Conceived and designed the experiments: ASK LCK UM TML KOD. Performed the experiments: ASK TML TBH KOD. Analyzed the data: ASK TML TBH PBM KOD. Contributed reagents/materials/analysis tools: LCK TML TBH PBM. Wrote the paper: ASK LCK TML UM KOD.
The authors have declared that no competing interests exist.
Autoimmune diseases (AID) predominantly affect women of reproductive age. While basic molecular studies have implicated persisting fetal cells in the mother in some AID, supportive epidemiological evidence is limited. We investigated the effect of vaginal delivery, caesarean section (CS) and induced abortion on the risk of subsequent maternal AID. Using the Danish Civil Registration System (CRS) we identified women who were born between 1960 and1992. We performed data linkage between the CRS other Danish national registers to identify women who had a pregnancy and those who developed AID. Women were categorised into 4 groups; nulligravida (control group), women who had 1st child by vaginal delivery, whose 1st delivery was by CS and who had abortions. Log-linear Poisson regression with person-years was used for data analysis adjusting for several potential confounders. There were 1,035,639 women aged >14 years and 25,570 developed AID: 43.4% nulligravida, 44.3% had their first pregnancy delivered vaginally, 7.6% CS and 4.1% abortions. The risk of AID was significantly higher in the 1st year after vaginal delivery (RR = 1.1[1.0, 1.2]) and CS (RR = 1.3[1.1, 1.5]) but significantly lower in the 1st year following abortion (RR = 0.7[0.6, 0.9]). These results suggest an association between pregnancy and the risk of subsequent maternal AID. Increased risks of AID after CS may be explained by amplified fetal cell traffic at delivery, while decreased risks after abortion may be due to the transfer of more primitive fetal stem cells. The increased risk of AID in the first year after delivery may also be related to greater testing during pregnancy.
Autoimmune diseases (AID) are most common among women and increase in incidence
following their reproductive years
The human immune system shows some degree of sexual dimorphism. In general, women
have higher CD4 cell counts than men, which contributes to an increased CD4/CD8
ratio
Whether pregnancy or parity influence the development of AID remains a subject of
much debate
Trafficking of fetal cells into the maternal circulation begins very early in the
pregnancy and the effects of this cell traffic are long lasting
Fetal microchimerism has now been investigated in many candidate AID, with some
results supporting a role in disease pathogenesis
Factors predisposing to the development of fetal microchimerism are much debated.
There is more fetomaternal cell trafficking where the placenta is abnormal and in
certain complications of the pregnancy such as fetal aneuploidy, pregnancy loss and
pre-eclampsia
The objective of this study was to find out whether risk of new onset autoimmune disease is higher after delivery by caesarean section compared to vaginal delivery and we also aimed to quantify the risk of autoimmune disease after abortion. We investigated the effect of vaginal delivery, caesarean section (CS) and abortion on the risk of subsequent maternal AID using data from the Danish National Registers.
The study cohort consisted of all women born in Denmark between January 1, 1962
and December 31, 1992. The data were obtained by linking the Danish Civil
Registration System
Women were grouped in four exposure categories based on their first pregnancy
only: 1) Women who had no previous pregnancy; 2) women who had a vaginal
delivery; 3) women who had a CS, and 4) women who had an abortion. Abortion was
defined as induced abortion before 20 weeks gestation based on International
Classification of Disease revisions 8 and 10 (ICD-8: 640, 641, 642 & ICD-10:
DO04)
Autoimmune Disease | Categorization | Prevalence per 1000 | ||
ICD8 | ICD10 | ICD8/ICD10 | ICD10 ONLY | |
Pernicious Anemia | 281.0 | D51.0 | 0.54 | 0.42 |
Autoimmune Hemolytic Anemia | 283.90–91 | D59.1 | 0.14 | 0.12 |
Idiopathic Thrombocytopenic Purpura | 446.49 | D69.3 | 0.49 | 0.48 |
Thyrotoxicosis | 242.00 | E05.0 | 4.99 | 4.82 |
Autoimmune Thyroiditis | 245.03 | E06.3 | 0.63 | 0.57 |
Type 1 Diabetes | 249 | E10 | 9.75 | 9.58 |
Primary Adrenocortical Insufficiency | 255.1 | E27.1 | 0.23 | 0.20 |
Multiple Sclerosis | 340 | G35 | 2.17 | 2.04 |
Guillain Barre Syndrome | 354 | G61.0 | 0.60 | 0.27 |
Iridocyclitis | 364 | H20 | 2.17 | 1.94 |
Crohn's Disease | 563.01 | K50 | 2.78 | 2.63 |
Ulcerative Colitis | 563.19 | K51 | 5.65 | 5.25 |
Autoimmune Hepatitis | 571.93 | K73 | 0.51 | 0.39 |
Primary Biliary Cirrhosis | 571.90 | K74.3 | 0.16 | 0.13 |
Coeliac Disease | 269.00 | K90.0 | 0.76 | 0.70 |
Pemphigus | 694 (×694.05) | L10 | 0.08 | 0.07 |
Pemphigoid | 694.05 | L12 | 0.14 | 0.14 |
Psoriasis vulgaris | 696.09–10, 696.19 | L40 (xL40.4) | 3.43 | 2.94 |
Alopecia Areata | 704.00 | L63 | 0.34 | 0.30 |
Vitiligo | 709.01 | L80.9 | 0.24 | 0.21 |
Seropositive Rheumatoid Arthritis | 712.19, 712.39, 712.59 | M05–M06 | 6.20 | 5.82 |
Juvenile Arthritis | 712.09 | M08 | 0.86 | 0.71 |
Wegener's Granulomatosis | 446.29 | M31.3 | 0.18 | 0.18 |
Dermatopolymyositis | 716 | M33 | 0.21 | 0.17 |
Polymyalgia Rheumatica | 446.30–31, 446.39 | M31.5–6, M35.3 | 3.02 | 2.78 |
Myasthenia Gravis | 733.09 | G70.0 | 0.22 | 0.19 |
Systemic Sclerosis | 734.0 | M34 | 0.30 | 0.28 |
Systemic Lupus Erythematosus | 734.19 | M32.1, M32.9 | 0.59 | 0.53 |
Sjogren's Syndrome | 734.90 | M35.0 | 0.78 | 0.75 |
Ankylosing Spondylitis | 712.49 | M45.9 | 0.85 | 0.75 |
The AID follow-up period was divided into 1) during pregnancy (this category was included for completeness), 2) first year following pregnancy, 3) second year following delivery, 4) third year following delivery, 5) more than three years but less than 10 years following delivery and 6) 10 years or more. This was also applied to the follow-up period following abortion. The follow-up period started in January 1, 1994 and ended in December 31, 2006. Women were followed-up for AID from their 14th birthday until their deaths, migration, onset of AID or end of study period, whichever came first. Women with a diagnosis of AID that included diabetes before the start of the follow-up period were excluded from the study cohort; as diabetes is generally accepted to have a different aetiology than other AID and its onset usually precedes the childbearing years.
Log-linear Poisson regression with aggregated person-years data was used to
estimate the relative risk of AID in relation to vaginal delivery, CS and
abortions
The Poisson models were run separately for vaginal delivery, CS and abortion. The reference group in all the models consisted of women who had no records of pregnancy including abortion. Sensitivity analyses were performed to examine whether age, infant sex or multiple gestation had an effect on association between risk of AID and mode of delivery.
This study was conducted according to the principles expressed in the Declaration of Helsinki. The study was approved by the Danish Data Protection Agency and the Danish National Board of Health. The study was based on secondary data and no individuals were approached, nor did we have access to any other information from the participants. Thus it was not necessary to seek written consent.
During the study period there were 1,035,639 women in Denmark aged 14 years or more. Of those women 25,570 (2.4%) had a diagnosis of AID during 10,786,229 person-years of follow-up. 459,049 women had their first pregnancy delivered vaginally and 11,439 (2.5%) had an AID. 78,694 women had their first pregnancy delivered by CS, of which 1,787 (2.3%) had an AID, and 186,220 had an abortion in their first pregnancy, of which 4,723 (2.5%) had an AID. 455,214 women had no record of a pregnancy during the study period, of which 11,165 (2.4%) had an AID diagnosis. Of the 186,220 women who had abortions, only 42,682 had no records of other pregnancies, thus the numbers do not add up to 1,035,639. When we excluded women who had records of childbirth and abortions in the study cohort, we had 334,205 women with a normal delivery and 60,000 delivered by CS, while 42,682 had abortions, 455,214 had no pregnancy, and 143,538 had abortions and delivery.
Variable | Cases | Person years | Incidence per 100,000 person years |
|
|||
Female | 6289 | 2300317 | 273.2 |
Male | 6572 | 2423568 | 271.2 |
Multiple gestation | 185 | 72368 | 255.6 |
No children | 12524 | 5989845 | 209.1 |
|
|||
14–19 | 3007 | 2100277 | 143.2 |
20–25 | 5021 | 2295805 | 218.7 |
26–29 | 4377 | 1694776 | 258.3 |
30–35 | 7188 | 2612313 | 275.2 |
36–41 | 4816 | 1669130 | 288.5 |
42+ | 1161 | 413795.5 | 280.6 |
|
|||
94–95 | 2941 | 1413014 | 208.1 |
96–97 | 3258 | 1502817 | 216.8 |
98–99 | 3723 | 1588335 | 234.4 |
2000–2001 | 4111 | 1676766 | 245.2 |
2002–2003 | 4654 | 1768593 | 263.1 |
2004–2005 | 4760 | 1866601 | 255.0 |
2006 | 2123 | 969972 | 218.9 |
|
|||
Capital city | 4585 | 1728824 | 265.2 |
Capital city suburbs | 2553 | 1084167 | 235.5 |
Large city | 3500 | 1399005 | 250.2 |
Small city | 9156 | 3871445 | 236.5 |
Rural area | 5776 | 2702656 | 213.7 |
a ‘No children’ includes abortions.
Follow-up period | AID and vaginal delivery (N) | Vaginal delivery adjusted RR (95% CI | AID and CS (N) | CS Adjusted RR (95% CI) | AID and abortions (N) | Abortion Adjusted RR (95% CI) |
No pregnancy | 11165 | Reference | 11165 | Reference | 11165 | Reference |
During first pregnancy | 105 | 0.76(0.63, 0.93) | 54 | 1.82(1.39, 2.38) | 25 | 0.92(0.62, 1.37) |
All follow-up period | 8206 | 0.91(0.84, 0.99) | 1317 | 1.02(0.94, 1.11) | 1154 | 0.97(0.92, 1.04) |
0 to 11 months | 673 | 1.15(1.03, 1.28) | 155 | 1.30(1.10, 1.55) | 78 | 0.70(0.56, 0.88) |
12 to 23 | 539 | 0.91(0.81, 1.02) | 111 | 0.99(0.81, 1.20) | 104 | 0.96(0.79, 1.16) |
24 to 35 | 544 | 0.90(0.81, 1.01) | 114 | 1.08(0.89, 1.31) | 93 | 0.90(0.74, 1.11) |
36 to 119 | 3425 | 0.84(0.78, 0.92) | 546 | 0.97(0.87, 1.07) | 566 | 1.02(0.94, 1.11 |
120+ | 3025 | 0.95(0.88, 1.04) | 391 | 1.01(0.89, 1.13) | 313 | 1.02(0.91, 1.15) |
Vaginal delivery and CS models were adjusted for age, calendar year, infant sex and place of birth. Abortion models were adjusted for age, calendar year and infant place of birth. We had no information about fetal sex or number of babies in abortions. Repeating vaginal delivery and CS models for singletons only did not change the estimates. Negative binomial regression models showed that the Poisson models were not over dispersed.
The risk of AID appeared to be moderately increased in the first year following a
pregnancy that ended in vaginal delivery (RR = 1.15,
[95% CI: 1.03, 1.28]), and CS (RR = 1.30,
[95% CI: 1.10, 1.55]) and moderately reduced in the first year
following abortion (RR = 0.70, [95% CI: 0.56,
0.88]). However, the risk of AID was not significantly changed after the first
year following delivery apart from a reduction of the risk between year three and
year 10 following normal delivery (
To examine the effect of age on the observed associations we repeated the Poisson models as described earlier for three age groups: 1) <24 years; 2) ≥24 and <35 years; 3) ≥35 years. The RR estimates of AID were similar in the three age groups following vaginal delivery and abortion. In contrast, the RR of AID in the first year following CS appeared to be higher in the younger (RR = 1.62; [95% CI: 1.03, 2.57]) and older women (RR = 1.61, [95% CI: 0.97, 2.68]). Also, there was a non-significant increase in risk of AID in the second year following CS in the older women (RR = 1.42, [95% CI: 0.87, 2.33]).
We also examined the effect of fetal sex and multiple gestations on the observed estimates. Separate analyses for males, females and singleton pregnancies did not change the results materially.
Follow-up period | Cases in vaginal delivery | Vaginal delivery adjusted RR (95% CI) | Cases in CS | CS Adjusted RR (95% CI) | Cases in abortions | Abortion Adjusted RR (95% CI) |
No pregnancy (reference) | 721 | Reference | 721 | Reference | 721 | Reference |
During pregnancy | 6 | 0.64(0.28 1.43) | 1 | 0.49(0.07, 3.46) | 1 | 0.57(0.09, 4.08) |
All follow-up period | 758 | 0.72(0.55, 0.96) | 143 | 1.17(0.88, 1.55) | 79 | 0.93(0.74, 1.18) |
0 to 11 months | 50 | 0.82(0.55, 1.21) | 10 | 1.01(0.58, 1.95) | 2 | 0.28(0.07, 1.12) |
12 to 23 | 26 | 0.41(0.26, 0.67) | 12 | 1.25(0.68, 2.32) | 7 | 0.99(0.47, 2.09) |
24 to 35 | 45 | 0.70(0.47, 1.05) | 10 | 1.09(0.56, 2.12) | 4 | 0.60(0.22, 1.59) |
36 to 119 | 293 | 0.64(0.48, 0.87) | 59 | 1.12(0.79, 1.59) | 37 | 0.97(0.69, 1.35) |
120+ | 344 | 0.86(0.64, 1.16) | 52 | 1.26(0.88, 1.81) | 29 | 1.16(0.79, 1.70) |
Vaginal delivery and CS models were adjusted for age, calendar year, infant sex and place of birth. Abortion models were adjusted for age, calendar year, infant place of birth. We had no information about fetal sex or number of babies in abortions.
Follow-up period | Cases in vaginal delivery | Vaginal delivery adjusted RR (95% CI) | Cases in CS | CS Adjusted RR (95% CI) | Cases in abortion | Abortion Adjusted RR (95% CI) |
No pregnancy (reference) | 865 | Reference | 865 | Reference | 865 | Reference |
During pregnancy | 8 | 0.58(0.29, 1.17) | 4 | 1.31(0.49, 3.50) | 3 | 1.51(0.48, 4.68) |
All follow-up period | 756 | 1.06(0.82, 1.38) | 109 | 0.93(0.71, 1.22) | 118 | 0.99(0.81, 1.20) |
0 to 11 months | 47 | 1.14(0.78, 1.68) | 12 | 1.26(0.69, 2.29) | 8 | 0.94(0.47, 1.88) |
12 to 23 | 25 | 0.58(0.36, 0.93) | 7 | 0.75(0.35, 1.63) | 9 | 1.01(0.52, 1.95) |
24 to 35 | 46 | 1.03(0.70, 1.52) | 5 | 0.56(0.23, 1.38) | 8 | 0.90(0.45, 1.81) |
36 to 119 | 333 | 1.03(0.78, 1.36) | 51 | 0.99(0.71, 1.40) | 52 | 0.94(0.71, 1.24) |
120+ | 305 | 1.18(0.89, 1.57) | 34 | 0.89(0.60, 1.32) | 41 | 1.08(0.79, 1.50) |
Vaginal delivery and CS models were adjusted for age, calendar year, infant sex and place of birth. Abortion models were adjusted for age, calendar year, infant place of birth. We had no information about fetal sex or number of babies in abortions.
Follow-up period | Cases in vaginal delivery | Vaginal delivery adjusted RR (95% CI) | Cases in CS | CS Adjusted RR (95% CI) | Cases in abortions | Abortion Adjusted RR (95% CI) |
No pregnancy (reference) | 1545 | Reference | 1545 | Reference | 1545 | Reference |
During pregnancy | 27 | 1.17(0.80, 1.72) | 11 | 2.14(1.18, 3.88) | 3 | 0.86(0.28, 2.67) |
All follow-up period | 1843 | 1.18(0.99, 1.41) | 278 | 1.18(0.99, 1.42) | 226 | 1.19(1.03, 1.37) |
0 to 11 months | 204 | 2.15(1.72, 2.68) | 40 | 1.87(1.33, 2.64) | 11 | 0.75(0.41, 1.35) |
12 to 23 | 149 | 1.51(1.19, 1.92) | 27 | 1.33(0.89, 1.98) | 15 | 0.99(0.60, 1.65) |
24 to 35 | 121 | 1.19(0.93, 1.53) | 20 | 1.04(0.66, 1.65) | 21 | 1.40(0.91, 2.17) |
36 to 119 | 721 | 1.01(0.83, 1.21) | 107 | 1.04(0.82, 1.31) | 113 | 1.23(1.02, 1.49) |
120+ | 648 | 1.14(0.94, 1.39) | 84 | 1.19(0.92, 1.54) | 66 | 1.23(0.95, 1.58) |
Vaginal delivery and CS models were adjusted for age, calendar year, infant sex and place of birth. Abortion models were adjusted for age, calendar year, infant place of birth. We had no information about fetal sex or number of babies in abortions.
Follow-up period | Cases in normal delivery | Normal delivery RR (95% CI) | Cases in CS | CS Adjusted RR (95% CI) | Cases in abortions | Abortion Adjusted RR (95% CI) |
No pregnancy (reference) | 3442 | Reference | 3442 | Reference | 3442 | Reference |
During pregnancy | 26 | 0.68(0.46, 1.00) | 17 | 2.16(1.34, 3.49) | 5 | 0.56(0.23, 1.35) |
All follow-up period | 1823 | 0.91(0.77, 1.07) | 263 | 0.85(0.71, 1.01) | 279 | 0.86(0.76, 0.97) |
0 to 11 months | 167 | 1.02(0.82, 1.27) | 33 | 0.98(0.68, 1.41) | 16 | 0.44(0.27, 0.72) |
12 to 23 | 144 | 0.90(0.71, 1.13) | 27 | 0.87(0.59, 1.30) | 26 | 0.74(0.50, 1.09) |
24 to 35 | 129 | 0.83(0.65, 1.05) | 30 | 1.06(0.73, 1.55) | 31 | 0.95(0.67, 1.36) |
36 to 119 | 802 | 0.86(0.72, 1.03) | 109 | 0.79(0.63, 0.99) | 156 | 1.00(0.85, 1.18) |
120+ | 581 | 0.97(0.81, 1.17) | 64 | 0.81(0.61, 1.07) | 50 | 0.78(0.58, 1.03) |
Vaginal delivery and CS models were adjusted for age, calendar year, infant sex and place of birth. Abortion models were adjusted for age, calendar year, infant place of birth. We had no information about fetal sex or number of babies in abortions.
In this study we report the risk of autoimmune disease during and after pregnancy. Overall the risk of AID in women was significantly higher in the first year following vaginal delivery or CS, but was lower in the first year following abortion. While the risk of AID was reduced between the 3rd and 10th year following vaginal delivery, there was no evidence of a change in the risk of AID beyond the first year following CS or abortion. However, women who were pregnant had a higher incidence of AID than those who had no pregnancy records.
Pregnancy has both short and long term effects on the woman's immune system
We hypothesized that the risk of AID is increased following pregnancy. Further, if
fetomaternal cell trafficking is implicated in the etiology of AID after pregnancy,
we expected the highest increase in AID diagnosis following (i) CS, due to increased
fetomaternal hemorrhage, and (ii) abortion, as fetal loss has been shown to be the
only pregnancy complication significantly influencing microchimerism. The first year
after pregnancy should be relevant, being the time period closest to the
fetomaternal hemorrhage occurring at delivery. Our results confirm an increase in
AID in the first year after CS. The unexpected finding of a reduction in AID risk
after abortion may be explained by the premise that early fetal loss allows a higher
number of fetal stem or progenitor cells to enter maternal blood, and that these
cell types are more likely to engraft maternal tissues long-term, and be beneficial
in their role
As pregnancy involves complicated and dynamic interactions between the endocrine and
immune systems, it is possible that it could have differential effects on the
development of an autoimmune disease depending on its timing or even complexity
relative to the events that are likely to precede obvious clinical disease
There were several limitations to our approach. First, since we included data on the
first pregnancy only, we did not account for the effect of subsequent pregnancies on
the risk of AID. However, the effect we observed on risk of AID was manifest in the
first year after pregnancy, which precludes subsequent pregnancies being responsible
in the vast majority of women. We accept that in some cases another pregnancy may
have occurred in the year follow-up period after a first trimester abortion and that
this instead may influence the reduction in AID found. Other studies have previously
failed to show an association with parity and the development of AID
Second, it is possible that the increased risk of AID that we observed is linked to the increased risk of AID presenting during pregnancy. Women may be more likely to be tested for AID (along with other diseases) during pregnancy, and it is also possible that some of these diagnoses were not confirmed until after pregnancy. Further, women with symptoms related to AID may experience a complicated pregnancy and thus require delivery by CS. If that is the case then the association that we describe could be related to more testing during pregnancy rather than effects of fetomaternal cell trafficking.
Third, another limitation of the study was the inability to report the risk of AID after spontaneous abortion. This would be relevant as not only are the risks of spontaneous abortion increased with some AID, but also microchimerism is more likely to be established after induced abortion. We were only able to obtain data on induced abortion from the Danish Medical Birth Register.
Finally, we report limited details on the increased risk of each individual AID, as small numbers of affected women in some disease categories during the follow-up period prevents accurate statistical analysis in all groups. Nonetheless we believe these data are important to report, as they show the relationship between pregnancy and maternal AID in a large population-based cohort over a detailed follow-up period.
We suggest an association between pregnancy and the risk of subsequent maternal AID, with a significant impact on the first year after delivery. However, given the number of unanswered questions and the available data, conclusions on the role of fetal microchimerism in the development of autoimmune diseases cannot be drawn.
We thank Marianne G. Pedersen, MSc, National Centre for Register-based Research, University of Aarhus, Denmark, for her assistance with the study design. We thank Professor William Eaton, Department of Mental Health, Johns Hopkins Bloomberg School of Public Health, for his contribution to the database used in the present study.