Celiac disease and obstetric complications: a systematic review and metaanalysis

Celiac disease and obstetric complications: a systematic review and metaanalysis

Accepted Manuscript Celiac disease and obstetric complications: a systematic review and meta-analysis Gabriele Saccone, MD, Vincenzo Berghella, MD, La...

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Accepted Manuscript Celiac disease and obstetric complications: a systematic review and meta-analysis Gabriele Saccone, MD, Vincenzo Berghella, MD, Laura Sarno, MD, Giuseppe M. Maruotti, MD, PhD, Irene Cetin, MD, Luigi Greco, MD, Ali S. Khashan, PhD, MD, PhD Fergus McCarthy, Domenico Martinelli, MD, Francesca Fortunato, MD, Pasquale Martinelli, MD PII:

S0002-9378(15)01194-1

DOI:

10.1016/j.ajog.2015.09.080

Reference:

YMOB 10668

To appear in:

American Journal of Obstetrics and Gynecology

Received Date: 26 May 2015 Revised Date:

11 September 2015

Accepted Date: 21 September 2015

Please cite this article as: Saccone G, Berghella V, Sarno L, Maruotti GM, Cetin I, Greco L, Khashan AS, McCarthy ; F, Martinelli D, Fortunato F, Martinelli P, Celiac disease and obstetric complications: a systematic review and meta-analysis, American Journal of Obstetrics and Gynecology (2015), doi: 10.1016/j.ajog.2015.09.080. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

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Celiac disease and obstetric complications: a systematic review and meta-analysis

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Gabriele Saccone MD;1 Vincenzo Berghella MD;2 Laura Sarno MD;1 Giuseppe M Maruotti MD,

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PhD;1 Irene Cetin MD;3 Luigi Greco MD;4 Ali S Khashan PhD;5,6 Fergus McCarthy MD, PhD;6,7

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Domenico Martinelli MD;8 Francesca Fortunato MD;8 Pasquale Martinelli MD1

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University of Naples Federico II, Naples, Italy

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Kimmel Medical College of Thomas Jefferson University, Philadelphia, PA, USA

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Department of Neuroscience, Reproductive Sciences and Dentistry, School of Medicine,

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Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, Sidney

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Department of Biomedical and Clinical Sciences, School of Medicine, University of Milan,

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Milan, Italy

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Naples, Italy

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Department of Epidemiology and Public Health, University College Cork, Cork, Ireland

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The Irish Centre for Fetal and Neonatal Translational Research (INFANT), University College

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Cork, Cork, Ireland

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Division of Women’s Health, Women’s Health Academic Centre, King’s College, London, UK

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Department of Medical and Surgical Sciences, School of Medicine, University of Foggia,

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Foggia, Italy

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Correspondence: Pasquale Martinelli, MD, Department of Neuroscience, Reproductive

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Sciences and Dentistry, School of Medicine, University of Naples Federico II, Naples, Italy

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Email: [email protected]

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Disclosure: The authors report no conflict of interest

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Financial Support: No financial support was received for this study

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Word count: Abstract 344; Text 2120; Tables 3; Figures 12

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Department of Translational Medicine, School of Medicine, University of Naples Federico II,

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Obstetrics

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Key words: Preterm birth; celiac disease; pregnancy; small for gestational age; metaanalysis

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Condensation

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Women with celiac disease had a significantly higher risk of developing obstetric complications.

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Short Title

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Celiac disease and obstetric complications

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ABSTRACT

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Objective: The aim of this meta-analysis was to evaluate the risk of developing obstetric

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complications in women with celiac disease.

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Data Sources: Electronic databases were searched from their inception until February 2015.

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Study eligibility criteria: We included all cohort studies reporting the incidence of obstetric

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complications in women with celiac disease compared to women without celiac disease (i.e.

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control group). Studies without a control group and case-control studies were excluded.

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Study appraisal and synthesis methods: The primary outcome was defined a priori and was the

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incidence of a composite of obstetric complications including intrauterine growth restriction

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(IUGR), small for gestational age (SGA), low birth weight (LBW), preeclampsia and preterm

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birth (PTB). Secondary outcomes included the incidence of PTB, IUGR, stillbirth, preeclampsia,

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SGA and LBW. The review was registered with PROSPERO (CRD42015017263) before data

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extraction. All authors were contacted in order to obtain the original databases and perform

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individual participant data (IPD) meta-analysis. Primary and secondary outcomes were assessed

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in the aggregate data analysis as well as in the IPD meta-analysis.

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Results: We included 10 cohort studies (4,844,555 women) in this meta-analysis. Four authors

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kindly provided the entire databases for the IPD analysis. Since that none of the included studies

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stratified data for the primary outcome (i.e. composite outcome) assessing this outcome for the

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aggregate analysis was not feasible. Aggregate data analysis showed that, compared to women in

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the control group, women with celiac disease (both treated and untreated) had a significantly

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higher risk of developing PTB (aOR 1.35, 95% CI 1.09 to 1.66), IUGR (OR 2.48, 95% CI 1.32

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to 4.67), stillbirth (OR 4.84, 95% CI 1.08 to 21.75), LBW (OR 1.63, 95% CI 1.06 to 2.51), and

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SGA (OR 4.52; 95% CI 1.02 to 20.08), while no statistically significant difference was found in

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the incidence of preeclampsia (OR 2.45, 95% CI 0.90 to 6.70). The risk of PTB was still

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significantly higher both in subgroup analysis of only diagnosed and treated celiac disease

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women (OR 1.26, 95% CI 1.06 to 1.48) and in subgroup analysis of only undiagnosed and

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untreated celiac disease women (OR 2.50, 95% CI 1.06 to 5.87). Women with diagnosed and

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treated celiac disease had a significantly lower risk of developing PTB compared to undiagnosed

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and untreated celiac disease (OR 0.80, 95% CI 0.64 to 0.99). The IPD meta-analysis showed that

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women with celiac disease had a significantly higher risk of composite obstetric complications

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compared to controls (OR 1.51, 95% CI 1.17 to 1.94). Our IPD concurs with the aggregate

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analysis for all the secondary outcomes.

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Conclusions: In summary, women with celiac disease had a significantly higher risk of

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developing obstetric complications including PTB, IUGR, stillbirth, LBW and SGA.

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Introduction

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Celiac disease is a genetically determined autoimmune condition, with an estimated worldwide

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prevalence of about 1%.1 It is usually diagnosed by duodenal biopsy performed at the time of endoscopy.1 Celiac disease is induced by the ingestion of gluten and the only treatment available

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is the elimination of gluten from the diet.1

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Once considered a gastrointestinal disease of childhood, celiac disease is now recognized as a

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systemic disease. The most frequent signs and symptoms are weight loss and chronic diarrhea.1

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Complications include disorders of fertility as well as pregnancy complications.1,2 Women with

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unexplained infertility or recurrent miscarriage were found to have a significantly higher risk of

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celiac disease than the general population maybe due to the nutrient deficiencies as well as the

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increased level of serum autoantibodies.1,2 In 2014 a large epidemiologic study showed an

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increased risk for malformation among the offspring of mothers or fathers with celiac disease.3

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Moreover, so far, the effect of a gluten-free diet on prevention of celiac disease complications in

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pregnancy is still a subject of debate.1

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Objective

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The aim of this meta-analysis was to evaluate the risk of developing obstetric complications in

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women with celiac disease.

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Methods

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Search strategy

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This review was performed according to a protocol designed a priori and recommended for

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systematic review.4 Electronic databases (MEDLINE, PROSPERO, Scopus, ClinicalTrials.gov,

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EMBASE, Sciencedirect, the Cochrane Library) were searched from their inception until

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February 2015 with no limit for language. Search terms used were the following text words:

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“celiac;” “celiac disease;” “coeliac;” “coeliac disease;” “preterm birth;” “small for gestational

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age;” “miscarriage;” “pregnancy;” “premature;” “newborn;” “low birth weight;” “fertility;”

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“preeclampsia;” “recurrent;” “intrauterine growth restriction;” “stillbirth;” “pregnancy;”

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“obstetric;” “complications” and “spontaneous preterm birth.” No restrictions for language or

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geographic location were applied. In addition, the reference lists of all identified articles were

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examined to identify studies not captured by electronic searches. The electronic search and the

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eligibility of the studies were independently assessed by two authors (GS, VB). Differences were

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discussed and consensus reached.

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Study selection

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We included all cohort studies reporting the incidence of obstetric complications in women with

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celiac disease compared to women without celiac disease (i.e. control group). Studies without a

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control group and case-control studies were excluded.

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Data extraction

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Data abstraction was completed by two independent investigators (GS, LS). Each investigator

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independently abstracted data from each study separately. Data from each eligible study were

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extracted without modification of original data onto custom-made data collection forms.

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Disagreements were resolved by consensus with a third reviewer (PM). Information on potential

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confounders that were adjusted for and adjusted risk estimates were collected when available. All

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authors were contacted in order to obtain the original databases and perform individual patient

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level meta-analysis.

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Two reviewers (GS, VB) independently assessed the risk of bias of the included studies via the

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Methodological Index for Non-Randomized Studies (MINORS).5 Seven domains related to risk

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of bias were assessed in each study: 1) Aim (i.e. clearly stated aim), 2) Rate (i.e. inclusion of

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consecutive patients and response rate), 3) Data (i.e. prospective collection of data), 4) Bias (i.e.

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unbiased assessment of study end points), 5) Time (i.e. follow-up time appropriate), 6) Loss (i.e.

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loss to follow-up), 7) Size (i.e. calculation of the study size).5 Review authors’ judgments were

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categorized as “low risk,” “high risk” or “unclear risk of bias.” Discrepancies were resolved by

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discussion with a third reviewer (PM).

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The primary outcome was defined a priori and was the incidence of a composite of obstetric

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complications including at least one of the following: intrauterine growth restriction (IUGR) (i.e.

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ultrasound estimated fetal weight <10th percentile for gestational age), small for gestational age

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(SGA) (i.e. birth weight <10th percentile for gestational age), low birth weight (LBW) (i.e. birth

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weight <2500 grams), preeclampsia and preterm birth (PTB) (i.e. PTB<37 weeks). Secondary

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outcomes included the incidence of PTB, IUGR, stillbirth, preeclampsia, SGA and LBW. We

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planned to assess the incidence of PTB in subgroup analysis in women with treated and untreated

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celiac disease. Diagnosed and treated celiac disease is thereafter called for simplicity just

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“treated celiac disease”; and undiagnosed and untreated celiac disease is called for simplicity just

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“untreated celiac disease.” Women were classified as having the celiac disease diagnosis and

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treatment before pregnancy (treated celiac disease) or afterward (untreated celiac disease).

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Data analysis

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The data analysis was completed independently by two authors (GS, VB) using Review Manager

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v. 5.3 (The Nordic Cochrane Centre, Cochrane Collaboration, 2014, Copenhagen, Denmark) and

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Statistical Package for Social Sciences (SPSS) v. 19.0 (IBM Inc., Armonk, New York, USA).

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Inconsistencies were discussed by the reviewers and consensus reached. Heterogeneity across

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studies was assessed using the Higgins I2 test.4 In case of statistically significant heterogeneity

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(I2≥0%) the random effects model of DerSimonian and Laird was used, otherwise a fixed effect

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model was performed. The pooled results from the aggregate meta-analysis were reported as

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odds ratio (OR) with 95% confidence interval (CI). Potential publication biases were assessed

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graphically by using funnel plot and statistically by using Begg’s and Egger’s tests.4

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In line with other meta-analyses, no adjustment for risk estimates was made.4 For studies which

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reported both unadjusted and adjusted risk for confounders statistically proven, we performed an

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aggregate data meta-analysis using generic inverse variance method in order to obtain the

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adjusted odds ratio (aOR) for the incidence of PTB in the aggregate data analysis.4,6

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To use the data as best as possible, we also combined the obtained databases in order to assess an

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individual patient-level meta-analysis. Primary and secondary outcomes were assessed in both

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aggregate and patient-level data analysis. We expressed continuous variables as mean with

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standard deviation and categorical variables as number with percentage. Chi-square Test and

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Fisher’s exact test were used for categorical variables and Student’s t test or Mann-Whitney Test

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for normally and non-normally distributed continuous variables, respectively. P-value <0.05 was

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considered statistically significant.

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The meta-analysis was reported following the Preferred Reporting Item for Systematic Reviews

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and Meta-analyses (PRISMA) statement.7 Before data extraction, the review was registered with

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the PROSPERO International Prospective Register of Systematic Reviews (registration No.:

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CRD42015017263) following the PRIMA guidelines for protocols (PRIMSA-P).8

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Results

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Study selection and study characteristics

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The flow of study identification is shown in Figure 1. Seventeen full-text articles were assessed

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for eligibility.9-25 Seven studies were excluded.15-20,25 Six because they evaluated the incidence of

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celiac disease among women with obstetric complications (i.e. case-control studies),15-20 and

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one25 since it was based on the same cohort as a more recent study.23

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Ten cohort studies, including 4,844,555 women, were analyzed.9-14,21-24 All studies reported the

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incidence of obstetric complications in women with celiac disease compared to women without

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celiac disease (i.e. control group). Four studies reported separate analyses and subgroup analysis

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for women with undiagnosed and untreated celiac disease (i.e. untreated celiac disease). 11,14,21,23

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In all included studies, diagnosis of celiac disease was based on either duodenal biopsy or level

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of serum autoantibodies.

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Risk of publication bias was assessed by visual inspection of funnel plot, and the symmetric plot

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suggested no publication bias (Figure 2). Publication bias, assessed using Begg’s and Egger’s

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tests, showed no significant bias (P=0.19 and P=0.10, respectively). Table 1 shows the

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characteristics of the included studies. Most of them (nine out of the ten) originated from Europe.

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Eight studies included only singleton gestations.9-11,14,21-24 The quality of the studies included in

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our meta-analysis was assessed by the MINORS’ tool for assessing the risk of bias (Figure 3).4

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All studies had low risk of bias in “aim,” and the majority in “rate” and in “time.” Four of the

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them were retrospective cohort studies,11-13,22 three were prospective,9,10,24 while the other three

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were large high-quality population-based cohort study.14,21,23 Four authors kindly provided the

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entire databases from their study in order to obtain additional and unpublished data and perform

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individual patient level meta-analysis.10,11,22,24

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Synthesis of results

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Since that none of the included studies stratified data for the primary outcome (i.e. composite

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outcome) assessing this outcome for the aggregate data analysis was not feasible.

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Compared to control group, women with celiac disease (both treated and untreated) had a

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significantly higher risk of developing PTB (OR 1.40, 95% CI 1.18 to 1.6, Figure 4; aOR 1.35,

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95% CI 1.09 to 1.66, Figure 5), IUGR (OR 2.48, 95% CI 1.32 to 4.67, Figure 6), stillbirth (OR

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4.84, 95% CI 1.08 to 21.75, Figure 7), LBW (OR 1.63, 95% CI 1.06 to 2.51, Figure 8), and SGA

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(OR 4.52; 95% CI 1.02 to 20.08; Figure 9), while no statistically significant difference was

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found in the incidence of preeclampsia (OR 2.45, 95% CI 0.90 to 6.70, Figure 10).

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The risk of PTB was still significantly higher both in subgroup analysis of only treated celiac

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disease women (OR 1.26, 95% CI 1.06 to 1.48; Figure 11) and in subgroup analysis of only

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untreated celiac disease women (OR 2.50, 95% CI 1.06 to 5.87; Figure 12). However, women

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with treated celiac disease had a significantly lower risk of developing PTB compared to those

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with untreated celiac disease (OR 0.80, 95% CI 0.64 to 0.99).

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Table 2 shows the characteristics of the women included in the individual participant data (IPD)

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meta-analysis. The two groups were similar in terms of maternal demographics. Four studies

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including 5,792 singleton gestations were analyzed.10,11,22,24 258 of the women included were

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women with celiac disease (both treated and untreated), while 5,534 were women without celiac

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disease. Table 3 shows the pooled results of the individual patient level meta-analysis. Not all the

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outcomes have been registered in every database; results therefore are accompanied with the

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number of cases in which the outcomes were registered. Compared to control group, women with

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celiac disease (both treated and untreated) had a significantly higher risk of developing PTB (OR

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2.08, 95% CI 1.36 to 3.20), IUGR (OR 5.01, 95% CI 1.25 to 20.04), stillbirth 24.94, 95% CI

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11.13 to 55.84), LBW (6.29, 95% CI 1.83 to 21.60), and SGA (OR 8.50, 95% CI 1.85 to 38.97),

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while no statistically significant difference was found in the incidence of preeclampsia (OR

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20.17, 95% CI 0.81 to 502.43). Using the IPD meta-analysis we were able to assess also the

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primary outcome (defined as at least one of the following: IUGR, SGA, LBW and PTB); women

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with celiac disease had a significantly higher risk of composite obstetric complications compared

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to controls (OR 1.51, 95% CI 1.17 to 1.94).

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Comment

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Main findings

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This meta-analysis showed that women with celiac disease (both treated and untreated) had a

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significantly higher risk of developing obstetric complications, including PTB, IUGR, stillbirth,

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LBW and SGA while no statistically significant difference was found in the incidence

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preeclampsia. The risk of PTB was higher both in treated and in untreated women. However,

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women with diagnosed and treated celiac disease had a 20% significant decrease of PTB

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compared to those with undiagnosed and untreated celiac disease at the time of pregnancy. Our

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individual patient level analysis concurs with the aggregate analysis.

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Comparison with existing literature

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A previous meta-analysis showed that celiac disease was associated with reproductive disorders

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and pregnancy complications (i.e. unexplained infertility and recurrent miscarriage).2 However,

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it did not include all currently available studies, outcomes considered were different, subgroup

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analyses and individual patient level meta-analysis were not performed and the number of

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included women was lower. Moreover, pooled adjusted risk estimates were not assessed.2 No

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other prior pertinent meta-analyses were found during the search process.

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Strengths and limitations

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Our study has several strengths. To our knowledge, no prior meta-analysis on this issue is as

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large or comprehensive. The number of the included women is very high. Most of the included

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studies had low risk of bias. Statistical heterogeneity between the studies was low. Individual

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patient level meta-analysis was assessed for studies in which the original databases were

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obtained.

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Limitations of our study are inherent to the limitations of the included studies. All the included

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studies were cohort studies. While all authors of the included studies were contacted, only four

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of them provide the entire database for the individual patient level analysis. Data regarding PTB

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referred to both spontaneous and indicated as etiology of PTB. Notably, although the OR was

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2.45 for preeclampsia in the celiac versus non-celiac disease group, this was not statistically

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significant with the frequency occurring in these two groups (2.7% vs 2.8%, respectively; Figure

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10). This could suggest that the difference noted in the PTB rate between the two groups was due

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to a spontaneous etiology, such as a preterm labor or preterm rupture of membranes. The

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prespecified primary outcome of our review registered on PROSPERO (CRD42015017263) was

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an obstetric complication composite; however, assessing this outcome in the aggregate data

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analysis was not feasible. The individual patient level meta-analysis was post hoc and so it is not

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reported in the PROSPERO. Most outcomes had very high statistically heterogeneity and this

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was a major shortcoming of the meta-analysis. Older studies may not reflect current practice and

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outcomes. None of the included studies adjusted for weight gain as possible confounder.

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Conclusions and Implications

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The biological plausibility to explain the higher risk of obstetrical complications in women with

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celiac disease is not completely clear. However, two main hypotheses can be made. The

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malabsorption which characterize celiac disease may lead to nutrient deficiencies, which can be

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associated with adverse pregnancy outcomes.26 Specifically, IUGR, SGA and LBW have been

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associated with maternal micronutrient deficiencies.27 Furthermore, women with celiac disease

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often show increased level of serum autoantibodies, including anti-transglutamines and anti-

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thyroid antibodies,1,28-31 which have been linked to several pregnancy complications such as PTB

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and stillbirth.32-34

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Since a gluten-free diet reduces antibodies and leads to an improvement of intestinal function

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and nutrients availability,1,35-37 this may explain why treated celiac women have better pregnancy

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outcomes than untreated women.

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In summary, women with celiac disease (both treated and untreated) had a significantly higher

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risk of developing obstetric complications. Since the treatment with gluten-free diet leads to a

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significant decrease of PTB, physicians should warn these women about the importance of a

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strict diet to improve obstetric outcomes. Future studies calculating cost-effectiveness of

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screening for celiac disease during pregnancy, which could be easily performed, economically

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and noninvasively,38 are needed. In addition, further studies are required to determine whether

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women with adverse pregnancy outcomes should be screened for celiac disease, particularly in

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countries where the prevalence is high.

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19. Wolf H, Ilsen A, van Pampus MG et al. Celiac serology in women with severe preeclampsia or delivery of a small for gestational age neonate. Int J Gynaecol Obstet, 2008;

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22. McCarthy FP, Khashan AS, Quigley E, Shanahan F, O Regan P, Cronin C, Kenny L. Undiagnosed maternal celiac disease in pregnancy and an increased risk of fetal growth restriction. J Clin Gastroenterol, 2009; 43:792-3

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23. Khashan AS, Henriksen TB, Mortensen PB et al. The impact of maternal celiac disease

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on birthweight and preterm birth: a Danish population-based cohort study. Human

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24. Martinelli D, Fortunato F, Tafuri S et al. Reproductive life disorders in Italian celiac women. A case-control study. BMC Gastroenterol, 2010; 10:89-97

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25. Norgard B, Fonager K, Sorensen HT, Olsen J. Birth outcomes of women with celiac

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disease: a nationwide historical cohort study. Am J Gastroenterol, 1999; 94:2435-40 26. Kubler W. Nutritional deficiencies in pregnancy. Bibl Nutr Dieta, 1981; 30:17-29

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27. Cetin I, Mando C, Calabrese S. Maternal predictors of intrauterine growth restriction.

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28. Dieterich W, Ehnis T, Bauer M et al. Identification of tissue transglutaminase as the autoantigen of celiac disease. Nature Med, 1997; 3:797-801

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29. Maki M. Tissue transglutaminase as the autoantigen of coeliac disease. Gut, 1997; 41:565-6

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30. Richey R, Howdle P, Shaw E, Stokes T. Guidelines Development Group. Recognition

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31. Ch’ng CL, Jones MK, Kingham JG. Celiac disease and autoimmune thyroid disease. Clin Med Res, 2007; 5:184-92

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34. Carp HJ, Meroni PL, Shoenfeld Y. Autoantibodies as predictors of pregnancy

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complications. Rheymatology, 2008; 47:6-8

35. Kupper. Dietary guidelines and implementation for celiac disease. Gastroenterology, 2005; 128:121-7

36. Ciacci C, Cirillo M, Cavallaro R, Mazzacca G. Long-term follow-up of celiac adults on

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gluten-free diet: prevalence and correlates of intestinal damage. Digestion, 2002;66:178-

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38. Troncone R, Maurano F, Rossi M et al. IgA antibodies to tissue transglutaminase: an effective diagnostic test for celiac disease. J Pediatr, 1999; 134:166-71

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TABLES

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Table 1. Characteristics of the included studies Study

Study period Type of

location

study

Number of

Confounders Outcomes

RI PT

427

included

adjusted

assessed

None

Miscarriage,

women* United

2005-2006

Kingdom Italy

cohort 1998-1999

200010

TE D

cohort

Italy

Greco

Prospective

136 (68 vs 68)

218 (12 vs

M AN U

Martinelli

Prospective

SC

Sher 19969

2001-2002

AC C

Tata 200512 United

Kingdom

1987-2002

Maternal age,

PTB,

prior PTB,

stillbirth

socioeconomic status, smoking

Retrospective

5,076 (79 vs Maternal age,

cohort

4,997)

EP

200411

206)

stillbirth

IUGR

smoking, socioeconomic status

Retrospective

9,244

Socio-

Cesarean

cohort

(1,521 vs

economic

section,

7,723)

status

Stillbirth, preeclampsia,

17

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IUGR 1964-2001

200521

Sheiner

Israel

1988-2002

200613 McCarthy

Ireland

N/R

200922

Population-

2,817,400

Maternal age,

PTB, IUGR,

based cohort

(2,071 vs

parity,

LBW

2,815,329)

nationality

Retrospective

143,711 (48

None

cohort

vs 143,663)

Retrospective

270 (118 vs

Maternal age,

SGA, Birth

152)

maternal

weight

Northern

201023

Europe

1979-2004

Italy

2008

201024 Abdul-

United

1997-2012

preeclampsia

gestational age, infant sex and year of birth

1,504,342

Maternal age,

based cohort

(1,451 vs

parity,

1,502,891)

paternal age,

PTB, SGA

maternal chronic

AC C Martinelli

IUGR,

BMI,

Population-

EP

Khashan

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M AN U

cohort

RI PT

Sweden

SC

Ludvigsson

medical conditions Prospective

228 (49 vs

cohort

179)

Population-

363,930

18

None

IUGR

BMI,

PTB,

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Sultan

Kingdom

based cohort

201414

(892 vs

smoking

363,038)

stillbirth, LBW, preeclampsia

-

-

-

4,844,555

-

RI PT

Total

-

(6,309 vs

4,838,246)

LBW, low birth weight; PTB, preterm birth; IUGR, intra uterine growth restriction; BMI, body

430

mass index; SGA, small for gestational age; N/R, not reported.

431

Boldface data: primary outcome. Primary outcome not reported for Ludvigsson et al.21 and

432

Abdul-Sultan et al.14

433

*Number (N) of included women: total N (N of celiac women vs N of non-celiac women)

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SC

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437

438

439

EP

436

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435

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434

440

441

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Table 2. Characteristics of the women included in the individual patient level meta-analysis

Age

Women with celiac

Women without celiac

disease

disease

N = 258

N = 5,534

27±4.5

26±3.7

p value

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442

0.87

0.91

25 (98.8%)

5504 (99.5%)

Others*

3 (1.2%)

30 (0.5%)

BMI

23±3.2

23±4.4

Smoker

25 (9.7%)

500 (9.0%)

0.94

Maternal Diabetes

4 (1.6%)

105 (1.8%)

0.72

Maternal

5 (1.9%)

112 (2.0%)

0.96

2190 (39.8%)

0.09

-

-

Hypertension or renal disease 113 (43.8%)

Untreated celiac

67 (26.0%)

disease women

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Nulliparous

SC

European

M AN U

Ethnicity

0.92

Data are presented as number (percentage) or as mean ± standard deviation; BMI, body mass

444

index; PTB, preterm birth; Untreated celiac disease women, women having the celiac disease

445

diagnosis after the index pregnancy.

446

*Others: including Caribbean, Asian, Sub-saharan Africa, Middle East

448 449

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Table 3. Outcomes of the women included in the individual patient level meta-analysis

Primary

Women with

Women without

celiac disease

celiac disease

107/258 (41.5%)

1,769/5,534

OR (95% CI)

10%

1.51 (1.17 to

(32.0%)

outcome* 35/91 (38.5%)

PTB

I2

1,264/5,203

1.94)

0%

(24.3%)

Preeclampsia

SGA

33/91 (36.3%)

43/142 (30.3%)

5/12 (41.7%)

22/5,203 (0.5%)

0%

512/5,203 (9.9%)

354/5,355 (6.7%)

21/206 (10.2%)

78%

5%

0%

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LBW

9/91 (9.9%)

0%

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Stillbirth

298/5,382 (5.6%)

2.08 (1.36 to 3.20)

M AN U

28/140 (20.0%)

IUGR

RI PT

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5.01 (1.25 to 20.04) 24.94 (11.13 to 55.84) 20.17 (0.81 to 502.43) 8.50 (1.85 to 38.97) 6.29 (1.83 to 21.60)

Data are presented as number (percentage); PTB, preterm birth; IUGR, intrauterine growth

455

restriction; SGA, small for gestational age, LBW, low birth weight; OR, odds ratio; CI,

456

confidence interval. Boldface data, statistically significant

457

Not all the outcomes have been registered in every database; results therefore are accompanied

458

with the number of cases in which the outcomes were registered (n). Proportions are presented

459

as percentage of n, rather than as percentages of the total population

460

* Incidence of composite obstetric complications including IUGR, SGA, LBW, preeclampsia and

461

PTB

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FIGURES

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Figure 1. Flow diagram of studies identified in the systematic review. (Prisma template

467

[Preferred Reporting Item for Systematic Reviews and Meta-analyses])

468

Figure 2. Funnel plot for assessing publication bias. OR, odds ratio; SE, standard error

469

Figure 3. Assessment of risk of bias. Aim, clearly stated aim; Rate, inclusion of consecutive

470

patients and response rate; Data, prospective collection of data; Bias, unbiased assessment of

471

study end points; Time, follow-up time appropriate; Loss, loss to follow-up; Size, calculation of

472

the study size. (A) Summary of risk of bias for each study. Plus sign, low risk of bias; minus

473

sign, high risk of bias; question mark, unclear risk of bias. (B) Risk of bias graph about each risk

474

of bias item presented as percentages across all included studies.

475

Figure 4. Unadjusted estimates forest plot for the risk of preterm birth in women with celiac

476

disease. M-H, Mantel-Haenszel test; CI, confidence interval; PTB, preterm birth

477

Figure 5. Adjusted estimates forest plot for the risk of preterm birth in women with celiac

478

disease. IV, independent variable; SE, standard error; CI, confidence interval; PTB, preterm

479

birth

480

Figure 6. Forest plot for the risk of intrauterine growth restriction (i.e. ultrasound estimated fetal

481

weight <10th percentile for gestational age) in women with celiac disease. M-H, Mantel-Haenszel

482

test; CI, confidence interval; IUGR, intrauterine growth restriction

483

Figure 7. Forest plot for the risk of stillbirth in women with celiac disease. M-H, Mantel-

484

Haenszel test; CI, confidence interval.

485

Figure 8. Forest plot for the risk of low birth weight (i.e. birth weight <2500 grams) in women

486

with celiac disease. M-H, Mantel-Haenszel test; CI, confidence interval, LBW, low birth weight

487

Figure 9. Forest plot for the risk of small for gestational age (i.e. birth weight <10th percentile

488

for gestational age) in women with celiac disease. SGA, small for gestational age; M-H, Mantel-

489

Haenszel test; CI, confidence interval.

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Figure 10. Forest plot for the risk of preeclampsia in women with celiac disease. M-H, Mantel-

491

Haenszel test; CI, confidence interval; PE, preeclampsia

492

Figure 11. Forest plot for the risk of developing preterm birth in women with treated celiac

493

disease. M-H, Mantel-Haenszel test; CI, confidence interval; PTB, preterm birth

494

Figure 12. Forest plot for the risk of developing preterm birth in women with untreated celiac

495

disease. M-H, Mantel-Haenszel test; CI, confidence interval; PTB, preterm birth

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