CD: Pregnancy Outcomes (2006)

Citation:
 
Study Design:
Class:
- Click here for explanation of classification scheme.
Quality Rating:
Research Purpose:
A case-control design was used to compare pregnancy outcome in untreated and treated women with celiac disease.  Second, treated women with celiac disease were analyzed to determine whether the outcome of pregnancy relates to the severity of the disease.  Finally, the intraindividual effect of gluten-free diet on outcome of pregnancy was analyzed in treated and untreated women with celiac disease.
Inclusion Criteria:
Celiac disease as confirmed by second jejunal biopsy that showed improvement of mucosal lesions after gluten-free diet, reporting at least 1 pregnancy after development of celiac disease.  Treated women had followed a gluten-free diet for 1 year.  The criteria for a "subclinical" (less severe) form of celiac disease were the presence/absence of diarrhea (3 or more bowel movements per day) or the presence/absence of anemia (blood hemoglobin <10 g/100 ml and/or recent IV iron therapy). 
Exclusion Criteria:
Excluded if not included above.  No cases of stillbirth and of voluntary interruption of  pregnancy were reported, therefore, these indices were not included in the analysis.
Description of Study Protocol:

Recruitment

Women with celiac disease treated by the National Health Care System who are currently seen and participate in a follow-up program.

Design

Designed as a case-control and before and after study.

Blinding used (if applicable)

Not applicable.

Intervention (if applicable)

Gluten-free diet for 1 year.

Statistical Analysis

The number of abortions and of other indices depending on the number of pregnancies were expressed in some analyses as the ratio of the given variable per pregnancy, to control for the differences in the reported number of pregnancies.  For duration of breast feeding, the absolute number of months was used for analysis.  For women reporting more than 1 baby, the average value was used.  Student's t test for unpaired and paired comparisons and the estimate of the odds ratio according to Maentel-Haenszel were used, as appropriate.  Data are presented as mean +/- SE unless otherwise indicated.

Data Collection Summary:

Timing of Measurements

Data at time of diagnosis with regard to age, anthropometry, 5 indices of pregnancy outcome, presence of diarrhea and of anemia were taken from patient clinical records.  After gluten-free diet treatment initiated, data about indices of pregnancy outcome collected yearly at follow-up exams.

Dependent Variables

  • Abortion, defined as interruption of pregnancy occurring within 28 weeks of conception
  • Threatened abortion, defined as abdominal pain followed by womb bleeding, not by abortion
  • Premature delivery, defined as labor occurring before the 36th week from conception
  • Low birth weight baby, defined as a newborn weighing less than 2500 g
  • Duration of breast feeding (months) per each pregnancy.  For formula feeding, duration was coded as 0.

Independent Variables

  • Gluten free diet for 1 year.  Diet not defined and compliance not monitored.

Control Variables

 

Description of Actual Data Sample:

Initial N: Subgroup of 137 women from the cohort. 

Attrition (final N): 125 women.  Case-control comparison consisted of untreated women (n=94) and treated women (n=31).  Before-after analysis based on 12 women.

Age:  Not mentioned.    

Ethnicity:  Not mentioned. 

Other relevant demographics:  Age at diagnosis was significantly lower among treated women (37.3 +/- 1.2 years vs 22.4 +/- 1.6 years), who had been followed for 9.2 +/- 1.4 years. 

Anthropometrics: At time of diagnosis, anthropometric indices were not different in the untreated and treated groups.

Location:  Italy 

 

Summary of Results:

 

 

 

Untreated

Treated

P value

Number of women

94

31

NS

Age at diagnosis (yr)

37.3 +/- 1.2

22.4 +/- 1.6

p < 0.01

Weight (kg)

50.6 +/- 1.9

50.0 +/- 1.6

NS

Height (m)

1.59 +/- 0.01

1.62 +/- 0.06

NS

BMI

20.1 +/- 1.2

19.4 +/- 0.9

NS

Number of pregnancies

258

42

NS

Number of pregnancies per woman

2.72 +/- 0.16

1.36 +/- 0.11

p < 0.0001

Number of abortions

46

1

NS

Number of abortions per woman

0.489 +/- 0.85

0.032 +/- 0.032

p < 0.0001

Abortion-to-pregnancy ratio

0.153 +/- 0.027

0.024 +/- 0.024

p < 0.005

Number of nonabortive pregnancies

212

41

NS

Threatened abortion-to-pregnancy ratio

0.062 +/- 0.023

0.050 +/- 0.037

NS

Premature delivery-to-pregnancy ratio

0.162 +/- 0.040

0.132 +/- 0.068

NS

Low birth weight baby-to-pregnancy ratio

0.126 +/- 0.037

0.024 +/- 0.024

p < 0.03

Duration of feeding, months

2.77 +/- 0.52

7.03 +/- 1.17

p < 0.0003

 

Other Findings

In the case-control study, comparison of 94 untreated with 31 treated celiac women indicated that the relative risk of abortion was 8.90 times higher (95% confidence limits:  1.19/66.3), the relative risk of low birth weight baby was 5.84 times higher (95% confidence limits:  0.77/44.2, 90% confidence limits:  1.07/31.9) and duration of breast feeding was 2.54 times shorter (p < 0.001) in untreated mothers.  The prevalence of abortion in pregnancies was 17.8% among untreated CD women and 2.4% among treated CD women (p < 0.001).  The prevalence of low birth weight babies in nonabortive pregnancies was 12.7% among untreated CD women and 2.4% among treated CD women (p < 0.05).

Abortion, low birth weight of baby, and duration of breast feeding did not significantly relate to the severity of celiac disease among untreated women.

In the before-after study, 12 pregnant celiac women in either treated or untreated condition were compared.  Results indicated that the gluten-free diet reduced the relative risk of abortion by 9.18 times (95% confidence limits:  1.05/79.9), reduced the number of low birth weight babies from 29.4% during the untreated period down to zero during treated (p < 0.05) and increased duration of breast feeding 2.38 times (p < 0.10).  The prevalence of abortion in pregnancies was 43.3% during the untreated period and7.7% during the treated period (p < 0.01).

Both case-control and before-after studies indicated that threatened abortion and premature delivery did not significantly relate to treatment of celiac disease.

Author Conclusion:
Data from this study show that celiac disease is associated with high rates of abortion, low weight in babies at birth, and short duration of breast feeding, whether celiac disease is overt or subclinical; these disorders are corrected by treatment with a gluten-free diet.  In summary, the data from the present study show that the incidence of abortions, the weight of babies at birth, and the duration of lactation are altered by celiac disease, independent of its severity.  These disorders are secondary to gluten-induced enteropathy, because they are corrected by treatment with a gluten-free diet.  Nondiagnosed celiac disease should therefore be suspected in women who have these disorders, particularly when other causes for altered pregnancy outcome can be excluded.
Funding Source:
University/Hospital: University of Naples Federico II (Italy), Northwestern University, Pollena
Reviewer Comments:
Gluten-free diet not defined or monitored.  Before-after study sample size very small.
Quality Criteria Checklist: Primary Research
Relevance Questions
  1. Would implementing the studied intervention or procedure (if found successful) result in improved outcomes for the patients/clients/population group? (Not Applicable for some epidemiological studies) Yes
  1. Would implementing the studied intervention or procedure (if found successful) result in improved outcomes for the patients/clients/population group? (Not Applicable for some epidemiological studies) Yes
  2. Did the authors study an outcome (dependent variable) or topic that the patients/clients/population group would care about? Yes
  2. Did the authors study an outcome (dependent variable) or topic that the patients/clients/population group would care about? Yes
  3. Is the focus of the intervention or procedure (independent variable) or topic of study a common issue of concern to dieteticspractice? Yes
  3. Is the focus of the intervention or procedure (independent variable) or topic of study a common issue of concern to dieteticspractice? Yes
  4. Is the intervention or procedure feasible? (NA for some epidemiological studies) Yes
  4. Is the intervention or procedure feasible? (NA for some epidemiological studies) Yes
 
Validity Questions
  1. Was the research question clearly stated? Yes
1. Was the research question clearly stated? Yes
  1.1. Was (were) the specific intervention(s) or procedure(s) [independent variable(s)] identified? Yes
  1.1. Was (were) the specific intervention(s) or procedure(s) [independent variable(s)] identified? Yes
  1.2. Was (were) the outcome(s) [dependent variable(s)] clearly indicated? Yes
  1.2. Was (were) the outcome(s) [dependent variable(s)] clearly indicated? Yes
  1.3. Were the target population and setting specified? Yes
  1.3. Were the target population and setting specified? Yes
  2. Was the selection of study subjects/patients free from bias? ???
2. Was the selection of study subjects/patients free from bias? ???
  2.1. Were inclusion/exclusion criteria specified (e.g., risk, point in disease progression, diagnostic or prognosis criteria), and with sufficient detail and without omitting criteria critical to the study? ???
  2.1. Were inclusion/exclusion criteria specified (e.g., risk, point in disease progression, diagnostic or prognosis criteria), and with sufficient detail and without omitting criteria critical to the study? ???
  2.2. Were criteria applied equally to all study groups? Yes
  2.2. Were criteria applied equally to all study groups? Yes
  2.3. Were health, demographics, and other characteristics of subjects described? ???
  2.3. Were health, demographics, and other characteristics of subjects described? ???
  2.4. Were the subjects/patients a representative sample of the relevant population? ???
  2.4. Were the subjects/patients a representative sample of the relevant population? ???
  3. Were study groups comparable? Yes
3. Were study groups comparable? Yes
  3.1. Was the method of assigning subjects/patients to groups described and unbiased? (Method of randomization identified if RCT) Yes
  3.1. Was the method of assigning subjects/patients to groups described and unbiased? (Method of randomization identified if RCT) Yes
  3.2. Were distribution of disease status, prognostic factors, and other factors (e.g., demographics) similar across study groups at baseline? Yes
  3.2. Were distribution of disease status, prognostic factors, and other factors (e.g., demographics) similar across study groups at baseline? Yes
  3.3. Were concurrent controls or comparisons used? (Concurrent preferred over historical control or comparison groups.) Yes
  3.3. Were concurrent controls or comparisons used? (Concurrent preferred over historical control or comparison groups.) Yes
  3.4. If cohort study or cross-sectional study, were groups comparable on important confounding factors and/or were preexisting differences accounted for by using appropriate adjustments in statistical analysis? N/A
  3.4. If cohort study or cross-sectional study, were groups comparable on important confounding factors and/or were preexisting differences accounted for by using appropriate adjustments in statistical analysis? N/A
  3.5. If case control study, were potential confounding factors comparable for cases and controls? (If case series or trial with subjects serving as own control, this criterion is not applicable.) Yes
  3.5. If case control study, were potential confounding factors comparable for cases and controls? (If case series or trial with subjects serving as own control, this criterion is not applicable.) Yes
  3.6. If diagnostic test, was there an independent blind comparison with an appropriate reference standard (e.g., "gold standard")? N/A
  3.6. If diagnostic test, was there an independent blind comparison with an appropriate reference standard (e.g., "gold standard")? N/A
  4. Was method of handling withdrawals described? ???
4. Was method of handling withdrawals described? ???
  4.1. Were follow-up methods described and the same for all groups? Yes
  4.1. Were follow-up methods described and the same for all groups? Yes
  4.2. Was the number, characteristics of withdrawals (i.e., dropouts, lost to follow up, attrition rate) and/or response rate (cross-sectional studies) described for each group? (Follow up goal for a strong study is 80%.) Yes
  4.2. Was the number, characteristics of withdrawals (i.e., dropouts, lost to follow up, attrition rate) and/or response rate (cross-sectional studies) described for each group? (Follow up goal for a strong study is 80%.) Yes
  4.3. Were all enrolled subjects/patients (in the original sample) accounted for? ???
  4.3. Were all enrolled subjects/patients (in the original sample) accounted for? ???
  4.4. Were reasons for withdrawals similar across groups? ???
  4.4. Were reasons for withdrawals similar across groups? ???
  4.5. If diagnostic test, was decision to perform reference test not dependent on results of test under study? N/A
  4.5. If diagnostic test, was decision to perform reference test not dependent on results of test under study? N/A
  5. Was blinding used to prevent introduction of bias? N/A
5. Was blinding used to prevent introduction of bias? N/A
  5.1. In intervention study, were subjects, clinicians/practitioners, and investigators blinded to treatment group, as appropriate? N/A
  5.1. In intervention study, were subjects, clinicians/practitioners, and investigators blinded to treatment group, as appropriate? N/A
  5.2. Were data collectors blinded for outcomes assessment? (If outcome is measured using an objective test, such as a lab value, this criterion is assumed to be met.) N/A
  5.2. Were data collectors blinded for outcomes assessment? (If outcome is measured using an objective test, such as a lab value, this criterion is assumed to be met.) N/A
  5.3. In cohort study or cross-sectional study, were measurements of outcomes and risk factors blinded? N/A
  5.3. In cohort study or cross-sectional study, were measurements of outcomes and risk factors blinded? N/A
  5.4. In case control study, was case definition explicit and case ascertainment not influenced by exposure status? N/A
  5.4. In case control study, was case definition explicit and case ascertainment not influenced by exposure status? N/A
  5.5. In diagnostic study, were test results blinded to patient history and other test results? N/A
  5.5. In diagnostic study, were test results blinded to patient history and other test results? N/A
  6. Were intervention/therapeutic regimens/exposure factor or procedure and any comparison(s) described in detail? Were interveningfactors described? ???
6. Were intervention/therapeutic regimens/exposure factor or procedure and any comparison(s) described in detail? Were interveningfactors described? ???
  6.1. In RCT or other intervention trial, were protocols described for all regimens studied? ???
  6.1. In RCT or other intervention trial, were protocols described for all regimens studied? ???
  6.2. In observational study, were interventions, study settings, and clinicians/provider described? N/A
  6.2. In observational study, were interventions, study settings, and clinicians/provider described? N/A
  6.3. Was the intensity and duration of the intervention or exposure factor sufficient to produce a meaningful effect? Yes
  6.3. Was the intensity and duration of the intervention or exposure factor sufficient to produce a meaningful effect? Yes
  6.4. Was the amount of exposure and, if relevant, subject/patient compliance measured? No
  6.4. Was the amount of exposure and, if relevant, subject/patient compliance measured? No
  6.5. Were co-interventions (e.g., ancillary treatments, other therapies) described? ???
  6.5. Were co-interventions (e.g., ancillary treatments, other therapies) described? ???
  6.6. Were extra or unplanned treatments described? ???
  6.6. Were extra or unplanned treatments described? ???
  6.7. Was the information for 6.4, 6.5, and 6.6 assessed the same way for all groups? Yes
  6.7. Was the information for 6.4, 6.5, and 6.6 assessed the same way for all groups? Yes
  6.8. In diagnostic study, were details of test administration and replication sufficient? N/A
  6.8. In diagnostic study, were details of test administration and replication sufficient? N/A
  7. Were outcomes clearly defined and the measurements valid and reliable? Yes
7. Were outcomes clearly defined and the measurements valid and reliable? Yes
  7.1. Were primary and secondary endpoints described and relevant to the question? Yes
  7.1. Were primary and secondary endpoints described and relevant to the question? Yes
  7.2. Were nutrition measures appropriate to question and outcomes of concern? Yes
  7.2. Were nutrition measures appropriate to question and outcomes of concern? Yes
  7.3. Was the period of follow-up long enough for important outcome(s) to occur? Yes
  7.3. Was the period of follow-up long enough for important outcome(s) to occur? Yes
  7.4. Were the observations and measurements based on standard, valid, and reliable data collection instruments/tests/procedures? Yes
  7.4. Were the observations and measurements based on standard, valid, and reliable data collection instruments/tests/procedures? Yes
  7.5. Was the measurement of effect at an appropriate level of precision? Yes
  7.5. Was the measurement of effect at an appropriate level of precision? Yes
  7.6. Were other factors accounted for (measured) that could affect outcomes? Yes
  7.6. Were other factors accounted for (measured) that could affect outcomes? Yes
  7.7. Were the measurements conducted consistently across groups? Yes
  7.7. Were the measurements conducted consistently across groups? Yes
  8. Was the statistical analysis appropriate for the study design and type of outcome indicators? Yes
8. Was the statistical analysis appropriate for the study design and type of outcome indicators? Yes
  8.1. Were statistical analyses adequately described and the results reported appropriately? Yes
  8.1. Were statistical analyses adequately described and the results reported appropriately? Yes
  8.2. Were correct statistical tests used and assumptions of test not violated? Yes
  8.2. Were correct statistical tests used and assumptions of test not violated? Yes
  8.3. Were statistics reported with levels of significance and/or confidence intervals? Yes
  8.3. Were statistics reported with levels of significance and/or confidence intervals? Yes
  8.4. Was "intent to treat" analysis of outcomes done (and as appropriate, was there an analysis of outcomes for those maximally exposed or a dose-response analysis)? N/A
  8.4. Was "intent to treat" analysis of outcomes done (and as appropriate, was there an analysis of outcomes for those maximally exposed or a dose-response analysis)? N/A
  8.5. Were adequate adjustments made for effects of confounding factors that might have affected the outcomes (e.g., multivariate analyses)? Yes
  8.5. Were adequate adjustments made for effects of confounding factors that might have affected the outcomes (e.g., multivariate analyses)? Yes
  8.6. Was clinical significance as well as statistical significance reported? Yes
  8.6. Was clinical significance as well as statistical significance reported? Yes
  8.7. If negative findings, was a power calculation reported to address type 2 error? N/A
  8.7. If negative findings, was a power calculation reported to address type 2 error? N/A
  9. Are conclusions supported by results with biases and limitations taken into consideration? Yes
9. Are conclusions supported by results with biases and limitations taken into consideration? Yes
  9.1. Is there a discussion of findings? Yes
  9.1. Is there a discussion of findings? Yes
  9.2. Are biases and study limitations identified and discussed? Yes
  9.2. Are biases and study limitations identified and discussed? Yes
  10. Is bias due to study's funding or sponsorship unlikely? Yes
10. Is bias due to study's funding or sponsorship unlikely? Yes
  10.1. Were sources of funding and investigators' affiliations described? Yes
  10.1. Were sources of funding and investigators' affiliations described? Yes
  10.2. Was the study free from apparent conflict of interest? Yes
  10.2. Was the study free from apparent conflict of interest? Yes