Gastroenterology

Gastroenterology

Volume 144, Issue 4, April 2013, Pages 726-735.e2
Gastroenterology

Original Research
Full Report: Clinical-Alimentary Tract
Levels of Antibodies Against Tissue Transglutaminase During Pregnancy Are Associated With Reduced Fetal Weight and Birth Weight

https://doi.org/10.1053/j.gastro.2013.01.003Get rights and content

Background & Aims

Celiac disease in pregnant women has been associated with poor growth of the fetus, but little is known about how the level of celiac disease affects fetal growth or birth outcomes. We assessed the associations between levels of antibodies against tissue transglutaminase (anti-tTG, a marker of celiac disease) and fetal growth and birth outcomes for pregnant women.

Methods

We performed a population-based prospective birth cohort study of 7046 pregnant women. Serum samples were collected during the second trimester of pregnancy and analyzed for levels of anti-tTG. Based on these levels, the women were categorized into 3 groups: negative anti-tTG (≤0.79 U/mL; n = 6702), intermediate anti-tTG (0.8 to ≤6 U/mL; n = 308), or positive anti-tTG (>6 U/mL; n = 36). Data on fetal growth and birth outcomes were collected from ultrasound measurements and medical records.

Results

Fetuses of women in the positive anti-tTG group weighed 16 g less than those of women in the negative anti-tTG group (95% confidence interval [CI], −32 to −1 g) during the second trimester and weighed 74 g less (95% CI, −140 to −8 g) during the third trimester. Newborns of women in the intermediate and positive anti-tTG groups weighed 53 g (95% CI, −106 to −1 g) and 159 g (95% CI, −316 to −1 g) less at birth, respectively, than those of women in the negative anti-tTG group. The reduction in birth weight in offspring of mothers in the intermediate anti-tTG group was 2-fold greater among mothers who carried HLA-DQ2 or -DQ8 than among those without HLA-DQ2 or -DQ8.

Conclusions

Levels of anti-tTG in pregnant women are inversely associated with fetal growth. Growth was reduced to the greatest extent in fetuses of women with the highest levels of anti-tTG (>6 U/mL). Birth weight was also reduced in women with intermediate levels of anti-tTG (0.8 to ≤6 U/mL) and further reduced in those carrying HLA-DQ2 and -DQ8.

Section snippets

Study Design

This study was embedded within the framework of the Generation R Study, a population-based prospective cohort study in The Netherlands from fetal life onward that has been described in detail previously.24, 25 A total of 8880 mothers with a delivery date between April 2002 and January 2006 were included in this study (Figure 2). Enrollment was aimed at early pregnancy but was allowed until the birth of the child.

Ethics approval for the study was obtained from the Medical Ethical Committee of

Results

Maternal and child characteristics are shown in Table 1. The mean (SD) age of the mothers at enrollment was 30 (5) years. Of the 7046 mothers enrolled in the study, 0.5% had positive anti-tTG levels during pregnancy and 4.4% had intermediate anti-tTG levels (Table 1 and Figure 2). Of the mothers with positive anti-tTG levels, 93% of the total study group and 100% of the Western mothers carried the HLA-DQ2 or -DQ8 molecule. Among the mothers with intermediate anti-tTG, 61% to 62% carried the

Discussion

This prospective observational study showed that both positive and intermediate anti-tTG titers during pregnancy have consequences on fetal growth and birth outcomes. The effect of intermediate anti-tTG levels on birth weight was 2 times greater among mothers carrying the HLA-DQ2 or -DQ8 molecule.

It has been debated whether general population screening for celiac disease is warranted, because large subsets of patients with celiac disease often remain undiagnosed.2, 11, 40 On the one hand, the

Acknowledgments

The Generation R Study is conducted by the Erasmus Medical Center in close collaboration with the Erasmus University Rotterdam School of Law and Faculty of Social Sciences, the Municipal Health Service Rotterdam area, Rotterdam, the Rotterdam Homecare Foundation, Rotterdam, and the Stichting Trombosedienst & Artsenlaboratorium Rijnmond (STAR), Rotterdam. The authors gratefully acknowledge the contribution of general practitioners, hospitals, midwives, and pharmacies in Rotterdam and thank

References (52)

  • F.P. Hadlock et al.

    Estimation of fetal weight with the use of head, body, and femur measurements—a prospective study

    Am J Obstet Gynecol

    (1985)
  • P. Collin

    Should adults be screened for celiac disease?What are the benefits and harms of screening?

    Gastroenterology

    (2005)
  • N.J. Robinson et al.

    Tissue transglutaminase expression and activity in placenta

    Placenta

    (2006)
  • J.J. Schweizer et al.

    Coeliac disease in The Netherlands

    Scand J Gastroenterol

    (2004)
  • A. Tommasini et al.

    Mass screening for coeliac disease using antihuman transglutaminase antibody assay

    Arch Dis Child

    (2004)
  • J. West et al.

    Seroprevalence, correlates, and characteristics of undetected coeliac disease in England

    Gut

    (2003)
  • A. Fasano et al.

    Prevalence of celiac disease in at-risk and not-at-risk groups in the United States: a large multicenter study

    Arch Intern Med

    (2003)
  • A. Tursi et al.

    Prevalence of antitissue transglutaminase antibodies in different degrees of intestinal damage in celiac disease

    J Clin Gastroenterol

    (2003)
  • A. Tursi et al.

    Effect of gluten-free diet on pregnancy outcome in celiac disease patients with recurrent miscarriages

    Dig Dis Sci

    (2008)
  • R. Pope et al.

    Celiac disease during pregnancy: to screen or not to screen?

    Arch Gynecol Obstet

    (2009)
  • A.S. Khashan et al.

    The impact of maternal celiac disease on birthweight and preterm birth: a Danish population-based cohort study

    Hum Reprod

    (2010)
  • K.S. Sher et al.

    Female fertility, obstetric and gynaecological history in coeliac disease: a case control study

    Acta Paediatr Suppl

    (1996)
  • P. Martinelli et al.

    Coeliac disease and unfavourable outcome of pregnancy

    Gut

    (2000)
  • L. Greco et al.

    Undiagnosed coeliac disease does not appear to be associated with unfavourable outcome of pregnancy

    Gut

    (2004)
  • I. Cetin et al.

    Role of micronutrients in the periconceptional period

    Hum Reprod Update

    (2010)
  • N. Anjum et al.

    Maternal celiac disease autoantibodies bind directly to syncytiotrophoblast and inhibit placental tissue transglutaminase activity

    Reprod Biol Endocrinol

    (2009)
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    Conflicts of interest The authors disclose no conflicts.

    Funding This phase of the Generation R Study was made possible by financial support from the Erasmus Medical Center Rotterdam, the Erasmus University Rotterdam, and the Netherlands Organization for Health Research and Development (ZonMw) and an unrestricted grant from European Container Terminals (ECT). The funding sources had no role in the study design, implementation, analysis, interpretation, and preparation of the manuscript.

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