89Crossref PubMed Scopus (95) Google Scholar, 10Sher K.S. Mayberry J.F. Female fertility, obstetric and gynaecological history in coeliac disease a case control study.Acta Paediatr Suppl. 1996; 412: 76-77Crossref PubMed Google Scholar, 12Martinelli P. Troncone R. Paparo F. et al.Coeliac disease and unfavourable outcome of pregnancy.Gut. 2000; 46: 332-335Crossref PubMed Scopus (171) Google Scholar, 13Ferguson R. Holmes G.K. Cooke W.T. Coeliac disease, fertility, and pregnancy.Scand J Gastroenterol. 1982; 17: 65-68Crossref PubMed Scopus (95) Google Scholar A plausible link to fertility or pregnancy problems also originates from the abnormal villous structure of the small intestine that is characteristic of celiac disease; it results in malabsorption and can lead to minor hematological abnormalities,14Logan R.F. Tucker G. Rifkind E.A. Heading R.C. Ferguson A. Changes in clinical features of coeliac disease in adults in Edinburgh and the Lothians 1960-79.BMJ. 1983; 286: 95-97Crossref PubMed Scopus (154) Google Scholar anemia,15West J. Logan R.F. Hill P.G. et al.Seroprevalence, correlates, and characteristics of undetected coeliac disease in England.Gut. 2003; 52: 960-965Crossref PubMed Scopus (436) Google Scholar and other selective nutrient deficiencies that play significant roles in pregnancy and fetal development.2Rostami K. Steegers E.A. Wong W.Y. Braat D.D. Steegers-Theunissen R.P. Coeliac disease and reproductive disorders a neglected association.Eur J Obstet Gynecol Reprod Biol. 2001; 96: 146-149Abstract Full Text Full Text PDF PubMed Scopus (93) Google Scholar Of particular importance is the risk of having babies with neural tube defects. This risk is increased with folate deficiency in pregnancy, but it has not yet been linked with celiac disease.16Dickey W. Stewart F. Nelson J. McBreen G. McMillan S.A. Porter K.G. Screening for coeliac disease as a possible maternal risk factor for neural tube defect.Clin Genet. 1996; 49: 107-108PubMed Google Scholar, 17Berry R.J. Li Z. Erickson J.D. et al.Prevention of neural-tube defects with folic acid in China China-U.S. Collaborative Project for Neural Tube Defect Prevention.N Engl J Med. 1999; 341 (corrected; erratum to be published): 1485-1490Crossref PubMed Scopus (1259) Google Scholar, 18Rothenberg S.P. da Costa M.P. Sequeira J.M. et al.Autoantibodies against folate receptors in women with a pregnancy complicated by a neural-tube defect.N Engl J Med. 2004; 350: 134-142Crossref PubMed Scopus (200) Google Scholar, 19Moore L.L. Bradlee M.L. Singer M.R. Rothman K.J. Milunsky A. Folate intake and the risk of neural tube defects an estimation of dose-response.Epidemiology. 2003; 14: 200-205Crossref PubMed Scopus (62) Google Scholar Furthermore, researchers have suggested that pregnancy-related risks are corrected after successful treatment with a gluten-free diet.8Norgard B. Fonager K. Sorensen H.T. Olsen J. Birth outcomes of women with celiac disease a nationwide historical cohort study.Am J Gastroenterol. 1999; 94: 2435-2440Crossref PubMed Google Scholar However, there have been no population-based studies large enough to adequately justify this claim. Establishing precisely the fertility experience and pregnancy-related risks is thus of great importance to women with celiac disease and to those who manage their care, both for general disease management and for pregnancy-planning advice. To establish a general population–based account of the reproductive experience in women with celiac disease and to determine the true magnitude of the associated risks, we have conducted the first and largest study of fertility rates in women with celiac disease compared with the general population. We investigated mode of delivery, pregnancy complications, stillbirths, miscarriages, and terminations to determine whether women with celiac disease have an increased risk of these adverse pregnancy-related events. In view of indications that folate is malabsorbed in celiac disease,20Hallert C. Grant C. Grehn S. et al.Evidence of poor vitamin status in coeliac patients on a gluten-free diet for 10 years.Aliment Pharmacol Ther. 2002; 16: 1333-1339Crossref PubMed Scopus (262) Google Scholar we additionally investigated the occurrence of neural tube defects in babies born to women in our study. We obtained data from the General Practice Research Database (GPRD), a source of longitudinal records of routine primary care visits for more than 8 million people registered at general practices across the United Kingdom.21Epidemiology and Pharmacology Information Center. The General Practice Research Database—a guide for researchers. London, England, 2001.Google Scholar, 22Lawrenson R. Williams T. Farmer R. Clinical information for research; the use of general practice databases.J Public Health Med. 1999; 21: 299-304Crossref PubMed Scopus (235) Google Scholar Participating practices must record all major diagnoses, medical events, and prescriptions, and audits are performed regularly to ensure that practice data are kept up to standard by including at least 95% of this information. Aggregated data are anonymized for research purposes, and independent studies, including studies of pregnancy outcomes and gastrointestinal diseases, have found high validity of diagnoses.3Wood S.L. Jick H. Sauve R. The risk of stillbirth in pregnancies before and after the onset of diabetes.Diabet Med. 2003; 20: 703-707Crossref PubMed Scopus (41) Google Scholar, 23Howard L.M. Kumar C. Leese M. Thornicroft G. The general fertility rate in women with psychotic disorders.Am J Psychiatry. 2002; 159: 991-997Crossref PubMed Scopus (91) Google Scholar, 24Howard L.M. Goss C. Leese M. Thornicroft G. Medical outcome of pregnancy in women with psychotic disorders and their infants in the first year after birth.Br J Psychiatry. 2003; 182: 63-67Crossref PubMed Scopus (73) Google Scholar, 25Lewis J.D. Brensinger C. Bilker W.B. Strom B.L. Validity and completeness of the General Practice Research Database for studies of inflammatory bowel disease.Pharmacoepidemiol Drug Saf. 2002; 11: 211-218Crossref PubMed Scopus (157) Google Scholar All people with a recorded diagnosis of celiac disease in their GPRD record between June 1987 and April 2002 were identified for the cohort. We then obtained up to 5 comparison subjects without celiac disease matched to each person in our celiac cohort by age, sex, general practice, and follow-up time of their general practice record. Potentially fertile women were identified as those contributing up-to-standard data at some point between 15 and 44 years of age, which we called their up-to-standard fertile period. Each woman with celiac disease was assigned a date of diagnosis corresponding to the date of her first record of celiac disease. Because general practitioners enter data for important historical medical events retrospectively, this date preceded the start of the up-to-standard GPRD fertile period for some women. We defined incident subjects with celiac disease as those individuals whose diagnosis date or first prescription of a gluten-free product occurred during their up-to-standard fertile period. All other subjects with celiac disease were defined as prevalent. Subjects in the comparison cohort were assigned a pseudodiagnosis date equivalent to the diagnosis date of the women with celiac disease to whom they were matched. We identified all live births during the up-to-standard fertile period for the calculation of fertility rates (Figure 1). For each fertile woman, we extracted data on all previous birth-related outcomes between the age of 15 and 44 years. This included events before their up-to-standard fertile period to obtain a complete pregnancy history. We extracted details of the mode of delivery, grouped as assisted delivery, cesarean section, or breech delivery. We also classified codes for the pregnancy complications preeclampsia, postpartum hemorrhage, ectopic pregnancy, stillbirth, termination (i.e., nonspontaneous abortion), and miscarriage. For each woman, we additionally extracted data on the following potential confounders of the relationship between a diagnosis of celiac disease and fertility: maternal age at first birth, total number of births, height, weight, smoking habits, diagnosed diabetes, diagnosed thyroid abnormality, diagnosed infertility, and infertility drug treatment (clomiphene, ganirelix, or cetrorelix). Finally, we obtained the GPRD records of children with codes for neural tube defects (spina bifida, hydrocephalus, meningocele, or meningomyelocele) born to women in our 2 cohorts and linked them to their mothers by using a family number. Using Poisson regression, we estimated fertility rates as the number of live births per 1000 person-years women contributed to the up-to-standard fertile period, which is equivalent to the official general fertility rate calculated yearly as a standard measure of fertility in populations.26Office for National Statistics. Population trends: summer 2003. No. 112. Published with permission of the Controller of Her Majesty's Stationery Office (HMSO). Office for National Statistics, London, England, 2003.Google Scholar To account for variation by age, we stratified fertility rates by 5-year age bands according to the standard presentation of general fertility rates.26Office for National Statistics. Population trends: summer 2003. No. 112. Published with permission of the Controller of Her Majesty's Stationery Office (HMSO). Office for National Statistics, London, England, 2003.Google Scholar By performing a Lexis expansion to construct an age-cohort model, we then calculated age-specific fertility rate ratios (FRR) comparing our cohort of women with celiac disease with the comparison cohort.27Breslow N.E. Day N.E. Statistical methods in cancer research Volume II—The design and analysis of cohort studies.IARC Sci Publ. 1987; 82: 1-406Google Scholar We calculated the proportion of birth events for each mode of delivery, and for our data on preeclampsia, postpartum hemorrhage, and ectopic pregnancy, we calculated rates as per 1000 live births. For stillbirths, terminations, and miscarriages, rates were calculated as per 1000 live births plus stillbirths, plus terminations, or plus miscarriages, respectively. In our multivariate analyses, we assessed the effect of age, body mass index (kilograms per square meter), smoking habits, diagnosed diabetes, diagnosed thyroid abnormality, diagnosed infertility, and infertility drug treatment (clomiphene, ganirelix, or cetrorelix) and retained only the variables that affected the magnitude of the effect estimate by ≥10%. Missing data were fitted as a separate category. To further investigate whether fertility varied in relation to diagnosis date of celiac disease, we conducted the same analyses of fertility rates and rate ratios (RRs) by separating women into groups based on their prevalent or incident status. For incident women in the celiac disease cohort who were diagnosed during their up-to-standard fertile period, we additionally investigated whether age-specific fertility rates differed before and after this diagnosis. We used the time contributed before and after diagnosis as proxy measures for untreated and treated celiac disease, respectively, and we assumed that women were compliant with treatment after their diagnosis of celiac disease (>90% had at least 1 gluten-free prescription in their general practice record). All analyses were conducted with Stata (release 8.0; Stata Corp., College Station, TX). From our initial cohort of 4732 people with celiac disease and 23,620 comparison subjects,28West J. Logan R.F. Card T.R. Smith C. Hubbard R. Fracture risk in people with celiac disease a population-based cohort study.Gastroenterology. 2003; 125: 429-436Abstract Full Text Full Text PDF PubMed Scopus (179) Google Scholar we identified 1521 and 7732 potentially fertile women, respectively, who were included in our study. There were no differences in the age at first birth (χ2 test for trend; P = .76) or in the total number of births between the 2 cohorts (χ2 test for trend; P = .87) (Table 1). Women with celiac disease were more likely to have never smoked (χ2; P < .01) and to have a lower body mass index (χ2 test for trend; P < .01) compared with women without celiac disease.Table 1Characteristics of Celiac Disease and Comparison CohortsaWomen contributing data during the up-to-standard fertile period.Celiac disease cohort (n = 1521)Comparison cohort (n = 7732)Variablen%n%Maternal age at first birth (y) <19.9493.23304.3 20–24.91268.37599.8 25–29.917511.581310.5 30–34.91278.35056.5 35–39.9402.61702.2 40–44.930.2310.4 Never had a birth100165.8512466.3Total number of births 0100165.8512466.3 126417.4123716.0 217711.697612.6 3614.02923.8 ≥4181.21031.3Smoking status Never smoker76750.4341344.1 Ex-smoker654.34105.3 Current smoker26217.2153719.9 Missing42728.1237230.7Body mass index (kg/m2) Underweight (≤18.5)835.51381.8 Normal (18.6–25.0)82654.3326842.3 Overweight (25.1–30.0)18512.2122115.8 Obese (≥30.1)553.66708.7 Missing37224.5243531.5Diabetes diagnosed342.2690.9Thyroid abnormality diagnosed835.51532.0Infertility diagnosed563.72773.6Infertility drug prescribed140.9761.0a Women contributing data during the up-to-standard fertile period. Open table in a new tab During the up-to-standard fertile period, women in the celiac disease cohort had 341 births and a median follow-up time of 4.3 years (interquartile range, 1.9–7.0 years), whereas women in the comparison cohort had 1903 births and a median follow-up time of 4.9 years (interquartile range, 2.5–7.5 years). Fertility rates were 48.2 and 47.7 live births per 1000 person-years for women with and without celiac disease, respectively, resulting in an overall FRR of 1.01 (95% confidence interval [CI], 0.90–1.14; Table 2). Age-specific fertility rates, however, showed that relative fertility between the 2 cohorts varied with age (Table 2 and Figure 2). Relative to the comparison group, women with celiac disease had 60% reduced fertility (FRR, 0.40; 95% CI, 0.16–0.99) in the 15- to 19.9-year-old age group but then seemed to "catch up" the 35- to 39.9-year-old age group, with 40% increased fertility (FRR, 1.39; 95% CI, 1.06–1.83). When we divided the cohorts on the basis of prevalent or incident status, there were 729 (48%) women with celiac disease in the prevalent group and 792 (52%) in the incident group, with 137 and 204 births, respectively. The median age at diagnosis was 21.5 years in the prevalent group and 35.4 years in the incident group. FRRs were similar to the overall analysis and showed no difference between the prevalent and incident groups (prevalent group: FRR, 1.07; 95% CI, 0.89–1.28; incident group: FRR, 0.99; 95% CI, 0.85–1.14; Table 3). Age-specific FRRs for prevalent and incident groups separately showed the same pattern as in the overall analysis: relative fertility in women with celiac disease increased with increasing age compared with women without the disease. We found a similar pattern when we analyzed only the incident group and adjusted for whether the contributed person-time was before or after celiac disease diagnosis in the up-to-standard fertile period.Table 2Age-Specific Fertility Rates and Rate RatiosFertile age band (y)Celiac disease cohort (n = 1521)Comparison cohort (n = 7732)Fertility rate ratio (95% CI)No. live birthsaIn up-to-standard fertile period.Fertile person-time (1000 p-y)Fertility rate95% CINo. live birthsaIn up-to-standard fertile period.Fertile person-time (1000 p-y)Fertility rate95% CI15–19.950.424311.84.9–28.3772.627929.323.4–36.60.40 (0.16–0.99)20–24.9430.767456.041.6–75.63194.792266.659.6–74.30.84 (0.61–1.16)25–29.91061.095796.780.0–120.06226.492095.888.6–100.01.01 (0.82–1.24)30–34.91191.404384.770.8–100.05917.794675.869.9–82.21.12 (0.92–1.36)35–39.9651.682638.630.3–49.32509.009327.924.6–31.51.39 (1.06–1.83)40–44.931.69861.80.6–5.5449.21324.83.6–6.40.37 (0.12–1.19)All ages3417.072948.243.4–53.6190339.929247.745.4–49.71.01 (0.90–1.14)P-y, person-years.a In up-to-standard fertile period. Open table in a new tab Table 3Age-Specific Fertility Rate RatiosaBased on births in up-to-standard fertile period; comparing celiac disease cohort with comparison cohort. by Prevalent and Incident StatusFertile age band (y)Prevalent groupIncident groupIncident group adjusted for diagnosis datebBefore or after diagnosis of celiac disease.Fertility rate ratio95% CIFertility rate ratio95% CIFertility rate ratio95% CI15–19.90.480.15–1.570.330.08–1.350.610.32–1.1720–24.90.960.57–1.590.790.53–1.190.860.61–1.2125–29.91.010.72–1.411.020.78–1.321.030.79–1.3330–34.91.170.86–1.601.090.85–1.411.311.01–1.6935–39.01.661.08–2.571.250.88–1.780.880.52–1.4840–44.90.270.04–1.980.460.11–1.940.970.12–8.06All ages1.070.89–1.280.990.85–1.141.020.85–1.18a Based on births in up-to-standard fertile period; comparing celiac disease cohort with comparison cohort.b Before or after diagnosis of celiac disease. Open table in a new tab P-y, person-years. Table 4, Table 5 show pregnancy-related outcomes for the fertility history of women in our cohorts. The proportion of births by cesarean section was approximately 30% higher for women with celiac disease than for women in the comparison group (Table 4), and deliveries of this type were more common in the older age groups, in which the FRRs were also higher in women with celiac disease (data not shown). Births by assisted delivery were also slightly increased; however, the odds ratio of 1.25 was not statistically significant (95% CI, 0.97–1.61). There was no difference in the proportion of births by breech delivery between the 2 cohorts. Rates of preeclampsia, postpartum hemorrhage, and ectopic pregnancy were also slightly increased in the celiac disease cohort; however, numbers of these outcomes were small, and CIs for RRs included 1 (Table 5). Stillbirth rates were 11.2 per 1000 live births and stillbirths in the celiac disease cohort compared with 8.8 per 1000 live births and stillbirths in the comparison cohort, which did not show a statistically significant difference (RR, 1.28; 95% CI, 0.64–2.55). Terminations of pregnancy were similar between the 2 cohorts, but miscarriages were slightly more common in women with celiac disease (RR, 1.31; 95% CI, 1.06–1.61). When we linked women to their children, we found only 1 child with spina bifida and 3 children with hydrocephalus, all of whom were born to women in the comparison cohort.Table 4Mode of DeliveryVariableCeliac disease cohort (n = 1521)Comparison cohort (n = 7723)Odds ratio (95% CI)naIn fertile period (age 15–44 years).% birthsaIn fertile period (age 15–44 years).naIn fertile period (age 15–44 years).% birthsaIn fertile period (age 15–44 years).Cesarean section9310.63688.21.33 (1.03–1.70)Assisted birth859.73547.91.25 (0.97–1.61)Breech birth151.7711.61.08 (0.57–1.92)a In fertile period (age 15–44 years). Open table in a new tab Table 5Pregnancy-Related OutcomesCeliac disease cohort (n = 1521)Comparison cohort (n = 7723)VariablenaIn fertile period (age 15–44 years).RatebPreeclampsia, postpartum hemorrhage, ectopic pregnancy: rate = per 1000 live births; sillbirth rate = per 1000 live births + still births; termination rate = per 1000 live births + terminations; miscarriage rate = per 1000 live births + miscarriages.naIn fertile period (age 15–44 years).RatebPreeclampsia, postpartum hemorrhage, ectopic pregnancy: rate = per 1000 live births; sillbirth rate = per 1000 live births + still births; termination rate = per 1000 live births + terminations; miscarriage rate = per 1000 live births + miscarriages.Rate ratio (95% CI)Preeclampsia1112.5388.41.48 (0.76–2.90)Postpartum hemorrhage910.2449.81.05 (0.51–2.15)Ectopic pregnancy1921.66113.51.60 (0.95–2.67)Stillbirth1011.2408.81.28 (0.64–2.55)Termination264230.81321226.61.02 (0.89–1.16)Miscarriage111112.042285.61.31 (1.06–1.61)a In fertile period (age 15–44 years).b Preeclampsia, postpartum hemorrhage, ectopic pregnancy: rate = per 1000 live births; sillbirth rate = per 1000 live births + still births; termination rate = per 1000 live births + terminations; miscarriage rate = per 1000 live births + miscarriages. Open table in a new tab In this large general population–based cohort study, we found that overall fertility rates are the same in women with diagnosed celiac disease compared with women in the general population. However, women with celiac disease tend to have their babies at an older age. The pattern of relative fertility increasing with age was similar in women with prevalent or incident celiac disease in our study. Within the incident group, we were additionally able to investigate whether their fertility changed after women were diagnosed—and, thus, treated for celiac disease—by adjusting for the date of their celiac disease diagnosis. We found that relative fertility did not change after their diagnosis compared to before their diagnosis and that the distribution of age-specific relative fertility held. This implies that overall fertility is equivalent to that of the general female population, even in women with untreated celiac disease, throughout most of their fertile years. Although it is possible that the age-shifted fertility pattern is a disease effect, our analyses comparing the untreated with treated women suggest that this is unlikely. It is perhaps more likely to reflect socioeconomic or educational advantage in women with celiac disease compared with those without the disease, because similar fertility patterns have been consistently found across socioeconomic and educational gradients.29Armitage B. Variation in fertility between different types of local area.Popul Trends. 1997; 87: 20-28PubMed Google Scholar, 30Office for National Statistics. Population trends: spring 2003. No. 111. Published with permission of the Controller of Her Majesty's Stationery Office (HMSO). Office for National Statistics, London, England, 2003.Google Scholar Women with celiac disease also had pregnancy experiences similar to those of women in the general population, such as risks of breech delivery and stillbirth, although they had moderately increased risks of cesarean section delivery and miscarriage. The proportion of babies born with neural tube defects to women in our comparison cohort (0.2%) is similar to other national prevalence figures.31Rankin J. Glinianaia S. Brown R. Renwick M. The changing prevalence of neural tube defects: a population-based study in the north of England, 1984–96: Northern Congenital Abnormality Survey Steering Group.Paediatr Perinat Epidemiol. 2000; 14: 104-110Crossref PubMed Scopus (73) Google Scholar Reassuringly, given concerns about the effects of folate deficiency during pregnancy,17Berry R.J. Li Z. Erickson J.D. et al.Prevention of neural-tube defects with folic acid in China China-U.S. Collaborative Project for Neural Tube Defect Prevention.N Engl J Med. 1999; 341 (corrected; erratum to be published): 1485-1490Crossref PubMed Scopus (1259) Google Scholar, 18Rothenberg S.P. da Costa M.P. Sequeira J.M. et al.Autoantibodies against folate receptors in women with a pregnancy complicated by a neural-tube defect.N Engl J Med. 2004; 350: 134-142Crossref PubMed Scopus (200) Google Scholar which may occur in celiac disease,16Dickey W. Stewart F. Nelson J. McBreen G. McMillan S.A. Porter K.G. Screening for coeliac disease as a possible maternal risk factor for neural tube defect.Clin Genet. 1996; 49: 107-108PubMed Google Scholar, 20Hallert C. Grant C. Grehn S. et al.Evidence of poor vitamin status in coeliac patients on a gluten-free diet for 10 years.Aliment Pharmacol Ther. 2002; 16: 1333-1339Crossref PubMed Scopus (262) Google Scholar none of the 1521 women with celiac disease had babies with neural tube defects. Given the total number of births to women with celiac disease in our study, our finding of no babies with neural tube defects born to these women is what would have been expected as a risk equivalent to that in the general population. With the advantages of a large cohort of women with celiac disease, a general population–based comparison cohort, and well-documented outcomes, we have been able, for the first time, to estimate both overall fertility and risks of various pregnancy-related outcomes with reasonable precision. We also stratified fertility rates by maternal age, making them equivalent and thus comparable to age-specific general fertility rates in national data.26Office for National Statistics. Population trends: summer 2003. No. 112. Published with permission of the Controller of Her Majesty's Stationery Office (HMSO). Office for National Statistics, London, England, 2003.Google Scholar There have been several validation studies of births and other pregnancy-related outcomes in the GPRD indicating that recording these outcomes in the up-to-standard general practice record is accurate and complete. We therefore believe that underrecording of birth outcomes and differential recording between women with and without celiac disease is unlikely. In relation to our cohort, celiac disease has not been specifically validated in the GPRD; however, Lewis and colleagues' finding25Lewis J.D. Brensinger C. Bilker W.B. Strom B.L. Validity and completeness of the General Practice Research Database for studies of inflammatory bowel disease.Pharmacoepidemiol Drug Saf. 2002; 11: 211-218Crossref PubMed Scopus (157) Google Scholar of a highly specific use of diagnostic codes in inflammatory bowel disease (92% confirmed with the diagnosis) is reassuring because this is an analogous gastrointestinal disease. In addition, when we increased the specificity of our diagnosis by restricting our analysis to only women with a record for a gluten-free prescription, our overall findings did not change substantially. Our choice of potential confounders was guided by the existing literature on celiac disease and pregnancy. We selected only covariates that had an independent relationship with both exposure and outcome32Rothman K.J. Greenland S. Modern epidemiology2nd ed. Lippincott-Raven, Philadelphia1998Google Scholar and could be considered to have unbiased recording in the GPRD with respect to celiac disease status. One example of a covariate that would not have met these criteria is iron-deficiency anemia, which is more likely to be investigated in people with celiac disease and may be part of the diagnostic process. The investigation of other pregnancy-related outcomes additionally used data before the up-to-standard fertile record, which means that we included events recorded retrospectively; underrecording was therefore possible. Of concern is whether there were differences in the ascertainment of these events between women with celiac disease and women in our comparison cohort. Women with celiac disease, for example, may have more complete recording of previous miscarriage because of general practitioner concern that miscarriage rates are higher in these women, and this may partially explain the increased risk found in our study. We do not believe that there was underascertainment of stillbirths, however, because the rates in our comparison cohort are similar to national population rates.30Office for National Statistics. Population trends: spring 2003. No. 111. Published with permission of the Controller of Her Majesty's Stationery Office (HMSO). Office for National Statistics, London, England, 2003.Google Scholar No important confounding effects by smoking habits or body mass index were found for fertility rates or pregnancy outcomes, but we acknowledge that missing data are a drawback of using general practice records. No previous study has calculated general fertility rates in women with celiac disease and compared them with rates of women in the general population, although 1 study did find a pattern similar to ours of a generally later maternal age at birth.8Norgard B. Fonager K. Sorensen H.T. Olsen J. Birth outcomes of women with celiac disease a nationwide historical cohort study.Am J Gastroenterol. 1999; 94: 2435-2440Crossref PubMed Google Scholar Small studies of infertile women and men compared with fertile controls have found contrasting results, with either similar33Kolho K.L. 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 Obstet Gynaecol. 1999; 106: 171-173Crossref PubMed Scopus (74) Google Scholar or excess10Sher K.S. Mayberry J.F. Female fertility, obstetric and gynaecological history in coeliac disease a case control study.Acta Paediatr Suppl. 1996; 412: 76-77Crossref PubMed Google Scholar, 11Meloni G.F. Dessole S. Vargiu N. Tomasi P.A. Musumeci S. The prevalence of coeliac disease in infertility.Hum Reprod. 1999; 14: 2759-2761Crossref PubMed Scopus (123) Google Scholar, 34Collin P. Vilska S. Heinonen P.K. Hallstrom O. Pikkarainen P. Infertility and coeliac disease.Gut. 1996; 39: 382-384Crossref PubMed Scopus (180) Google Scholar rates of celiac disease. Not in keeping with our findings, Sher and Mayberry10Sher K.S. Mayberry J.F. Female fertility, obstetric and gynaecological history in coeliac disease a case control study.Acta Paediatr Suppl. 1996; 412: 76-77Crossref PubMed Google Scholar suggested that overall differences in fertility are due to relative infertility before but not after the diagnosis of celiac disease; however, 2 other studies did not find an increase in pregnancies after a gluten-free diet was started.7Smecuol E. Maurino E. Vazquez H. et al.Gynaecological and obstetric disorders in coeliac disease frequent clinical onset during pregnancy or the puerperium.Eur J Gastroenterol Hepatol. 1996; 8: 63-89Crossref PubMed Scopus (95) Google Scholar, 9Ciacci C. Cirillo M. Auriemma G. Di Dato G. Sabbatini F. Mazzacca G. Celiac disease and pregnancy outcome.Am J Gastroenterol. 1996; 91: 718-722PubMed Google Scholar General concern over a link between fertility or pregnancy problems and celiac disease partially originates from the characteristic abnormal villous structure of the small intestine, which results in malabsorption and can lead to minor hematologic abnormalities,14Logan R.F. Tucker G. Rifkind E.A. Heading R.C. Ferguson A. Changes in clinical features of coeliac disease in adults in Edinburgh and the Lothians 1960-79.BMJ. 1983; 286: 95-97Crossref PubMed Scopus (154) Google Scholar anemia,15West J. Logan R.F. Hill P.G. et al.Seroprevalence, correlates, and characteristics of undetected coeliac disease in England.Gut. 2003; 52: 960-965Crossref PubMed Scopus (436) Google Scholar and other selective nutrient deficiencies that play significant roles in pregnancy and fetal development.2Rostami K. Steegers E.A. Wong W.Y. Braat D.D. Steegers-Theunissen R.P. Coeliac disease and reproductive disorders a neglected association.Eur J Obstet Gynecol Reprod Biol. 2001; 96: 146-149Abstract Full Text Full Text PDF PubMed Scopus (93) Google Scholar Studies of adverse pregnancy-related events in women with celiac disease, however, have not consistently shown them to be at increased risk. Two previous studies reported no higher risk of cesarean delivery in women with celiac disease.35Ludvigsson J.F. Ludvigsson J. Coeliac disease in the father affects the newborn.Gut. 2001; 49: 169-175Crossref PubMed Scopus (74) Google Scholar, 36Greco L. Veneziano A. Di Donato L. et al.Undiagnosed coeliac disease does not appear to be associated with unfavourable outcome of pregnancy.Gut. 2004; 53: 149-151Crossref PubMed Scopus (66) Google Scholar In 2 reports of women with recurrent miscarriage, celiac disease was not found to be a risk factor,33Kolho K.L. 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 Obstet Gynaecol. 1999; 106: 171-173Crossref PubMed Scopus (74) Google Scholar, 34Collin P. Vilska S. Heinonen P.K. Hallstrom O. Pikkarainen P. Infertility and coeliac disease.Gut. 1996; 39: 382-384Crossref PubMed Scopus (180) Google Scholar but 2 other studies found a marginal increase in miscarriage for women with untreated celiac disease but not with treated disease.7Smecuol E. Maurino E. Vazquez H. et al.Gynaecological and obstetric disorders in coeliac disease frequent clinical onset during pregnancy or the puerperium.Eur J Gastroenterol Hepatol. 1996; 8: 63-89Crossref PubMed Scopus (95) Google Scholar, 10Sher K.S. Mayberry J.F. Female fertility, obstetric and gynaecological history in coeliac disease a case control study.Acta Paediatr Suppl. 1996; 412: 76-77Crossref PubMed Google Scholar, 13Ferguson R. Holmes G.K. Cooke W.T. Coeliac disease, fertility, and pregnancy.Scand J Gastroenterol. 1982; 17: 65-68Crossref PubMed Scopus (95) Google Scholar Martinelli et al.12 found increased risks of miscarriage, termination, and breech deliveries in women with untreated celiac disease; however, this study was based on only 12 such women, and a subsequent study by the same researchers36Greco L. Veneziano A. Di Donato L. et al.Undiagnosed coeliac disease does not appear to be associated with unfavourable outcome of pregnancy.Gut. 2004; 53: 149-151Crossref PubMed Scopus (66) Google Scholar found no increased risk of termination in 63 women with undiagnosed celiac disease or celiac disease diagnosed around pregnancy. A higher incidence of stillbirth has been found in women with celiac disease compared with those without the disease,10Sher K.S. Mayberry J.F. Female fertility, obstetric and gynaecological history in coeliac disease a case control study.Acta Paediatr Suppl. 1996; 412: 76-77Crossref PubMed Google Scholar and a higher risk of termination has been found in women with untreated vs. treated celiac disease.9Ciacci C. Cirillo M. Auriemma G. Di Dato G. Sabbatini F. Mazzacca G. Celiac disease and pregnancy outcome.Am J Gastroenterol. 1996; 91: 718-722PubMed Google Scholar Despite concern over the consequences of folate deficiency in celiac disease, a lack of data has limited investigation of possible associated congenital anomalies. In a study of 60 cases of neural tube defects, only 1 child was born to a woman with celiac disease.16Dickey W. Stewart F. Nelson J. McBreen G. McMillan S.A. Porter K.G. Screening for coeliac disease as a possible maternal risk factor for neural tube defect.Clin Genet. 1996; 49: 107-108PubMed Google Scholar Our findings represent the largest study of pregnancy-related outcomes in women with celiac disease, and this is the first study that has estimated their fertility. Compared with women in the general population, women with celiac disease have lower fertility at younger ages but catch up at older ages, and this results in the same overall fertility. Because the distribution of age-specific relative fertility was similar in the untreated and treated periods, we think that it is unlikely that the higher relative fertility in the older age groups is due to lower disease activity after women seek treatment in their midfertile years. If it were, then this age-related pattern would not have been apparent after adjusting for whether women were untreated or treated for celiac disease. A more plausible explanation of this later increase in fertility is that it reflects socioeconomic advantages in women with celiac disease. The increased proportion of cesarean section deliveries in women with celiac disease was mostly in the older age groups, and this is also consistent with socioeconomic advantage. Our results indicate that the risks of adverse pregnancy-related outcomes for women with celiac disease are not as high as previously reported. The authors thank the staff of EPIC for their help with the data extraction and Dr. Denise Kendrick for her statistical advice. This article is dedicated to the late Dennis Joseph West.
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