(2024) 22:339
Singh et al. BMC Medicine
https://doi.org/10.1186/s12916-024-03550-5

BMC Medicine

REVIEW

Open AccessPregnancy complications and autoimmune
diseases in women: systematic review
and meta‑analysis
Megha Singh1 , Fathima Fazla Ahamed Fayaz1 , Jingya Wang1 , Steven Wambua1 ,Anuradha Subramanian1 , John A. Reynolds2 , Krishnarajah Nirantharakumar1* , Francesca Crowe1    andon behalf of MuM-PreDiCT

Abstract
Background Pregnancy complications might lead to the development of autoimmune diseases in women. This
review aims to summarise studies evaluating the association between pregnancy complications and the development of autoimmune diseases in women.
Methods Medline, CINAHL, and Cochrane databases were searched up to January 2024. Nineteen pregnancy complications and 15 autoimmune conditions were included. Title, abstract, full-text screening, data extraction, and quality assessment were performed by two reviewers independently. Data were synthesised using narrative and quantitative methods. Results were presented using odds ratios (OR), relative risks (RR), incidence rate ratios (IRR), and 95%
confidence intervals (CI).
Results Thirty studies were included. One study reported composite exposure to pregnancy complications had a riskof any autoimmune disease RR 3.20 (2.90–3.51) compared to women without pregnancy complications. Women
with hyperemesis gravidarum had a higher risk of developing coeliac disease (n = 1) IRR 1.98 (1.27–2.94), Crohn’s disease (n = 1) IRR 1.61 (1.25–2.04), psoriasis (n = 1) IRR 1.33 (1.01–1.71), and rheumatoid arthritis (n = 2) IRR 1.35 (1.09–
1.64). Miscarriage associated with subsequent diagnosis of Sjogren syndrome (n = 2) IRR 1.33 (1.06–2.81) and rheumatoid arthritis (n = 4) OR 1.11 (1.04–1.20). Gestational hypertension/preeclampsia was linked with the developmentof systemic sclerosis (n = 2) IRR 2.60 (1.10–4.60) and T1DM (n = 2) IRR 2.37 (2.09–2.68). Stillbirth associated with composite autoimmune conditions (n = 2) RR 5.82 (95% CI 4.87–6.81) and aIRR 1.25 (1.12–1.40). Postpartum psychosis
was associated with autoimmune thyroid disease (n = 1) aIRR2.26 (1.61–2.90).
Conclusions Women with pregnancy complications subsequently had a higher risk of being diagnosed with autoimmune conditions. Whether this is due to pre-existing undiagnosed health conditions or being causally linked to pregnancy complications is not known.
Keywords Pregnancy complications, Autoimmune disease, Pregnancy*Correspondence:
Krishnarajah Nirantharakumar
k.nirantharan@bham.ac.uk
1
Institute of Applied Health Research, University of Birmingham,
Birmingham, UK
2
Institute of Inflammation and Ageing, University of Birmingham,
Birmingham, UK

What is already known about this subject?
• The prevalence of autoimmune conditions and pregnancy complications has increased globally.
• Women with pregnancy complications are at higher
risk of cardiometabolic conditions in later life.

© The Author(s) 2024. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which
permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to theoriginal author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images orother third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line
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Singh et al. BMC Medicine(2024) 22:339

What does this study add?
• This systematic review consolidates evidence fromstudies which have studied the association of pregnancy complications and the later development of
autoimmune diseases in women.
• This review provides new knowledge to help establish
the association of pregnancy complications and autoimmune diseases and identifies the need for further
research to establish the true association between
few conditions like the development of SLE or rheumatoid arthritis followed by miscarriage.

How might this impact on clinical practice?
• This study will be useful for health professionals andpolicymakers to navigate the research findings andidentify the need for clinical guidelines beyond postnatal care for women with pregnancy complications.

Background
The prevalence of autoimmune diseases has been increasing globally over the last decade [1], and in the UK, 1 in
10 people have an autoimmune disease [1–3]. The majority of autoimmune diseases are more common in womenthan men [4] and are a leading cause of death in women
between the age of 65 and 75 in the US and UK [5, 6].
Although the aetiology of autoimmunity is still not fully
understood, the increased prevalence of autoimmune
disease has been linked to defective X chromosome inactivation [7, 8] and the effects of female hormones [9].
During pregnancy, there are significant fluctuations
in hormone levels and increased physiological stress.
Women with pre-existing autoimmune diseases may
experience flare-ups or a decrease in their symptoms.
For example, rheumatoid arthritis, Grave’s disease,or psoriasis may improve during pregnancy [10–12],
whilst patients with systemic lupus erythematosus (SLE)or multiple sclerosis are at an increased risk of disease exacerbations [13, 14]. With an increasing trend in
pregnancy complications due to factors such as older
age at pregnancy and women entering pregnancy withpre-existing long-term health conditions [15–23], it isimportant to study the role of pregnancy complicationsin the development of autoimmune diseases. Whilst it
is well-established that women with autoimmune diseases have an increased risk of fertility problems andadverse pregnancy outcomes such as miscarriage andfoetal growth restriction [24–30], less is known about therisk of developing autoimmunity in women who experience pregnancy complications [31]. Some studies have

Page 2 of 19

shown an association between parity and increased riskof Hashimoto thyroiditis, Sjögren’s syndrome, Graves’disease, and rheumatoid arthritis [32, 33]. Moreover, theassociation between gestational diabetes mellitus (GDM)
and the development of type 1 diabetes (T1DM) is wellestablished [34]. Some pregnancy complications such as
hyperemesis gravidarum and gestational hypertension
have been associated with the development of rheumatoid arthritis [35, 36], whilst other studies have reported
that pregnancy loss and gestational hypertension areassociated with the development of SLE and systemicsclerosis [37, 38]. But other studies conducted on theseassociations have reported contradictory/inconsistentfindings [39, 40].
This systematic review aims to determine the association between a wide range of pregnancy complications
and the development of autoimmune diseases in women.

Methods
This systematic review and meta-analysis have been conducted and reported according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses(PRISMA) and Reporting Guidelines for Meta-analyses ofObservational Studies (MOOSE) (Additional file 1 table 2
and Additional file 2 table 1) [41]. The protocol for thisreview was registered with Prospero CRD42023412549.
Inclusion and exclusion criteria

Cohort, cross-sectional, or case-control studies reporting on the associations between pregnancy complications
and the risk of autoimmune diseases were included. No
language restrictions were applied. The population considered were pregnant women without any age restriction. The pregnancy complications (19) and autoimmune
diseases (15) selected for inclusion were those that weremore common in women, after consultation with experts
in the subject (obstetricians, obstetric physicians, rheumatologists, and epidemiologists), and after input frompatient and public involvement and engagement (PPIE)
group members.
The pregnancy complications included are listed inTable 1 and autoimmune disease in Table 2.
Search strategy

Medline, CINAHL, and Cochrane Library were searched
for studies from 2010 till January 2024.
The search strategies used pre-defined keywords ofthe exposures (pregnancy complications) and outcomes(autoimmune disease). Terms/keywords for each of thepregnancy complications (early adj3 pregnancy loss*,
mp.miscarriage.mp, GDM) and autoimmune diseases(for example arthritis, rheumatoid systemic lupus, or
SLE) were used in the search strategy. Google Scholar

Singh et al. BMC Medicine(2024) 22:339

Page 3 of 19

Table 1 List of pregnancy complications (exposures) included in the systematic review
1. Hyperemesis Gravidarum
2. Miscarriage—missed abortion, recurrent miscarriage, spontaneous pregnancy loss or induced abortion
3. Ectopic pregnancy
4. Molar pregnancy/choriocarcinoma
5. Hypertensive disorders of pregnancy, pre-eclampsia—early or late onset, recurrent pre-eclampsia, eclampsia, HELLP (haemolysis, elevated liver
enzymes, and low platelets)
6. Gestational diabetes mellitus
7. Intrahepatic cholestasis of pregnancy
8. Pelvic girdle pain
9. Placental disorders—placenta previa, placental abruption, placenta accrete, placenta percreta
10. Gestational diabetes mellitus
11. Intra-uterine growth restriction
12. Obstetric haemorrhage (postpartum)
13. Perineal trauma—third and fourth degree
14. Caesarean birth, instrumental birth
15. Postpartum depression
16. Puerperal psychosis
17. Pre-term birth, recurrent pre-term birth
18. Low birth weight
19. Small for gestational age

Table 2 List of autoimmune diseases (outcomes) included in thesystematic review
1. Alopecia areata
2. Ankylosing spondylitis or axial spondyloarthropathy.
3. Autoimmune thyroid disease (Grave’s disease, Hashimoto’s disease)
4. Coeliac disease
5. Inflammatory bowel disease (Crohn’s disease and ulcerative colitis)
6. Multiple sclerosis
7. Myasthenia gravis
8. Psoriasis
9. Psoriatic arthritis
10. Rheumatoid arthritis
11. Sjögren’s syndrome
12. Systemic lupus erythematosus (SLE)
13. Systemic sclerosis
14. T1DM
15. Vitiligo

was searched to identify other grey literature. In addition, the reference list of the included studies, systematic
reviews, and scoping reviews were searched manually tominimise the possibility of missing any relevant studies.
Letters, commentaries, or editorials were excluded andstudies that did not involve humans were also excluded.
The searches were repeated periodically to identify newly
published studies. The detailed search strategy for Medline is presented in the Additional file 1 table 1 (Table 1).

This search strategy was adapted for use in other databases (CINAHL and Cochrane library). Pragmatic
approach was taken given there was a substantial number of studies that needed screening (n = 24,340) and thestudy period was limited from 2010 to 2023 (n = 13,234).
But this was complimented by a secondary search strategy looking at references of included studies, systematic
reviews, scoping reviews, and by discussing with topic
experts (KN, FC) to minimise the possibility of missing
any study before 2010.
Study selection

EndNote reference manager [42] was used for the title
and abstract screening by two researchers independently(MS, JW). Full text of the eligible reviews was screenedby two researchers independently (MS, FF). Covidence
software [43] was used for full-text screening and data
extraction. A third senior researcher was consulted toresolve any discrepancies in the selection of the studies(FC, KN).
Data extraction

Two reviewers extracted data from the included studies.
The data extraction form was adapted from JBI (Joanna
Briggs Institute) data extraction form [44]. A standardised data extraction form was used and was piloted before
use. The data were extracted for the following fields:
author/s, year of publication, geographical area, aim of
the study, population, exposures, comparator, outcomes,

Singh et al. BMC Medicine(2024) 22:339

Page 4 of 19

The effect estimates were reported as adjusted incidence
rate ratios (aIRR), adjusted hazards ratios (aHR), adjusted
odds ratios (aOR), or adjusted relative risks (aRR) and
95% confidence intervals (CI). We converted these effectestimates using appropriate methods (where possible)
to maintain uniformity across studies [46]. Where morethan one study reported the same exposure and outcome,a meta-analysis was conducted using a random effects
model to generate a summary estimate. Statistical heterogeneity was estimated using the I2 statistic. To deal withpotentially missing data (sample size, number exposed
and unexposed), Additional file 1 of each included study
was checked thoroughly, and the authors of the studies
were contacted to request the data. If the data was notavailable and a meta-analysis could not be conducted,
then effect estimates were reported as they were published. Where statistical pooling was not possible, thefindings were presented in a narrative form includingtables and figures to aid data presentation. R (3.3.0) andR Studio (12.1) were used to conduct statistical analysis[47–49].

Results
Out of the 13,234 records identified from the search
and after full-text screening of 85 studies, 30 studies
were included [31, 34–36, 39, 40, 50–73]. Studies were
excluded if they did not qualify in the study inclusion
criteria based on the study design (n = 22), population(n = 5), intervention (2), outcome (23), and comparator(3). The selection process is shown in the PRISMA
diagram (Fig. 1) [41]. The list of excluded studies is provided in Additional file 1 table 3.
Characteristics of the included studies are reported inTable 3. Out of the 30 studies, the majority were prospective cohort studies (n = 21), 8 were retrospective case–control studies, and 1 was a cross-sectional study. There
were 23 studies conducted in Europe, the remainder
were in Taiwan (2), China (2), South Korea (1), and theUnited States (2). In most cohort studies (n = 14), information about the pregnancy complications and autoimmune diseases was collected through medical records.
Medical records were used to establish the autoimmune
diseases in case–control studies, and questionnaires
were used to determine the pregnancy complications.
The follow-up period of the cohort studies varied from
9 months to 26 years with a median of 12 years. Out of
the 21 cohort studies, 9 used the data from the samecohort (Danish national registry) [31, 36, 39, 53, 54,
63, 64, 69]. In the instance of two studies reporting thesame exposure and outcome, the most recent study wasused to avoid duplication. We have done this in accordance with the Cochrane handbook for systematic reviews[74]. For instance, two studies, Mikkelsen et al. [63] andNielsen et al. [64], were both reporting the associationof pregnancy complications and the future development of multiple sclerosis in women using Danish Civil
Registration System. Mikkelsen et al.’s study was used
to report the findings in this review. Details have been
added in Additional file tables 1 and 5 [75, 76]. A totalof 18 different pregnancy complications and 12 autoimmune diseases (including an overall “all autoimmune diseases”) were investigated across the studies. Rheumatoid
arthritis (8 studies) and SLE (5 studies) were two of themost included outcomes. The meta-analysis performedin this systematic review is included in Additional file 1
figure 1.1–1.11.

Patient and public involvement

Quality assessment

covariates, study design, definition of exposure, risk ofbias assessment tool and result, number of participants
included in the study, summary estimates, authors’ conclusion, and study limitations. The data extraction form is
enclosed in Additional file Table 6.
Quality assessment

The quality of included cohort, cross-sectional, and casecontrol studies was assessed using the Newcastle–Ottawa
scale that measures study quality based on selection, comparability of the exposure and comparator groups, and theascertainment of outcomes and exposures [45]. The scale
has an overall score of 8 points for cohort or case–control
studies, and 7 for cross-sectional studies with a maximumof 1 point for each numbered item within the selection
and outcome/exposure categories and a maximum of 2
points for the comparability category. We defined studies
with a score of ≥ 7 points as low-risk of bias studies (verygood), studies with a score of 6 points as moderate-risk ofbias studies (good), and those with a score of ≤ 5 points as
high-risk of bias studies (satisfactory).
Data synthesis

Patient and public involvement and engagement (PPIE)
representatives (RP and NM) participated in formulating the research question. They have also played key rolein collaboration with clinicians and researchers to identify and consider the list of pregnancy complications andautoimmune diseases in the study. They will play a keyrole in disseminating the results.

Results of the quality assessment of the studies using the
Newcastle–Ottawa scale are shown in Fig. 2 and Additional file 1 Table 4.1–4.3 [77]. Eighteen out of 30 studies
had a low risk of bias with an overall “very good” rating.
The principal areas of concern were the comparability ofcohorts and the adequacy of follow-up.

Singh et al. BMC Medicine(2024) 22:339

Page 5 of 19

Fig. 1 Preferred reporting items for systematic review and meta-analysis (PRISMA) flow diagram

All autoimmune diseases

There was more than a threefold higher risk of developing autoimmune diseases (n = 7) in women with pregnancy complications (n = 6) RR 3.20 (95% CI 2.90–3.51)
when compared with women without pregnancy complications [58]. Out of the pregnancy complications
studied individually, two studies reported, women withprevious miscarriage RR 3.41 (3.03–3.85) and aIRR 1.10
(1.07–1.14) was reported to have higher risk [58]. One
cohort and one case–control study reported a higher
risk of autoimmune diseases in women with gestational
hypertension or pre-eclampsia; RR 2.05 (1.70–2.48) andaIRR 1.21 (1.16–1.26) [54, 58], respectively. Women withstillbirth were reported to have higher chances to haveautoimmune disease in later life reported by two studies RR 5.82 (4.97–6.81) [58] and aIRR 1.25 (1.12–1.40)[54]. There was a significantly higher risk of developing

autoimmune diseases for women with preterm birth
RR 2.35 (1.89–2.92) [58]. There was little association
reported with caesarean section, induced abortion, or
postpartum depression with the development of autoimmune diseases [31, 54, 61]. However, a study reported ahigher risk of developing autoimmune diseases in womenwith perinatal depression aHR 1.52 (1.46–1.58), withantenatal depression aHR 1.50 (1.43–1.58), and postpartum depression aHR 1.55 (1.45–1.65) [73].
Autoimmune thyroid diseases

Hyperemesis gravidarum aIRR 1.49 (1.28–1.72), gestational hypertension or pre-eclampsia aIRR 1.20 (1.10–1.30), and postpartum depression aHR 1.57 (1.05–2.33)[54, 60] were all associated with a higher risk of Grave’s
disease but there was no significant association between
ectopic pregnancy and Grave’s disease aIRR 1.04

Auvinen 2020 [34]Bergink, 2011 [50]Bergink 2018 [51]Bränn 2023 [73]Hardy 1999 [52]Harpsoe 2013 [53]Jørgensen 2010 [36]Jørgensen 2012 [54]Jørgensen 2014 [39]Kamper 2018 [56]

Khashan 2011 [31]Lee 2022 [59]Lin 2018 [60]Lin 2016 [61]Mao 2022 [62]Mikkelsen 2022 [63]Nielsen 2011 [64]

1.

2.

3.

4.

5.

6.

7.

8.

9.

10.

11.

12.

13.

14.

15.

16.

17.

Prospective cohort studies

Serial number Author, year

Denmark

Denmark

China

TaiwanTaiwanSouth Korea

Denmark

Denmark

Denmark

Denmark

Denmark

Denmark

UK

SwedenDenmark

The Netherlands

Finland1,035,639

778, 758

97,0771,564,567

7017

56,108314

530,397

312,779148

782

45,451Danish Civil Registration System

Danish Civil Registration System

National Health and Nutrition Examination Survey cohort

6332

1,513,560

11,997National Health Insurance programme 145,455

National Health Insurance Research
Database

Inflammatory bowel disease

Systemic lupus erythematosus

Autoimmune diseases

Autoimmune thyroid dysfunction

Autoimmune thyroid dysfunction

Type 1 diabetes mellitus

Autoimmune disease(s) considered(outcome)

Myasthenia gravis

Rheumatoid arthritis

Systemic lupus erythematosus

Autoimmune diseases

Systemic sclerosis

Any autoimmune disease

Systemic sclerosis

Rheumatoid arthritis

Autoimmune diseases

Miscarriage, ectopic pregnancy,
Multiple sclerosis
hyperemesis gravidarum, gestational
hypertension, pre-eclampsia, stillbirth,

Miscarriage

Gestational diabetes mellitus

Gestational hypertension

Postpartum depression

Caesarean section

Caesarean section, induced abortion

Pre-eclampsia

Gestational hypertension, preeclampsia, hyperemesis gravidarum

Hyperemesis gravidarum, gestational
hypertension, preeclampsia, spontaneous abortions, missed abortions,ectopic pregnancies

Hyperemesis gravidarum, ectopic
Rheumatoid arthritis
pregnancies, miscarriage, Induced
abortions missed abortions, hydatidiform moles, gestational hypertension,and pre-eclampsia

Hyperemesis gravidarum, gestational
hypertension, pre-eclampsia

Pregnancy loss (spontaneous abortion, stillbirth, miscarriage, or ectopic
pregnancy), Induced abortion

Perinatal depression

Postpartum psychosis

Postpartum psychosis

Gestational diabetes mellitus

Sample size Pregnancy complication(s)considered (exposure)

National health insurance corporation 2,260,952

Danish Civil Registration System,
the Danish National Hospital Register[28] and the Danish Medical BirthRegister

Danish Medical Birth Register

Danish National Birth Cohort

Danish women born between 1955
and 1993

Danish civil Registration System

Danish National Birth Cohort

Patients from Nottingham

Swedish National Medical BirthRegister

Danish national registry

Department of psychiatry at the Erasmus Medical Centre for evidenceof postpartum psychosis

University hospital

Geographical area Database/heath care setting

Table 3 Basic characteristics of included thirty studies

Singh et al. BMC Medicine(2024) 22:339
Page 6 of 19

Stuart 2018 [68]Ulff-Møller 2009 [69]Wikstrom 2015 [72]

19.

20.

21.

Kither 2020 [58]

Ma 2014 [40]Siamopoulou 1988 [66] Greece

Spector 1990 [67]

Van Wyk 2011 [70]Wallenius 2011 [71]

3.

4.

5.

6.

7.

8.

Hee 2022 [35]China

NorwayThe Netherlands

UK

USA

UK

China Kadoorie Biobank (CKB)

Medical Birth Registry of Norway

Leiden University Medical Centre(LUMC) and the VU Medical Centreof Amsterdam (VUMC) in the Netherlands

American Rheumatism Association
criteria

Greek married womenGroup Health Cooperative, a large
Seattle-based consumer-governed
non-profit health care system

Clinical Practice Research Datalink

American Rheumatism Association

miscarriage induced abortion,
stillbirth

657

302,510335,377

Rheumatoid arthritis

Systemic lupus erythematosus, Rheumatoid arthritis

Miscarriage

Pre-eclampsia, caesarean section,
postpartum haemorrhage, lowbirth weight, preterm delivery, small
for gestational age,

Rheumatic arthritis

Chronic inflammatory arthritis RA/PSA/
ANK S

miscarriage, gestational hypertension, Systemic sclerosis
intrauterine growth restriction

miscarriage, preterm birth, stillbirth,206

Connective tissue disease, Systemic
lupus erythematosus

Rheumatoid arthritis

Systemic lupus erythematosus

Inflammatory bowel disease

Systemic lupus erythematosus

Type 1 diabetes mellitus

Type 1 diabetes mellitus

Low birth weight, small for gestational Rheumatoid arthritis
age

miscarriage, gestational hypertension, intrauterine growth restriction,
placental complications Stillbirth

miscarriage, stillbirth

573

1304

117,446

418

Spontaneous abortion, stillbirth,preterm birth, intrauterine growth
restriction

Intrahepatic cholestasis of pregnancy

Abortion (spontaneous, missed,
induced), ectopic pregnancy, molar
pregnancy

Low birth weight

Gestational hypertension

Autoimmune disease(s) considered(outcome)(2024) 22:339

NOS Newcastle–Ottawa’s scale for quality assessment of the cohort, cross-sectional, or case–control studies, RA/PSA/ANK S Rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis, T1DM type 1 diabetes
mellitus

1.

Cross-sectional study

Kay 1965 [57]2.

UK

Julkunen 1993 [55]125,2812,140,000

1,873,440

849,639

Sample size Pregnancy complication(s)considered (exposure)

Fourth and Second Departments
659
of Medicine and the Departmentof Dermatology of the Helsinki University Central Hospital

Swedish Medical Birth Register

SwedenFinland

Civil Registration System

Swedish National Board of Healthand the data

Data on all births in hospitals in New
York City, New York

Denmark

SwedenUSA

Geographical area Database/heath care setting

1.

Retrospective case–control studies

Savitz 2014 [65]18.

Serial number Author, year

Table 3 (continued)

Singh et al. BMC Medicine
Page 7 of 19

Singh et al. BMC Medicine(2024) 22:339

Page 8 of 19

Fig. 2 Quality assessment of included studies (Newcastle–Ottawa scale). A Cohort studies (21). B Case–control studies (8). C Cross-sectional study (1)Singh et al. BMC Medicine(2024) 22:339(0.93–1.17) [54]. Gestational hypertension/pre-eclampsia
aIRR 1.41 (1.17–1.68) was associated with a higher riskof Hashimoto’s thyroiditis but there was little associationof hyperemesis gravidarum or ectopic pregnancy with
Hashimoto’s thyroiditis; aIRR 1.38 (0.95–1.92) and aIRR
0.92 (0.68–1.21), respectively [54]. Two cohort studies
reported a greater risk of autoimmune thyroid disease in
women with postpartum psychosis aOR 2.78 (1.08–7.17)
at 9 months and aIRR 2.26 (1.61–2.90) with 2 years follow-up postpartum when compared with women without postpartum psychosis [50, 51].
Coeliac disease

Women who experienced hyperemesis gravidarum had
almost a twofold risk of coeliac disease compared to
women without; aIRR 1.98 (1.27–2.94) [54]. None of theother pregnancy complications were significantly associated with coeliac disease; ectopic pregnancy aIRR 1.12
(0.75–1.61), gestational hypertension, pre-eclampsia
aIRR 1.19 (0.89–1.56), and intrahepatic cholestasis ofpregnancy aHR 1.20 (0.82–1.74) [54, 72].
Inflammatory bowel disease (Crohn’s disease
and ulcerative colitis)

Out of the five pregnancy complications reported for
IBD (hyperemesis gravidarum, missed abortion, gestational hypertension, pre-eclampsia, and Caesarean
section), none of these associations were statisticallysignificant. However, studies reporting ulcerative colitis
and Crohn’s disease separately found significant associations. Hyperemesis was significantly associated with thedevelopment of both ulcerative colitis and Crohn’s disease, aIRR 1.34 (1.09–1.62) and aIRR 1.61 (1.25–2.04),
respectively [54]. Furthermore, a higher risk of Crohn’sdisease was also observed in women with intrahepaticcholestasis of pregnancy, HR 1.55 (1.14–2.10) [72]. No
other pregnancy complications were associated with thedevelopment of IBD as reported in Fig. 4.
Ankylosing spondylitis

Out of the three pregnancy complications studied withthe development of ankylosing spondylitis in women,
there was no significant association for hyperemesis
gravidarum IRR 1.63 (0.96–2.25) or ectopic pregnancy
IRR 1.02 (0.66–1.50); a significant association was notedwith gestational hypertension and pre-eclampsia IRR
1.40 (1.06–1.82) [54] (Fig. 5).
Rheumatoid arthritis

Out of the five studies reporting the association of miscarriage and rheumatoid arthritis, four were metaanalysed to estimate 11% higher odds: pooled OR 1.11

Page 9 of 19(1.04–1.20) with the other study showing a slightly elevated risk that was not statistically significant aIRR 1.06
(0.97–1.15) [35, 36, 54, 57, 66, 67]. A significant association was also reported with hyperemesis, gestational
hypertension, and pre-eclampsia with aIRR 1.35 (1.09–
1.64), aIRR 1.18 (1.05–1.31), respectively [54]. [35, 36,
54, 57, 66, 67]. Whilst three studies were pooled to derivea significant association between rheumatoid arthritis
and induced abortion 1.46 OR (1.01–2.12). Women withany pregnancy loss were reported to be at higher risk ofdeveloping the disease in one study aIRR 1.12 (1.06–1.12)
and others reported no association aIRR 1.01 (0.67–1.44),
and this will require further research to establish the trueassociation. The association for induced abortion or any
pregnancy loss with rheumatoid arthritis reported mixed
findings with significant association reported by few
studies and insignificant by others as shown in Fig. 5 [31,35, 36, 54, 57, 66, 67]. A higher risk of developing rheumatoid arthritis was observed in women who delivered“extremely low birth weight” babies (< 1000 g) with RR
3.70 (1.00–13.20) or “low birth weight” babies (< 2500 g)
with RR 1.40 (1.00–2.10) when compared to women who
delivered normal birth weight babies [40]. An increased
risk of rheumatoid arthritis was also reported for womenwith postpartum depression with aHR 2.62 (1.28–5.39)[60]. No other pregnancy complications studied in relation with the development of rheumatoid arthritis were
statistically significant (Fig. 5). There was also no significant association with the development of rheumatoid
arthritis as reported in women who delivered very low
birth weight babies (< 1500 g) in a study with a small sample size (n = 20) [40].
Rheumatoid arthritis, psoriatic arthritis, and ankylosing
spondylitis (composite outcome)

There were no other significant associations with rheumatoid arthritis or the composite outcome with otherpregnancy complications studied (gestational hypertension or pre-eclampsia, caesarean section, postpartum
haemorrhage, or mothers delivering preterm births or
low birth weight babies) (Fig. 5) [71]. Women who delivered small for gestational age babies were more likely
to have the composite outcome of rheumatoid arthritis,
psoriatic arthritis, and ankylosing spondylitis aOR 1.60
(1.00–2.56) when compared to women with normal for
gestational age babies.
Connective tissue diseases (systemic lupus erythematosus,
Sjogren syndrome, systemic sclerosis)
Connective tissue disease

Seven pregnancy complications were reported in association with connective tissue disease (CTD). Women withplacental abruption or preterm birth had significantly

Singh et al. BMC Medicine(2024) 22:339

higher risk of CTD; RR 3.39 (1.96–5.89) and RR 1.78
(1.12–2.82), respectively, [58] in Fig. 6. The associationsof gestational hypertension, intrauterine growth restriction (IUGR), miscarriage, stillbirth, and composite pregnancy complications with CTD were not statisticallysignificant [58].
Systemic lupus erythematosus (SLE)

Results for an association between miscarriage and SLE
were mixed with one study reporting aIRR of 1.43 (1.08–
1.88), and a pooled RR for two smaller studies showing
no significant association 0.94 (0.37–2.40) [54, 58, 66,69]. However, there was a significant association reportedwith any pregnancy loss and future development of thedisease with OR 1.87 (1.31–2.67) [52, 55]. Missed abortions were associated with a higher risk of SLE; IRR 2.13
(1.48–2.98) [54, 69]. Women with history of IUGR had
almost a fivefold higher risk of SLE; RR 4.80 (1.60–14.50)
when compared with women with no IUGR [55]. Resultsfrom three studies showed that a history of stillbirth was
associated with a four times higher risk of SLE, pooled
RR 4.01 (3.11–5.17) and pooled IRR 3.29 (3.22–4.88) [54,58, 66, 69].
Systemic sclerosis

There was an association between gestational hypertension or pre-eclampsia and systemic sclerosis in
two studies: OR 2.60 (1.10–4.60). Kamper et al. [56]reported a significant association with the developmentof localised scleroderma in women with pre-eclampsia
with IRR 1.69 (1.02–2.80) but a nonsignificant association with subset of systemic disease aIRR 1.46 (0.75–2.80) [56, 70]. There was a three- to fourfold higher riskof systemic sclerosis for women with IUGR comparedwith women with normal foetal growth OR 3.90 (1.20–
12.30) [70] and caesarean birth compared to vaginal
birth RR 3.09 (1.96–4.63) [59].
Sjögren’s syndrome

There were seven pregnancy complications examinedin relation to Sjögren’s syndrome with results showing
a greater risk with hyperemesis gravidarum, aIRR 1.79
(1.06–2.81); miscarriage, aIRR 1.33 (1.08–1.63); induced
abortion, aIRR 1.18 (1.01–1.38); and gestational hypertension or pre-eclampsia, aIRR 1.43 (1.09–1.85) [54]. The
associations for ectopic pregnancy, missed abortion, orpreterm birth, aIRR 1.18 (0.79–1.68), aIRR 1.12 (0.80–1.51), and RR 0.09 (0.04–18.09), respectively [54, 58, 66],
were not statistically significant.
Type 1 diabetes mellitus (T1DM)

Hyperemesis gravidarum aIRR 1.05 (0.74–1.45) andectopic pregnancy aIRR 1.06 (0.58–1.77) were notPage 10 of 19

significantly associated with T1DM [34, 54, 65, 68] in
Fig. 7. Results from one cohort study showed that gestational hypertension or pre-eclampsia was associated with a twofold higher risk of T1DM; aIRR 2.37
(2.09–2.68) [68], whereas in the other study, the association was higher but not statistically significant; OR 1.80
(0.80–3.80) [65]. Results from two studies showed thatthe risk of T1DM for women with gestational diabetes
was considerably higher; pooled OR 40.89 (24.31–68.78)[34, 65]. There was almost a fourfold higher risk of T1DM
in women who delivered large for gestational age babies
compared to women delivering normal weight for gestational age babies aHR 3.60 (3.23–4.01) [68]. There was no
significant association for women who delivered small for
gestational age babies and T1DM; aHR 1.11 (0.94–1.30)[62, 71].
Psoriasis

Out of the seven pregnancy complications, five complications were associated with a higher risk of psoriasis:
hyperemesis gravidarum HR 1.33 (1.01–1.71), ectopic
pregnancy aIRR 1.28 (1.07–1.53), induced abortions
aIRR 1.33 (1.24–1.42), gestational hypertension or preeclampsia aIRR 1.22 (1.06–1.40), and intrahepatic cholestasis of pregnancy aIRR 1.27 (1.07–1.51) [54, 61, 72].
Missed abortion and postpartum depression were notsignificantly associated with the risk of psoriasis (Fig. 7)[54, 61].
Associations of pregnancy complications with othermiscellaneous autoimmune conditions

No significant association was reported with pregnancy
complications studied (hyperemesis, ectopic pregnancy,
miscarriage, or gestational hypertension) and the development of multiple sclerosis as mentioned in Fig. 7 [64].
The association of postpartum depression and alopecia
areata (HR 1.97, 0.72–5.37) [60], and recurrent pregnancy loss and myasthenia gravis (RR 0.85, 0.54–1.31)
were not statistically significant [63].
Timing of developing autoimmune diseases
following pregnancy/pregnancy complications

Four studies reported the occurrence of autoimmune diseases following pregnancy over different follow-up times[31, 51, 54, 69]. Following a pregnancy complication, awoman’s risk of developing Grave’s disease or SLE washigher in the early years after childbirth in comparison tolater in life [35, 39, 54, 63, 69]. For instance, there was ahigher risk of SLE in women with pregnancy loss in thefirst year postpartum IRR 2.64 (1.18–6.29), whereas there
was no significant association noted after two or more
years postpartum IRR 1.90 (0.87–4.48) [69]. Conversely,
the risk of developing rheumatoid arthritis (RR 1.05;

Singh et al. BMC Medicine(2024) 22:339

0.98–1.13, 5+ years: RR 2.24; 1.58–3.05, and multiple
sclerosis) (RR 1.00; 0.91–1.09, 5+ years: RR 2.20; 1.72–
2.77) was greater after 5 or more years postpartum. Also,
women with hyperemesis gravidarum were at a greaterrisk of developing rheumatoid arthritis in the first 4 years
post birth; this reduced after 5 years, IRR 1.40 (1.09–1.76)
and IRR 1.02 (0.59–1.11), respectively [54, 69]

Discussion
This systematic review provides an overview of the associations of 18 pregnancy complications with the risk ofdeveloping 15 autoimmune diseases. This review compiles all the available evidence on pregnancy complications linked to the development of autoimmune diseases
in women in later life (Figs. 2, 3, 4, 5, 6 and 7) and generates new evidence by quantitative or qualitative analysisof the studies studying the same exposure and outcomes(Additional file 1 figure 1.10). This also further points out
the differences in the results observed in two or more

Page 11 of 19

studies analysing the association of the same pregnancy
complication and autoimmune disease (Additional file 1
fig. 1.11).
Studies reported associations for gestational hypertension/preeclampsia followed by preterm birth, hyperemesis gravidarum and ectopic pregnancy, and future
autoimmunity. However, there was little or no researchon some complications such as molar pregnancy or placental disorders. From the perspective of autoimmune
disease outcomes, most studies examined the associations with rheumatoid arthritis followed by autoimmune
thyroid diseases, Sjögren’s syndrome, and psoriasis. In
contrast, there were very few studies that included vitiligo or myasthenia gravis.
Many of the pregnancy complications increased therisk of overall autoimmune diseases almost threefold,particularly hyperemesis gravidarum, miscarriage, gestational hypertension, stillbirth, and antenatal/postpartum depression. Apart from the known association

Fig. 3 Forest plot association of pregnancy complications and autoimmune diseases (overall) and autoimmune thyroid diseases

Singh et al. BMC Medicine(2024) 22:339

Page 12 of 19

Fig. 4 Forest plot-association of pregnancy complications and coeliac disease or inflammatory bowel disease (Crohn’s disease and ulcerative colitis)of gestational diabetes and T1DM, results from thisreview showed that IUGR or stillbirth were associatedwith almost three- to fourfold increased risk of systemicsclerosis or systemic lupus erythematosus. There wasa higher risk of rheumatoid arthritis with preterm birthand low birth weight babies.
There are findings which require further research, forexample, the association of miscarriage and development of SLE [58, 65, 69] and the association of gestational hypertension with T1DM [54, 65]. The differencein the findings could possibly be due to the varying study
designs or difference in the sample size of the studies. There had been mixed findings amongst the studies
included and these may be due to the varying sample sizeor the study designs.
Earlier studies focused on the association of pregnancy
complications with child outcomes such as caesarean
birth or pre-eclampsia and the association with longterm health conditions in babies [78–84]. However, more
recently, studies have reported the association of pregnancy complications and the development of long-term

conditions in the mother [31, 85]. Reproductive factors
and pregnancy complications were found to be associatedwith later development of metabolic conditions [86–88].
An association between pregnancy itself, irrespective ofpregnancy complications, and the development of autoimmune diseases has been reported [31]. Some studies
identified the association between parity and the development of systemic sclerosis; however, the findings havebeen conflicting [89–92].
It is not clear whether the observed pregnancy complications occur in women with preclinical autoimmune
disease or whether these events directly pre-dispose to
the development of autoimmune disease [93]. In termsof the former, women with undifferentiated connective
tissue disease (UCTD), who have features compatible
with a CTD but do not have a defined CTD [94], havean increased risk of pregnancy complications includingpremature delivery, pre-eclampsia, and stillbirth [95].
As approximately 30% of UCTD may progress to CTD,
typically SLE, it is possible that some of the pregnancy
complications occurred in women who were in the initial

Singh et al. BMC Medicine(2024) 22:339

Page 13 of 19

Fig. 5 Forest plot- association of pregnancy complications and Ankylosing spondylitis, rheumatoid arthritis, or RA/PSA/ANK S

stages of UCTD, i.e. the pregnancy complications were
due to a subclinical autoimmune disease.
On the other hand, pregnancy/pregnancy complications bring about fluctuations in female sex hormones
accompanied by physiological stress [96]. The bloodlevels of both oestrogen and progesterone increase rapidly from the middle of the second trimester, peaking
at term. Oestrogen and progesterone have broad effects
on the function of both innate and adaptive immune
cells (including monocytes/macrophages, neutrophils,

dendritic cells, and T and B lymphocytes) [97]. In pregnancy, placental production of oestriol (E3) increases
dramatically. Oestriol has potent anti-inflammatory
effects including reducing pro-inflammatory cytokine
production, increasing anti-inflammatory cytokines,
and reducing CD4+ and CD8+ T cells [98]. Similarly,
progesterone increases regulatory T cells and reduces
natural killer cell function systemically and within theplacenta [98]. It is possible, therefore, that hormonal fluctuations and the loss of this anti-inflammatory

Singh et al. BMC Medicine(2024) 22:339

Fig. 6 Forest plot showing the association of pregnancy complications and connective tissue diseases

Page 14 of 19

Singh et al. BMC Medicine(2024) 22:339

Page 15 of 19

Fig. 7 Forest plot showing the association of pregnancy complications and alopecia areata, multiple sclerosis, myasthenia gravis, psoriasis, or T1DM

state postpartum could accelerate the development of
autoimmune disease. Furthermore, oestrogens reduce
B cell apoptosis which, whilst contributing to maternal
humoral immunity, may promote autoreactive B cell
survival and drive the immune system toward autoimmunity [99].
A key driver of future autoimmune disease may befoetal microchimerism [100]. Foetal cells are present
at a low frequency in the maternal circulation postpartum and may persist for decades [57, 101–103]. Foetal origin microchimerism is observed at increased
rates during pregnancy complications such as miscarriage, pre-eclampsia, foetal growth restriction [104], or

premature labour [102, 105]. The mechanisms by which
foetal microchimeric cells mediate an increased risk of
autoimmunity is not understood although an increased
number of these cells is observed in the thyroid gland of
women with autoimmune thyroid disease [106]. To date,a pathogenic role for foetal microchimeric cells has notbeen demonstrated, and these cells may induce maternal tolerance to foetal antigens and via a bystander effectreduce the severity of some autoimmune diseases such as
RA during pregnancy [106].
Our study has several strengths. The scope ofour review was broad and summarises the association of pregnancy complications and the subsequentSingh et al. BMC Medicine(2024) 22:339

development of a wide range of autoimmune diseases,
and we were able to perform a meta-analysis of studies
reporting the same exposure and outcome where possible. We employed rigorous methodology with a pre-specified protocol, and our systematic search was conductedwithout language restriction and two reviewers screened,
extracted data, and appraised the quality of the studies.
There are, however, some limitations. A meta-analysis could not be performed for some of the studies due
to missing data such as the sample size or number of
exposed/unexposed. Some of the results reported therefore are as reported in one study. Also, nine studies wereconducted using the same cohort (Danish birth cohort);
this may have a disproportionate effect on our findings.
However, efforts were made to avoid duplication in thereporting of results. This study is not able to determine
causality and there is a possibility that the women alreadyhave undiagnosed preclinical autoimmune diseases,
which increased their risk of pregnancy complications instudies, especially those with shorter follow-up time.
Additional research is required that incorporates acomprehensive analysis of pregnancy complications andcharacterise the phenotype and functionality of persistent
foetal origin cells in women with autoimmune diseases
compared with healthy women. The exact pathophysiology behind the development of these conditions remains
unclear and we do not know why some pregnancy complications have a larger effect than others. To addressthese questions, prospective longitudinal studies following up on women who experienced pregnancy complications are needed, observing when autoantibodies are firstdetected [107]. Furthermore, larger epidemiological studies would be required to define whether autoimmune disease is more prevalent in women who have experienced
pregnancy complications and if there is a clear underlying association.

Conclusions
This review has reported that there is an association
between pregnancy complications and the subsequentdevelopment of autoimmune diseases in women. To further address this question, prospective longitudinal studies following up on women who experienced pregnancy
complications are needed, observing when autoantibodies are first detected. Meanwhile, clinicians should be vigilant and detect autoimmune conditions early in womenwith a history of pregnancy complications.
Abbreviations
95% CI	95% Confidence intervals
aHR	Adjusted hazard ratioaIRR	Adjusted incidence risk ratioaOR	Adjusted odds ratioaRR	Adjusted risk ratio
AxSpA	Axial spondyloarthropathy

Page 16 of 19

CD	Clusters of differentiation
CS	Caesarean section
CTD	Connective tissue diseases
GDM	Gestational diabetes mellitus
GHT or PE	Gestational hypertension or pre-eclampsia
HELLP	Haemolysis, elevated liver enzymes, and low platelet syndrome
IBD	Inflammatory bowel disease
IUGR​	Intrauterine growth retardation
LBW	Low birth weight
MESH	Medical subject headings
MOOSE	Meta-analyses of observational studies
MS	Multiple sclerosis
NA	Not applicable
NOS	Newcastle–Ottawa scale
PPIE	Patient and public involvement and engagement
PRISMA	Preferred reporting items for systematic review and metaanalysis
RA/PSA/ANK S	Rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis
SGA	Small for gestational age
SLE	Systemic lupus erythematosus
T1DM	Type 1 diabetes mellitus
UCTD	Undifferentiated connective tissue disease
UK	United Kingdom
US	United States

Supplementary Information
The online version contains supplementary material available at https://​doi.​
org/​10.​1186/​s12916-​024-​03550-5.
Additional file 1: Table 1. Search Strategy MEDLINE. Table 2. The Preferred
Reporting Items for Systematic reviews and Meta-Analyseschecklist.
Table 3. List of excluded studies. Table 4.1. Quality assessment of the
Cohort studies using NOS. Table 4.2. Quality assessment of the case control studies using NOS. Table 4.3. Quality assessment of the cross-sectional
studies using NOS. Figure 1.1. Meta-analysis of two studies reporting
association of miscarriage and future development of SLE. Figure 1.2.
Meta-analysis of two studies reporting association of miscarriage andfuture development of rheumatoid arthritis. Figure 1.5. Meta-analysis of
two studies reporting association of stillbirth and future development of
SLE. Figure 1.6. Meta-analysis of two studies reporting association of gestational hypertension or pre-eclampsia and future development of SLE.
Figure 1.7. Meta-analysis of two studies reporting association of preterm
birth and future development of SLE. Figure 1.8. Meta-analysis of two
studies reporting association of preterm birth and future developmentof rheumatoid arthritis. Figure 1.9. Meta-analysis of two studies reporting
association of gestational diabetes and future development of T1DM.
Figure 1.10. The new findings from this review. Figure 1.11. The mixed
findings of this review. Table 5. Cohort studies with same or overlapping
cohorts. Table 6. Data Extraction form.
Additional file 2.
Acknowledgements
MuM-PreDiCT consortium
Authors’ contributions
MS was responsible for the analysis and drafting of the manuscript. FF/JW
were the second reviewers for the study selection, data extraction check,and quality appraisal. FC and KN were the third reviewers and provided their
inputs and guidance at each step of the review. KN, JR, AS, FC, and SW were
responsible for revising the manuscript critically and for important intellectual
content. All authors read and approved the final manuscript.
Authors’ Twitter handles
Twitter handles: @Nirantharakumar (Krishnarajah Nirantharakumar), @StevenWambua (Steven Wambua), @meghasingh_16 (Megha Singh)

Singh et al. BMC Medicine(2024) 22:339

Funding
This work was funded by the Strategic Priority Fund ‘Tackling multimorbidity
at scale’ programme (grant number-MR/W014432/1) delivered by the Medical
Research Council and the National Institute for Health and Care Research inpartnership with the Economic and Social Research Council and in collaboration with the Engineering and Physical Sciences Research Council.
Availability of data and materials
No datasets were generated or analysed during the current study.

Declarations
Ethics approval and consent to participate
Since this review analyses the data from the prior systematic reviews, no ethical approval is required. Consent to participate is not applicable.
Consent for publication
Not applicable.
Competing interests
Co-author AS was part of university of Birmingham when this review was initiated but moved to work with Astrazeneca. She currently holds an honorary
contract with the University of Birmingham. All the other authors declare thatthey have no competing interests.
Received: 17 April 2024 Accepted: 29 July 2024

References
1. Miller FW. The increasing prevalence of autoimmunity and autoimmune
diseases: an urgent call to action for improved understanding, diagnosis,
treatment, and prevention. Curr Opin Immunol. 2023;80:102266.
2. Conrad N, et al. Incidence, prevalence, and co-occurrence of autoimmune disorders over time and by age, sex, and socioeconomic status:
a population-based cohort study of 22 million individuals in the UK.
Lancet. 2023;401(10391):1878–90.
3. Lerner A, Jeremias P, Matthias T. The world incidence and prevalence ofautoimmune diseases is increasing. Int J Celiac Dis. 2015;3(4):151–5.
4. Ngo ST, Steyn FJ, McCombe PA. Gender differences in autoimmune
disease. Front Neuroendocrinol. 2014;35(3):347–69.
5. Thomas SL, et al. Burden of mortality associated with autoimmune
diseases among females in the United Kingdom. Am J Public Health.
2010;100(11):2279–87.
6. Mallampalli MP, et al. Role of environment and sex differences in thedevelopment of autoimmune diseases: a roundtable meeting report.
J Womens Health. 2013;22(7):578–86.
7. Miquel CH, Faz-Lopez B, Guéry JC. Influence of X chromosome in sexbiased autoimmune diseases. J Autoimmun. 2023;137:102992.
8. Souyris M, et al. Female predisposition to TLR7-driven autoimmunity: gene dosage and the escape from X chromosome inactivation.
Semin Immunopathol. 2019;41(2):153–64.
9. Merrheim J, et al. Estrogen, estrogen-like molecules and autoimmune
diseases. Autoimmun Rev. 2020;19(3):102468.
10. Nelson JL, et al. Remission of rheumatoid arthritis during pregnancy
and maternal-fetal class II alloantigen disparity. Am J Reprod Immunol. 1992;28(3–4):226–7.
11. Zakarija M, McKenzie JM. Pregnancy-associated changes in the thyroidstimulating antibody of Graves’ disease and the relationship to neonatal hyperthyroidism*. J Clin Endocrinol Metab. 1983;57(5):1036–40.
12. Boyd AS, et al. Psoriasis and pregnancy: hormone and immune
system interaction. Int J Dermatol. 1996;35(3):169–72.
13. Khamashta MA, Ruiz-Irastorza G, Hughes GR. Systemic lupus
erythematosus flares during pregnancy. Rheum Dis Clin North Am.
1997;23(1):15–30.
14. Schubert C, et al. Postpartum relapse risk in multiple sclerosis: asystematic review and meta-analysis. J Neurol Neurosurg Psychiatry.
2023;94(9):718–25.

Page 17 of 19

15. Castles A, et al. Effects of smoking during pregnancy: five metaanalyses. Am J Prev Med. 1999;16(3):208–15.
16. Cnattingius S, Lambe M. Trends in smoking and overweight during pregnancy: prevalence, risks of pregnancy complications, andadverse pregnancy outcomes. Semin Perinatol. 2002;26(4):286–95.
https://​doi.​org/​10.​1053/​sper.​2002.​34771.
17. DiFranza JR, Lew RA. Effect of maternal cigarette smoking on pregnancy complications and sudden infant death syndrome. Eur J Gen
Pract. 1995;1(3):117–117.
18. Meltzer HM, et al. Effect of dietary factors in pregnancy on risk of pregnancy complications: results from the Norwegian Mother and Child
Cohort Study. Am J Clin Nutr. 2011;94(suppl_6):1970S-1974S.
19. Ovesen P, Rasmussen S, Kesmodel U. Effect of prepregnancy maternal
overweight and obesity on pregnancy outcome. Obstet Gynecol.
2011;118(2 Part 1):305–12.
20. Ramachenderan J, Bradford J, Mclean M. Maternal obesity andpregnancy complications: a review. Aust N Z J Obstet Gynaecol.
2008;48(3):228–35.
21. Jaffar F, Laycock K, Huda MSB. Type 1 diabetes in pregnancy: areview of complications and management. Curr Diabetes Rev.
2022;18(7):e051121197761.
22. Naik VD, et al. Effects of nutrition and gestational alcohol consumption
on fetal growth and development. Nutr Rev. 2022;80(6):1568–79.
23. Upala S, Yong WC, Sanguankeo A. Association between primary
Sjögren’s syndrome and pregnancy complications: a systematic review
and meta-analysis. Clin Rheumatol. 2016;35(8):1949–55.
24. Khizroeva J, et al. Infertility in women with systemic autoimmune
diseases. Best Pract Res Clin Endocrinol Metab. 2019;33(6):101369.
25. Carp HJ, Selmi C, Shoenfeld Y. The autoimmune bases of infertility andpregnancy loss. J Autoimmun. 2012;38(2–3):J266–74.
26. Bobotsis R, et al. Psoriasis and adverse pregnancy outcomes: a systematic review of observational studies. Br J Dermatol. 2016;175(3):464–72.
27. Arvanitakis K, et al. Adverse pregnancy outcomes in women with celiac
disease: a systematic review and meta-analysis. Ann Gastroenterol.
2023;36(1):12–24.
28. Smyth A, et al. A systematic review and meta-analysis of pregnancy
outcomes in patients with systemic lupus erythematosus and lupus
nephritis. Clin J Am Soc Nephrol. 2010;5(11):2060–8.
29. Finkelsztejn A, et al. What can we really tell women with multiple
sclerosis regarding pregnancy? A systematic review and meta-analysisof the literature. BJOG. 2011;118(7):790–7.
30. Wei S, et al. Systemic lupus erythematosus and risk of preterm birth: asystematic review and meta-analysis of observational studies. Lupus.
2017;26(6):563–71.
31. Khashan AS, et al. Pregnancy and the risk of autoimmune disease. PLoS
One. 2011;6(5):e19658.
32. Jørgensen KT, et al. Childbirths and risk of female predominant andother autoimmune diseases in a population-based Danish cohort. J
Autoimmun. 2012;38(2–3):J81–7.
33. Sobanski V, et al. Special considerations in pregnant systemic sclerosis
patients. Expert Rev Clin Immunol. 2016;12(11):1161–73.
34. Auvinen AM, et al. Type 1 and type 2 diabetes after gestational diabetes: a 23 year cohort study. Diabetologia. 2020;63(10):2123–8.
35. Hee JY, et al. Pregnancy loss and the risk of rheumatoid arthritis in Chinese women: findings from the China Kadoorie biobank. BMC Public
Health. 2022;22(1):1768.
36. Jorgensen KT, et al. National cohort study of reproductive risk factors
for rheumatoid arthritis in Denmark: a role for hyperemesis, gestational
hypertension and pre-eclampsia? Ann Rheum Dis. 2010;69(2):358–63.
37. Gleicher N. Reproductive failure prior to the onset of clinical autoimmune disease. Rheumatology. 1999;38(6):485–7.
38. Chakravarty E. Pre-disease pregnancy complications and systemicsclerosis: pathogenic or pre-clinical? Arthritis Res Ther. 2012;14(1):102.
39. Jorgensen KT, et al. Increased risk of rheumatoid arthritis in
women with pregnancy complications and poor self-rated health:a study within the Danish National Birth Cohort. Rheumatology.
2014;53(8):1513–9.
40. Ma KK, et al. Adverse pregnancy outcomes and risk of subsequent
rheumatoid arthritis. Arthritis Rheumatol. 2014;66(3):508–12.
41. Page MJ, et al. The PRISMA 2020 statement: an updated guideline forreporting systematic reviews. Syst Rev. 2021;10(1):89.

Singh et al. BMC Medicine(2024) 22:339

42. Team TE. EndNote, Philadelphia,PA. Clarivate. EndNote 20. 64 bit. 2013.
43. Covidence Systematic Review Software. Veritas Health Innovation,
Melbourne Australia. www.​covid​ence.​org. Accessed July 2024.
44. Aromataris E, Munn Z, editors. JBI manual for evidence synthesis. JBI;
2020. Available from https://​synth​esism​anual.​jbi.​global. https://​doi.​org/​
10.​46658/​JBIMES-​20-​01.
45. Wells G, Shea B, O’Connell D, Peterson J, Welch V, Losos M, et al. The
Newcastle Ottawa Scale (NOS) for assessing the quality of nonrandomized studies in meta analysis. Available from: http://​www.​ohri.​ca/​
progr​ams/​clini​cal_​epide​miolo​gy/​oxford.​asp. Assessed on Nov 2023.
46. Fusar-Poli P, Radua J. Ten simple rules for conducting umbrella reviews.
Evid Based Ment Health. 2018;21(3):95–100.
47. StataCorp. Stata statistical software: release 17. College Station: StataCorp LLC; 2021.
48. RStudio Team. RStudio: integrated development for R. Boston: RStudio,Inc.; 2019. http://​www.​rstud​io.​com/.
49. R Core Team. R: a language and environment for statistical computing.
Vienna: R Foundation for Statistical Computing; 2020. https://​www.R-​
proje​ct.​org/.
50. Bergink V, et al. Prevalence of autoimmune thyroid dysfunction in
postpartum psychosis. Br J Psychiatry. 2011;198(4):264–8.
51. Bergink V, et al. Comorbidity of autoimmune thyroid disorders and psychiatric disorders during the postpartum period: a Danish nationwide
register-based cohort study. Psychol Med. 2018;48(8):1291–8.
52. Hardy C, et al. Pregnancy outcome and family size in systemic
lupus erythematosus: a case-control study. Rheumatology (Oxford).
1999;38(6):559–63.
53. Harpsoe MC, et al. Risk of inflammatory bowel disease according
to self-rated health, pregnancy course, and pregnancy complications: a study within the Danish National Birth Cohort. PLoS One.
2013;8(3):e59698.
54. Jørgensen KT, et al. Hyperemesis, gestational hypertensive disorders, pregnancy losses and risk of autoimmune diseases in a Danish
population-based cohort. J Autoimmun. 2012;38(2):J120–8.
55. Julkunen H, et al. Fetal outcome in lupus pregnancy: a retrospective case-control study of 242 pregnancies in 112 patients. Lupus.
1993;2(2):125–31.
56. Kamper-Jorgensen M, Gammill HS, Nelson JL. Preeclampsia and scleroderma: a prospective nationwide analysis. Acta Obstet Gynecol Scand.
2018;97(5):587–90.
57. Kay A, Bach F. Subfertility before and after the development of rheumatoid arthritis in women. Ann Rheum Dis. 1965;24(2):169–73.
58. Kither H, et al. Adverse pregnancy outcomes and subsequent development of connective tissue disease in the UK: an epidemiological study.
BJOG. 2020;127(8):941–9.
59. Lee KA, et al. Pregnancy-associated risk factors and incidence of systemic sclerosis in primiparous women: a nationwide population-based
cohort study. Mod Rheumatol. 2022;32(1):149–54.
60. Lin CY, et al. Postpartum depression and subsequent autoimmune
diseases in Taiwan. Int J Environ Res Public Health. 2018;15(8):20.
61. Lin LT, et al. Increased risk of systemic lupus erythematosus in
pregnancy-induced hypertension: a nationwide population-based
retrospective cohort study. Medicine. 2016;95(30):e4407.
62. Mao Y, et al. Association between history of gestational diabetes
mellitus and the risk of arthritis in women. Front Public Health.
2022;10:878845.
63. Mikkelsen AP, et al. Pregnancy loss and risk of multiple sclerosis andautoimmune neurological disorder: a nationwide cohort study. PLoS
One. 2022;17(3):e0266203.
64. Nielsen NM, et al. Reproductive history and risk of multiple sclerosis.
Epidemiology. 2011;22(4):546–52.
65. Savitz DA, et al. Pregnancy-induced hypertension and diabetes and therisk of cardiovascular disease, stroke, and diabetes hospitalization in theyear following delivery. Am J Epidemiol. 2014;180(1):41–4.
66. Siamopoulou-Mavridou A, et al. Outcome of pregnancy in patients with
autoimmune rheumatic disease before the disease onset. Ann Rheum
Dis. 1988;47(12):982–7.
67. Spector TD, Silman AJ. Is poor pregnancy outcome a risk factor inrheumatoid arthritis? Ann Rheum Dis. 1990;49(1):12.
68. Stuart AE, Amer-Wahlin I, Kallen KBM. Neonatal delivery weight and risk
of future maternal diabetes. Int J Gynaecol Obstet. 2018;140(1):111–7.

Page 18 of 19

69. Ulff-Møller CJ, et al. Reproductive factors and risk of systemic lupus
erythematosus: nationwide cohort study in Denmark. J Rheumatol.
2009;36(9):1903–9.
70. van Wyk L, et al. Increased incidence of pregnancy complications inwomen who later develop scleroderma: a case control study. Arthritis
Res Ther. 2011;13(6):R183.
71. Wallenius M, et al. Pregnancy and delivery in women with chronic
inflammatory arthritides with a specific focus on first birth. Arthritis
Rheum. 2011;63(6):1534–42.
72. WikstromShemer EA, et al. Intrahepatic cholestasis of pregnancy andcancer, immune-mediated and cardiovascular diseases: a populationbased cohort study. J Hepatol. 2015;63(2):456–61.
73. Brann E, et al. Bidirectional association between autoimmune disease
and perinatal depression: a nationwide study with sibling comparison.
Mol Psychiatry. 2024;09:09.
74. Higgins JPT, Thomas J, Chandler J, Cumpston M, Li T, Page MJ, Welch
VA, editors. Cochrane handbook for systematic reviews of interventions
version 6.4 (updated August 2023). Cochrane; 2023. Available fromwww.​train​ing.​cochr​ane.​org/​handb​ook.
75. Tramèr MR, et al. Impact of covert duplicate publication on meta-analysis: a case study. BMJ. 1997;315(7109):635–40.
76. von Elm E, et al. Different patterns of duplicate publication: an analysisof articles used in systematic reviews. JAMA. 2004;291(8):974–80.
77. Wells GA, Shea B, O’Connell D, Peterson J, Welch V, Losos M, Tugwell P.
The Newcastle-Ottawa Scale (NOS) for assessing the quality of nonrandomised studies in meta-analyses.
78. Bi S, et al. Long-term effects of preeclampsia on metabolic and biochemical outcomes in offspring: what can be expected from a metaanalysis? Obes Rev. 2022;23(5):e13411.
79. Black M, et al. Planned cesarean delivery at term and adverse outcomesin childhood health. JAMA. 2015;314(21):2271–9.
80. Bruce A, Black M, Bhattacharya S. Mode of delivery and risk of inflammatory bowel disease in the offspring: systematic review and meta-analysis of observational studies. Inflamm Bowel Dis. 2014;20(7):1217–26.
81. Cardwell CR, et al. Birthweight and the risk of childhood-onset type1 diabetes: a meta-analysis of observational studies using individual
patient data. Diabetologia. 2010;53(4):641–51.
82. Dalla Costa G, et al. Caesarean section and infant formula feeding areassociated with an earlier age of onset of multiple sclerosis. Mult Scler
Relat Disord. 2019;33:75–7.
83. Nielsen NM, et al. Maternal diabetes and risk of multiple sclerosis in theoffspring: a Danish nationwide register-based cohort study. Mult Scler.
2021;27(11):1686–94.
84. Nakamura N, et al. Mortality and neurological outcomes in extremely
and very preterm infants born to mothers with hypertensive disordersof pregnancy. Sci Rep. 2021;11(1):1729.
85. Jones WR. Autoimmune disease and pregnancy. Aust N Z J Obstet
Gynaecol. 1994;34(3):251–8.
86. Neiger R. Long-term effects of pregnancy complications on maternal
health: a review. J Clin Med. 2017;6(8):76.
87. Panaitescu AM, et al. Pregnancy complications can foreshadow future
disease-long-term outcomes of a complicated pregnancy. Medicina(Kaunas). 2021;57(12):1320.
88. Okoth K, et al. Association between the reproductive health of young
women and cardiovascular disease in later life: umbrella review. BMJ.
2020;371:m3502.
89. Cockrill T, Del Junco DJ, Arnett FC, Assassi S, Tan FK, McNearney T, et al.
Separate influences of birth order and gravidity/parity on the development of systemic sclerosis. Arthritis Care Res. 2010;62(3):418–24. https://​doi.​org/​10.​1002/​acr.​20096.
90. Pisa FE, et al. Reproductive factors and the risk of scleroderma: an Italiancase-control study. Arthritis Rheum. 2002;46(2):451–6.
91. Russo PA, Lester S, Roberts-Thomson PJ. Systemic sclerosis, birth orderand parity. Int J Rheum Dis. 2014;17(5):557–61.
92. Lambe M, et al. Childbearing and the risk of scleroderma: a populationbased study in Sweden. Am J Epidemiol. 2004;159(2):162–6.
93. Beneventi F, et al. Impact of pregnancy on progression of preclinicalautoimmune disorders: a prospective cohort study. Rheumatology.
2022;62(9):2971–8.
94. Antunes M, et al. Undifferentiated connective tissue disease: state of theart on clinical practice guidelines. RMD Open. 2018;4(Suppl 1):e000786.

Singh et al. BMC Medicine(2024) 22:339

95. Spinillo A, et al. The effect of newly diagnosed undifferentiated connective tissue disease on pregnancy outcome. Am J Obstet Gynecol.
2008;199(6):632.e1-6.
96. Assad S, et al. Role of sex hormone levels and psychological stressin the pathogenesis of autoimmune diseases. Cureus. 2017;9:e1315.
https://​doi.​org/​10.​7759/​cureus.​1315.
97. Serena C, et al. Undifferentiated connective tissue disease in pregnancy:
a topic yet to be explored. Front Pharmacol. 2022;13:820760.
98. Robinson DP, Klein SL. Pregnancy and pregnancy-associated hormones
alter immune responses and disease pathogenesis. Horm Behav.
2012;62(3):263–71.
99. Ding J, Zhu BT. Unique effect of the pregnancy hormone estriol on
antigen-induced production of specific antibodies in female BALB/cmice. Steroids. 2008;73(3):289–98.
100. Ubeda F, Wild G. Microchimerism as a source of information on future
pregnancies. Proc R Soc Lond B Biol Sci. 2023;290(2005):20231142.
101. Nelson JL. The otherness of self: microchimerism in health and disease.
Trends Immunol. 2012;33(8):421–7.
102. Bianchi DW, et al. Male fetal progenitor cells persist in maternal
blood for as long as 27 years postpartum. Proc Natl Acad Sci U S A.
1996;93(2):705–8.
103. Adams Waldorf KM, Nelson JL. Autoimmune disease during pregnancy and the microchimerism legacy of pregnancy. Immunol Invest.
2008;37(5–6):631–44.
104. Al-Mufti R, et al. Fetal cells in maternal blood of pregnancies with severe
fetal growth restriction. Hum Reprod. 2000;15(1):218–21.
105. Leung TN, et al. Maternal plasma fetal DNA as a marker for pretermlabour. Lancet. 1998;352(9144):1904–5.
106. Fugazzola L, Cirello V, Beck-Peccoz P. Microchimerism and endocrine
disorders. J Clin Endocrinol Metab. 2012;97(5):1452–61.
107. Luiro K, et al. Autoantibodies predict type 1 diabetes after gestational
diabetes - a 23-year cohort study. Front Endocrinol. 2023;14:1286375.

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