SEARCH

SEARCH BY CITATION

Abstract

  1. Top of page
  2. Abstract
  3. SUBJECTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. AUTHOR CONTRIBUTIONS
  7. Acknowledgements
  8. REFERENCES

Objective

To assess whether onset of rheumatoid arthritis (RA) prior to conception is associated with a delayed time to pregnancy (TTP).

Methods

The study included pregnant women from across Denmark who enrolled in the Danish National Birth Cohort between 1996 and 2002 and had planned or partly planned the cohort pregnancy. RA diagnosis was identified using the Danish National Hospital Discharge Registry. Self-reported data, including TTP, maternal age, parity, prepregnancy height and weight, maternal occupational status, smoking, and alcohol consumption, were collected using a detailed computer-assisted telephone interview at ∼16 weeks of gestation. We used logistic regression analyses as well as a complementary log regression model to examine whether TTP was influenced by RA, adjusting for the abovementioned variables.

Results

Overall, compared with women with no recorded RA (n = 74,255), women with prevalent RA (onset prior to conception) (n = 112) were slightly older (mean ± SD age 30.8 ± 4.3 years versus 29.7 ± 4.1 years), were more likely to have been treated for infertility (9.8% versus 7.6%), and were more likely to have taken >12 months to conceive (25.0% versus 15.6%). The association between RA and TTP was borderline significant after adjusting for covariates in the regression analyses (odds ratio 1.6 [95% confidence interval 1.0–2.4]). Similar results were obtained after restricting the analyses to women who had planned the pregnancy or those who were nulliparous before the cohort pregnancy.

Conclusion

Women with RA onset prior to conception had a slightly longer TTP compared with those who did not have RA, indicating a slight reduction in fecundity.

Although rheumatoid arthritis (RA) tends to have a late onset, the disease also occurs during the childbearing years and may interfere with procreation (1). It is, however, not entirely clear whether fecundity (i.e., probability of conception) is affected by the disease or its treatment. Investigations of fecundity and RA have been few, as shown by the sparse reports in the literature spanning the last several decades. A few case–control studies have found RA patients to have reduced fecundity prior to disease onset (2, 3). Women with prevalent RA at the time of conception were also found to have a longer waiting time to pregnancy (TTP) than women without RA (2), perhaps reflecting a reduced fecundity. Given the practical difficulties in assembling data sets of RA patients to investigate associations with fecundity, this topic has not been further investigated. In the present study, we used a nationwide cohort of pregnant women in Denmark to assess whether prevalent RA prior to conception was associated with a longer TTP (i.e., the time it takes to obtain a clinically recognized pregnancy).

SUBJECTS AND METHODS

  1. Top of page
  2. Abstract
  3. SUBJECTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. AUTHOR CONTRIBUTIONS
  7. Acknowledgements
  8. REFERENCES

Study subjects.

The initial study population consisted of 92,892 pregnancies from the Danish National Birth Cohort (DNBC). Pregnant women from across Denmark had been enrolled in the DNBC between 1996 and 2002, with the goal of exploring the potential importance of social, environmental, and lifestyle factors during pregnancy and early childhood on the health and development of children and adults (4). Only coded data were available for the present analyses, and hence, the study was exempt from human subjects research requirements. Approval for the study was obtained from the Danish Data Protection Agency and the DNBC Steering Committee.

RA diagnosis.

To identify women diagnosed as having RA, the DNBC database was linked to the Danish National Hospital Discharge Registry, in which clinical diagnoses for inpatients have been recorded since 1977 and also for outpatients since 1995. The Danish National Hospital Discharge Registry allows for up to 20 diagnoses other than the reason for hospitalization to be recorded (for each hospitalization) in addition to the primary diagnosis for which the patient was hospitalized. Thus, prior to 1995, we identified women who had a recorded diagnosis of RA irrespective of whether RA was the primary reason for hospitalization or was one of the other conditions they had at the time of hospitalization. From 1995 onward, the RA patients we identified also included outpatients attending the hospital for RA treatment. RA diagnoses were identified using International Classification of Diseases, Eighth Revision (ICD-8) codes 712.19, 712.39, and 712.59 and ICD-10 codes M05 and M06 (except for M06.1, adult-onset Still's disease). ICD-9 codes have not been used in Denmark. Subjects with a diagnosis of other rheumatic diseases (ICD-8 codes 712.09, 712.29, and 712.49 and ICD-10 codes M06.1 and M07–M14.8), including juvenile-onset RA, were excluded (n = 521).

For each RA patient identified from the Danish National Hospital Discharge Registry, we determined whether there was a recorded diagnosis of RA prior to the DNBC cohort pregnancy. This group of patients who had prevalent RA before pregnancy constituted our primary patient group for our data analyses. For women who had a recorded diagnosis of RA only after the computed conception date, we assumed that they developed the disease after conception, and we used the date of hospitalization when RA diagnosis was first recorded in the Danish National Hospital Discharge Registry as the date of RA onset, assuming that diagnosis occurred close to the time of disease onset.

Pregnancy-related data.

Self-reported information on sociodemographic, environmental, and lifestyle factors was collected through a computer-assisted telephone interview at ∼16 weeks of gestation. Women were asked whether their pregnancy was planned, if they had been treated for infertility, and for how long they had tried to become pregnant before succeeding. Data collected on maternal age, parity, prepregnancy height and weight, maternal occupational status, smoking in early pregnancy, and alcohol consumption (number of units/week) before pregnancy were also used in the present analyses. Subjects who were missing data for any of these variables were excluded from the analyses (n = 4,269).

Time to pregnancy.

Since TTP was the main outcome of interest in the present study, subjects for whom the TTP could not be determined because they had not planned the pregnancy or “did not try to get pregnant” were excluded from the analyses (n = 13,575). For the remaining 74,527 subjects whose pregnancy had been “planned” or “partly planned,” TTP was recorded as 4 categories: 0–2 months, 3–5 months, 6–12 months, or >12 months. In the analyses, TTP was dichotomized as ≤12 months and >12 months, ≤6 months and >6 months or was used as recorded.

Statistical analysis.

We used logistic regression analyses to examine whether TTP (≤12 months versus >12 months) was influenced by RA status, with our primary focus on RA onset prior to conception. Hence, for these analyses, subjects who had a diagnosis of RA during or after the documented pregnancy were excluded. Covariates that were adjusted for in the regression models included maternal age, parity, prepregnancy body mass index (BMI), maternal occupational status, smoking in early pregnancy, and alcohol consumption before pregnancy. Occupational status was categorized as follows for the regression analyses: high (managers, professionals, and technicians), medium (clerks, service and sales workers, skilled agricultural workers, and craft workers), low (unskilled workers), students, or unemployed. Alcohol consumption was categorized as 0–<1, 1–<2, 2–<3, or ≥3 units/week. Variables such as oral contraceptive use prior to conception, number of previous spontaneous abortions, infertility treatment, age at menarche, and having irregular periods (which could themselves directly affect TTP) were not included as covariates in the main model, but we checked whether they affected the association.

In addition to the logistic regression models, we used a complementary log regression model to make use of the recorded TTP distribution (all 4 categories). We also repeated all analyses using subjects who had RA onset during or after the pregnancy, instead of those with prevalent RA, to determine whether future onset of RA was associated with TTP. Odds ratios (ORs), fecundity ratios, and 95% confidence intervals (95% CIs) are provided.

RESULTS

  1. Top of page
  2. Abstract
  3. SUBJECTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. AUTHOR CONTRIBUTIONS
  7. Acknowledgements
  8. REFERENCES

A total of 74,527 women were included in the present study, after exclusion of subjects diagnosed as having other rheumatic diseases and those who had not planned the pregnancy or who were missing data for key variables (Figure 1). Of those, 112 women had been hospitalized with a diagnosis of RA prior to the documented pregnancy (i.e., at the time they were trying to conceive), and 160 had a recorded diagnosis date up to 9 years after the pregnancy. The remaining 74,255 subjects did not have a recorded diagnosis of RA within our followup time.

thumbnail image

Figure 1. Selection of study subjects from the Danish National Birth Cohort. RA = rheumatoid arthritis.

Download figure to PowerPoint

The characteristics of the women with and without prevalent RA at conception (excluding those who subsequently developed the disease) are summarized in Table 1. Overall, a higher proportion of women with RA took >12 months to conceive, compared with those who did not have RA (25.0% versus 15.6%). Women with prevalent RA were also slightly older than those who did not have RA (mean ± SD age 30.8 ± 4.3 years versus 29.7 ± 4.1 years) and were more likely to have been treated for infertility (9.8% versus 7.6%).

Table 1. Baseline characteristics of women with and those without RA in the Danish National Birth Cohort*
 Women with prevalent RA at conception (n = 112)Women without RA (n = 74,255)
  • *

    Except where indicated otherwise, values are the number (%). IQR = interquartile range; BMI = body mass index.

  • No rheumatoid arthritis (RA) diagnosis before or after conception.

Time to pregnancy, months  
0–246 (41.1)35,434 (47.7)
3–521 (18.8)15,234 (20.5)
6–1217 (15.2)12,035 (16.2)
>1228 (25.0)11,552 (15.6)
Time since RA diagnosis, median (IQR) years4.9 (2.3–9.0)
Age at conception, mean ± SD years30.8 ± 4.329.7 ± 4.1
Had infertility treatment11 (9.8)5,615 (7.6)
Parity  
No children52 (46.4)35,560 (47.9)
1 child45 (40.2)28,394 (38.2)
≥2 children15 (13.4)10,301 (13.9)
Prepregnancy BMI, mean ± SD kg/m223.6 ± 4.723.6 ± 4.2
Smoked during pregnancy27 (24.1)17,638 (23.8)

As shown in Table 2, prevalent RA was associated with longer TTP (>12 months versus ≤12 months) (crude OR 1.8). After adjusting for covariates, the association between RA and TTP was borderline significant (adjusted OR 1.6 [95% CI 1.0–2.4]). When the analyses were restricted to those women who had planned the pregnancy (100 women with prevalent RA and 66,118 women without RA), after excluding those who “partly planned,” the results were very similar to those described above for the entire cohort (crude OR 1.9; adjusted OR 1.7 [95% CI 1.1–2.7]). Similarly, when we restricted the analyses to women who were nulliparous at the time of conception (52 women with prevalent RA and 35,560 women without RA), the results were very similar to those described for the entire cohort (crude OR 1.9; adjusted OR 1.7 [95% CI 0.9–3.2]).

Table 2. Subfecundity among women with RA compared with women with no recorded RA*
TTPOdds ratio or fecundity ratio95% confidence interval for adjusted odds ratio or adjusted fecundity ratio
CrudeAdjusted
  • *

    See Table 1 for other definitions.

  • Odds ratios are shown for the logistic regression models with time to pregnancy (TTP) >6 months or >12 months as the outcome variables (with referents of ≤6 months and ≤12 months, respectively). Fecundity ratios are shown for the complementary log regression model with TTP as 4 categories (with referent of 0–2 months).

  • Covariates that were adjusted for in the model were maternal age (as a continuous variable), parity (0, 1, 2, or ≥3 children), BMI (continuous), occupational status (categorical, 5 levels), alcohol consumption (categorical, 4 levels), and smoking (binary).

>6 months1.41.40.9–2.0
>12 months1.81.61.0–2.4
3–5 months, 6–12 months, or >12 months0.80.80.6–1.0

A weaker association was found when using TTP >6 months versus TTP ≤6 months as the outcome variable, after adjusting for the same covariates (adjusted OR 1.4 [95% CI 0.9–2.0]) (Table 2). When using the entire TTP distribution (0–2 months, 3–5 months, 6–12 months, or >12 months) in the complementary log regression analysis, similar results were found for fecundity (adjusted fecundity ratio 0.8 [95% CI 0.6–1.0]), indicating as before a longer waiting TTP among women with RA. Similar results were found for women who had planned the pregnancy, and also for nulliparous women. When we considered “onset of RA during or after pregnancy” as our exposure of interest (i.e., a subject population of 160 women who later developed RA and 74,255 women without RA), we found a lower and nonsignificant association between this exposure and TTP (>12 months versus ≤12 months) (crude OR 1.3; adjusted OR 1.2 [95% CI 0.8–1.8]).

DISCUSSION

  1. Top of page
  2. Abstract
  3. SUBJECTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. AUTHOR CONTRIBUTIONS
  7. Acknowledgements
  8. REFERENCES

We found that women who had RA at the time of trying to become pregnant had slightly longer waiting TTP compared with those who did not have RA, irrespective of whether they were experiencing a first pregnancy or were multiparous. Reports of previous investigations on the topic of fecundity and RA are rare in the existing literature (2, 3), and these investigations have examined associations between future onset of RA and fecundity. The case–control study by Del Junco et al also examined a possible association between prevalent RA and fecundity and showed a reduced fecundity among women with RA compared with controls (2). Thus, the results from our nationwide DNBC cohort support these previous findings of Del Junco et al (2). The exact mechanism by which RA may influence fecundity is not clear, especially since the underlying disease mechanisms are largely unknown. A reduced fecundity could be caused by the disease, its treatment, or something else that correlates with RA. Since it is current practice that women with RA who are planning a pregnancy are advised by their physicians to stop taking disease-modifying antirheumatic drugs at least 3 months prior to trying to conceive (1), it is possible that they may experience flares of disease activity while trying to conceive which may contribute to delayed conception.

The mean ± SD maternal age was slightly higher among the women with RA compared with those without the disease (30.8 ± 4.3 years versus 29.7 ± 4.1 years), and since increasing maternal age has been associated with reduced fecundity (5), the unadjusted association between RA and TTP was confounded by maternal age. The other variables in the model (i.e., parity, smoking, BMI, occupational status, and alcohol consumption) did not appear to confound the observed association between prevalent RA and longer TTP once the analysis was adjusted for age, although they were all independently associated with TTP, as expected (6–9).

A total of 420 women in the DNBC cohort had a self-reported diagnosis of RA when specifically asked during the interview if they had ever been diagnosed as having the disease; of those 420 women, 313 remained in the final analysis data set, and only 73 of the 313 also had a diagnosis of RA from the Danish National Hospital Discharge Registry. We do not know if the self-reported data on RA diagnosis are reliable or whether the 240 women who did not have a recorded diagnosis in the Registry had mild disease and were not hospitalized. Including these 240 women in the analyses did not change the results (data not shown). Further, when we examined the subset of 160 women who did not have RA at conception but subsequently developed the disease, we did not find prolonged TTP to be a strong marker of future onset of RA. All of these women had a recorded diagnosis of RA between 1999 and 2008, when outpatient records were being included in the Registry, and thus we assumed that these correctly represented the dates of diagnosis as being after conception. The results, however, were not consistent with previous reports of reduced fecundity prior to the onset of RA (2, 3), but differences in methods as well as in sources of data make the studies difficult to compare.

The identification of RA cases in our cohort through linkage with the Danish National Hospital Discharge Registry is likely to have introduced oversampling of more severe cases of RA, although we did not have data on severity of RA for these patients. It is possible that the association with longer TTP may be with the severity of the disease rather than with RA itself, although it has been reported that fecundity is not associated with joint damage over time (10). We did consider the possibility that duration of RA (time since diagnosis) may influence TTP, since the disease may progress to more severe forms over time; however, within the subset of women with RA in our cohort, we did not find any correlation between RA duration and TTP (data not shown).

This study has a number of limitations that should be recognized. First, data on RA diagnosis were available from the Danish National Hospital Discharge Registry, and it is possible that some of the women in our “no RA” group had been diagnosed outside the hospital system as having the disease. Nonetheless, we do not expect to have many such misclassified cases. Second, we may have underestimated the association between fecundity and RA, since any women with RA who had planned a pregnancy but did not get pregnant would not be represented in our data set. Third, although TTP data were collected after the end of the waiting time and may have been subject to recall bias, we believe that any such misclassification will be small; the recall time was short and nondifferential since this specific study was not mentioned at recruitment.

In summary, our results show that women with RA had longer waiting TTP compared with those who did not have RA, indicating a slight reduction in fecundity.

AUTHOR CONTRIBUTIONS

  1. Top of page
  2. Abstract
  3. SUBJECTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. AUTHOR CONTRIBUTIONS
  7. Acknowledgements
  8. REFERENCES

All authors were involved in drafting the article or revising it critically for important intellectual content, and all authors approved the final version to be published. Dr. Jawaheer had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Study conception and design. Jawaheer, Zhu, Nohr, Olsen.

Acquisition of data. Jawaheer, Zhu, Nohr, Olsen.

Analysis and interpretation of data. Jawaheer, Zhu, Olsen.

Acknowledgements

  1. Top of page
  2. Abstract
  3. SUBJECTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. AUTHOR CONTRIBUTIONS
  7. Acknowledgements
  8. REFERENCES

We would like to thank Ms Inge Eisensee for data extraction.

REFERENCES

  1. Top of page
  2. Abstract
  3. SUBJECTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. AUTHOR CONTRIBUTIONS
  7. Acknowledgements
  8. REFERENCES