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Timing of Pregnancy in Relation to the Onset of Rheumatoid Arthritis.

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152
TIMING OF PREGNANCY IN RELATION TO THE
ONSET OF RHEUMATOID ARTHRITIS
ALAN SILMAN, APRIL KAY, and PAUL BRENNAN
The interval between the onset of rheumatoid
arthritis (RA) and the most recent pregnancy prior to
RA onset in 88 women was determined. These data were
compared with data obtained from a group of 144
age-matched normal women (controls) who had been
assigned a “dummy date for RA onset” for the purposes
of analysis. The frequency of disease onset during 3 time
intervals within the period from conception to 1 year
postpartum was compared with the frequency of disease
onset outside this period. There was a reduction in the
incidence of disease onset during pregnancy (adjusted
odds ratio [OR] 0.30, 95% confidence interval [CI]
0.W2.6) and a numerically greater increased risk of
RA onset during the first 3 months postpartum (OR 5.6,
95% CI 1.8-17.6), which persisted for the subsequent 9
months (OR 2.6, 95% CI 0.8-7.9). A reduction in the
incidence of disease onset was seen during all pregnancies; in contrast, the postpartum increase was greater in
those with RA onset after the first pregnancy. The
reduced incidence of RA onset during pregnancy, with
the increased risk postpartum, mirrors the previously
described suppression of disease activity during p r e g
nancy and the subsequent flare postpartum in women
with established RA. In addition, the increased postpartum risk after the first pregnancy might suggest that in
susceptible women, either the hormonal changes or the
From the Arthritis and Rheumatism Council, Epidemiology
Research Unit, Manchester University Medical School, Manchester, England.
Alan Silman, MD; Paul Brennan, MSc.
Dr. Kay is deceased.
Address correspondence to Alan Silman, MD, Arthritis and
Rheumatism Council, Epidemiology Research Unit, Manchester
University Medical School, Manchester MI3 9PL, UK.
Submitted for publication March 14, 1991; accepted in
revised form September 26, 1991.
Arthritis and Rheumatism, Vol. 35, No. 2 (February 1992)
exposure to the fetus’s paternal HLA might represent a
risk factor for disease causation.
There is a long-recognized influence of pregnancy on the activity of rheumatoid arthritis (RA),
with a reduction in inflammatory activity during pregnancy and a “relapse” afterwards (1-3). There may be
a physiologic explanation for this phenomenon given
the antiinflammatory activity of some of the proteins
produced by the body during pregnancy (4). It is thus
of interest to investigate whether pregnancy can also
suppress the onset of RA, or conversely, whether the
postpartum period is associated with an increased risk
of disease presentation. Women with RA are more
likely to be nulliparous prior to disease onset (5,6).
There is, however, no increased risk in those who are
unmarried (6,7), which suggests that in its subclinical
phase, RA affects fertility, rather than fertility having
any etiologic importance. It is of interest that the
apparent protective effect of oral contraceptive use (8)
might be enhanced in parous women (6).
In the present study, we investigated the relationship between the timing of pregnancy and the
onset of RA and specifically examined whether the
disease is less likely to start during pregnancy and
more likely to start postpartum. In addition, we aimed
to study whether these effects were the same in all
pregnancies.
PATIENTS AND METHODS
Patients and controls. The study had a case-control
design, investigating the time of the most recent pregnancy
as the variable of interest in women with RA and in agematched normal control subjects.
PREGNANCY AND RA ONSET
Women were recruited from 3 rheumatology centers.
Physicians at these centers were asked to contact those
women who were ages 1 8 4 0 on January 1, 1984, and who
had been diagnosed as having RA of <2 years duration based
on the onset of first symptoms, according to the patient’s
recollection. The medical records were checked, and the
women were eligible for study inclusion if they met the 1958
criteria for definite RA (9) and if the recollection of the onset
of first symptoms as stated in the records was consistent
with a duration of <2 years.
Of the eligible women with RA, a total of 88 were
studied (cases). Each patient was asked to provide the
names of 2 friends of similar age ( 2 5 years) who could be
asked to participate as study controls. In some instances,
these friends could not be contacted, or the patient declined
to provide such information. Control subjects were excluded
if they were related to any of the case patients or if at the
time of the interview, they had evidence of RA or other
inflammatory arthritis. Eligible controls were available for 78
(88%) of the cases; 66 (75%) of the cases had 2 controls.
Questionnaire. Information regarding demographic
factors, timing and outcome of pregnancies, oral contraceptive use, and other factors concerning reproduction was
obtained via a telephone interview, which was the same for
the 2 groups. The interviewer was not blinded to the case/
control status of the subject.
Statistical analysis. The controls were assigned a
“dummy date for RA onset,” which was the month and year
of disease onset in their respective matched case; thus,
comparable exposure histories were available for analysis.
The date at onset was chosen in preference to the actual age
at onset because of the exposure bias that would have
resulted between the 2 groups. This bias would be a consequence of 2 aspects of the study design: (a) the matching
procedure allowed the control subjects to be up to 5 years
younger than their respective case subject, and (b) most
interviews took place soon after the onset of RA. Thus,
some controls were younger at the time of the survey than
was their matched case at the time of disease onset. Taking
the chronological age at onset as the dummy date would
have inappropriately forced an equal time of exposure upon
the controls as for the cases. It was also possible to adjust for
any differences in age at RA onset during the analysis.
Demographic and reproductive characteristics at
baseline were compared between the RA and the control
group, and 95% confidence intervals (CI) were calculated.
The onset of RA was assessed for 3 distinct time intervals:
the 9 months prior to childbirth (pregnancy), the first 3
months postpartum, and the subsequent 9 months following
childbirth. The reference group consisted of women whose
RA onset date (or dummy onset date) occurred outside the
interval of pregnancy to 1 year postpartum. An unconditional logistic regression analysis was used to calculate the
odds ratios (OR) for RA onset and 95% CIS during these time
periods. The ORs were adjusted for parity, age, and oral
contraceptive use. This analysis was more efficient than a
conditional analysis (i.e., retaining the matching) because it
incorporated the 10 patients who were unable to supply any
controls. The consequences of this technique are minimal in
the absence of serious confounding. The unconditional approach would, in general, give a more conservative estimate
153
Table 1. Baseline characteristics of study subjects
Year of birth, mean (SD)
Age at disease onset, mean (SD)
Parous, no. (%)
No. of children of parous women,
mean (SD)
Age at birth of first child in parous
women, mean (SD)
Oral contraceptive use
Ever, no. (%)
Current, no. (%)
Cases
(n = 88)
Controls
(n = 144)
1954 (6.1)
30.9 (6.2)
57 (64.8)
1.93 (0.73)
1954 (6.3)
30.7* (6.5)
94 (65.3)
1.96 (0.73)
24.3 (4.0)
24.0 (3.3)
70 (80)
15 (17)
119 (83)
41 (28)
* Dummy age at disease onset, based on calendar month and year of
onset of rheumatoid arthritis in the matched case (see Patients and
Methods for details).
of the odds ratio. Further analysis in which the matching of
the 78 cases with an available control was retained did not
yield any important difference in the results.
All statistical analysis was carried out using the SAS
software system with the Logist procedure (10).
RESULTS
The case and control women were very similar
with respect to age, parity, age at the birth of the first
child, and mean number of children (Table 1).
A protective effect of pregnancy against the
onset of RA was suggested (Table 2), showing an odds
ratio of 0.3. The 95% confidence interval, 0.04-2.6,
was wide because of the low number of occurrences
during the period. The relationship was reversed in the
first 3 months postpartum, with an odds ratio of 5.6
(95% CI 1.8-17.6). This effect was still as apparent but
was less strong in the remaining 9 months of the
postpartum period, with an odds ratio of 2.6 (95% CI
0.8-7.9). After restricting the analysis only to incidents
of RA onsets during and after the first pregnancy,
there was a greater divergence. There were no onsets
Table 2. Occurrence of rheumatoid arthritis onset around the
pregnancy period
Category
During pregnancy, no. (%)
0-3 months -postpartum,
no. (%)
3-12 months postpartum,
no. (%)
Outside the pregnancypostpartum period,
no. (%)
Odds ratio
Case
Control (95% confidence
(n = 88) (n = 144)
interval)
1 (1.1)
12 (13.6)
.
.
9 (6.2)
5 (3.5)
.
.
0.3 (0.04-2.6)
5.6 (1.8-17.6)
8 (9.1)
8 (5.6)
2.6 (0.8-7.9)
67 (76.1) 122 (84.7)
1
SILMAN ET AL
154
among the cases and 4 onsets among the controls
during pregnancy. Postpartum, the odds ratios were
10.8 (95% CI 1.3-91) for the first 3 months and 2.4
(95% CI 0.5-1 1) for the subsequent 9 months.
DISCUSSION
In the present investigations, there was no
difference in parity between the cases and the controls, but there was a reduction in the incidence of RA
onset during pregnancy, although the confidence interval was wide. There was an increased incidence of RA
onset postpartum, particularly during the first 3
months. That effect seemed to be greater with the first
pregnancy, although the numbers are small.
There are a number of methodologic issues that
warrant consideration. First, the study was designed
as a matched study, but the failure to obtain a suitable
control for 12% of the cases necessitated an unmatched analysis. There was no evidence from considering the pregnancy history of the 10 unmatched
cases that failure to obtain a matched control was
associated with an increased postpartum risk of RA.
Thus, it is unlikely that this resulted in bias. Second,
friends who serve as controls are more likely to be
similar to the case patients than random population
controls. The advantage of selecting the former is the
potential for a higher response rate and a reduction in
the likelihood of major lifestyle differences that could
confound the results obtained. The similarity in cases
and controls might have masked a difference in nulliparity, which has been found in other studies (5,6).
This similarity, in contrast, would not detract from the
positive results of the study of the timing of pregnancy. Third, neither the subject nor the interviewer
was blinded to the disease status of the cases, and
thus, interviewer and recall bias may have occurred.
We believe that the nature of the major exposure
variable investigated-the
date of birth of each
child-is less subject to these biases than are many
other recalled data. Further, the subjects were unaware of the direction of the hypothesis being tested.
A more likely explanation for the study’s findings is the postponement of the perception of symptom
onset until after childbirth. Thus, the RA patients
might have developed the disease at the same frequency during pregnancy, but the disease was not
recognized until the postpartum period. Indeed, the
same factors that suppress established disease during
pregnancy (1-3) might reasonably be expected to
suppress newly developing disease. Although we be-
lieve this to be a possible explanation for these data,
there are 2 difficulties. First, the “rebound” of inflammatory activity postpartum is both greater than the
reduction prenatally and persists for at least 12
months. Second, the suppression seems to be greater
during the first pregnancy.
We hypothesized recently (1 1) that pregnancy
might be a risk factor for RA. Subsequent investigation both by ourselves (6) and by others (12) suggested
that this was not generally true, and that nulliparity
might be a risk factor. The results from the current
study are therefore compatible with the hypothesis
that pregnancy suppresses the onset and activity of
rheumatoid arthritis, but that in a group of susceptible
women, pregnancy might paradoxically induce disease
onset, the presentation of which is delayed. It is during
pregnancy that the mother is exposed to the fetus’s
paternal HLA. In this regard, it is of interest that
disease activity during pregnancy is related to the
similarity between maternal and fetal HLA (13). It
would also be relevant to investigate these factors of
RA onset as they relate to breast feeding, since the
associated hormonal changes might influence the timing of RA onset.
REFERENCES
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3. Persellin RH: The effect of pregnancy on rheumatoid
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4. Ungar A, Kay A, Griffin JA, Panayi GS: Disease activity
in rheumatoid arthritis during pregnancy. Br Med J
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5. Kay A, Bach F: Subfertility before and after the development of rheumatoid arthritis in women. Ann Rheum
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6. Spector TD, Roman E, Silman AJ: The pill, parity, and
rheumatoid arthritis. Arthritis Rheum 33:782-789, 1990
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Medica, 1968
8. Spector TD, Hochberg MC: The protective effect of the
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Epidemiol43:1221-1230, 1990
9. Ropes MW, Bennett GA, Cobb S, Jacox R, Jessar RA:
1958 revision of diagnostic criteria for rheumatoid arthritis. Bull Rheum Dis 9:175-176, 1958
PREGNANCY AND RA ONSET
10. Hastings RP: SAS Users Group International (SUGI)
Supplement Library Users Guide. Version 5. Cary NC,
SAS Institute, 1986
11. Silman AJ: Is pregnancy a risk factor for rheumatoid
arthritis? Ann Rheum Dis 45:1031-1034, 1986
12. Hazes JMW, Dijkmans BAC, Vandenbroucke JP, de
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155
ing rheumatoid arthritis. Arthritis Rheum 33: 177G1775,
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s10, 1990
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