Association between adverse pregnancy outcomes and psoriasis: Findings from a Danish case-control study

Psoriasis affects between 2% and 4% of the world’s population, and nearly half of all cases occur in women, mostly of childbearing age.¹ Chronic systemic inflammation associated with psoriasis may increase the risk of adverse pregnancy outcomes (APOs) by affecting the fertility of women and leading to spontaneous abortion, ectopic pregnancy (EP), intrauterine fetal death, and stillbirth.

Psoriasis shares pathophysiological pathways with other inflammatory diseases, including inflammatory bowel disease, inflammatory arthritis, and psoriatic arthritis (PsA), which have been associated with APOs. In addition, women with psoriasis have a higher prevalence of other risk factors associated with APOs, including obesity, smoking, gestational hypertension, use of nonsteroidal anti‑inflammatory drugs, low socioeconomic status, diabetes, preconception hypertension, thyroid diseases, and low fertility rates.

Here, we summarize the key findings from a nationwide Danish case-control study investigating the association between psoriasis and APOs, which was published by Johansen, et al.¹ in the Journal of the American Academy of Dermatology International.

Study design

The design of the Danish case-control study is shown in Figure 1.

APO, adverse pregnancy outcome; EP, ectopic pregnancy; ICD-10, International Classification of Diseases 10th Revision; IUFD, intrauterine fetal death; PsA, psoriatic arthritis.
*Adapted from Johansen, et al.¹

Results

A total of 491,274 women were included in the study, of which 6,426 had psoriasis, and the mean age at index date was 30.3 years. There was a higher prevalence of all comorbidities, including pregnancy-related comorbidities, in women with psoriasis (Table 1).

In women with moderate-to-severe psoriasis, there were fewer “1–2 previous live births” reported compared with in those without psoriasis (11.94% vs 22.45%, respectively). The prevalence of 1–2 previous assisted reproductive technology-based treatments was highest in women with moderate-to-severe psoriasis compared with in those with mild psoriasis or those without psoriasis (8.46% vs 5.88% vs 4.40%, respectively).  

Table 1. Baseline characteristics (N = 491,274)*

BMI, body mass index; NA, not applicable; NSAIDs, non-steroidal anti-inflammatory drugs; SD, standard deviation. *Adapted from Johansen, et al.1 †Microdata on 1 or 2 individuals was reported as <3 owing to data security. ‡Due to referable microdata.
Characteristic, % (unless stated otherwise)	Without psoriasis (n = 484,848)	With psoriasis (n = 6,426)	Mild psoriasis (n = 6,225)	Moderate-to-severe psoriasis (n = 201)
Mean age at index (SD), years	30.10 (5.14)	30.40 (5.11)	30.67 (5.10)	30.02 (5.25)
Mean age at the first registered psoriasis diagnosis (SD), years	NA	23.64 (6.58)	23.74 (6.57)	20.64 (6.15)
Mean duration of psoriasis at index (SD), years	NA	7.01 (4.80)	6.93 (4.77)	9.38 (4.91)
Pregnancy-related comorbidities
Gestational diabetes	2.59	3.63	3.63	3.48
Pre-eclampsia	4.23	5.06	5.09	3.98
Gestational hypertension	2.21	2.65	2.65	2.49
Smoking status
Non-smoker	79.46	75.82	75.87	74.13
Stopped in first trimester	2.63	3.47	3.44	4.48
Stopped after first trimester	0.53	0.72	0.74	0.00
Active throughout pregnancy	10.23	13.17	13.14	13.93
Smoking status unknown	7.14	6.83	6.81	7.46
Mean BMI
<18.5 kg/m2 (underweight)	5.10	3.95	4.02	1.99
18.5–24.9 kg/m2	60.75	57.63	57.85	50.75
25.0–29.9 kg/m2 (overweight)	18.29	19.97	19.94	20.90
≥30.0 kg/m2 (obese)	4.93	4.95	4.88	6.97
Administered systemic psoriasis treatment during pregnancy
Biologics†	0.01	0.05	—	—
Cyclosporin†	0.00	—	—	0.00
Redeemed co-medication during pregnancy, n
NSAIDs	2,151	31	31	0
Methotrexate†	6	<3	0	<3
Acitretin	4	3	<3	<3
Antidepressants†	1,314	22	Not shown‡	<3
Mean age at the first live birth (SD), years	28.90 (4.85)	29.36 (4.95)	29.37 (4.94)	29.01 (5.21)

The risk of EP was higher in all women with psoriasis when compared with women without psoriasis (1.50% vs 1.87%, respectively), and this risk remained after adjusting for age, body mass index, and smoking, as shown in Table 2. The post hoc analysis showed that the risk of EP was not affected when adjusting for pelvic inflammatory disease and endometriosis.

The risk of EP was higher in women with mild psoriasis when compared with women without psoriasis (odds ratio [OR], 1.21). EP risk was even higher in women with moderate-to-severe psoriasis (3.98%) when compared with women without psoriasis (1.50%; OR, 2.77), which equated to a 2.48% higher absolute risk of EP.

Table 2. Crude and adjusted models for APOs*

CI, confidence interval; EP, ectopic pregnancy; IUFD, intrauterine fetal death; NA, not applicable; OR, odds ratio. *Adapted from Johansen, et al.1 †No adjustment. Microdata on 1 or 2 individuals was reported as <3 owing to data security. ‡Adjusted for age. §Adjusted for age, BMI, and smoking. ‖Adjusted for age, BMI, smoking, income, educational level, assisted reproductive technologies, cardiometabolic diseases (preconceptional hypertension, hypercholesterolemia, diabetes, and polycystic ovary syndrome), chronic immune-mediated diseases (rheumatoid arthritis, ankylosing spondylitis, Crohn’s disease, and ulcerative colitis), thyroid diseases, combined depression and anxiety, pregnancy-related comorbidities (gestational diabetes, preeclampsia, and gestational hypertension), and exposure to nonsteroidal anti-inflammatory drugs. Adjustment for acitretin, biologics, cyclosporin, methotrexate, and antidepressants failed in the analysis due to small numbers; hence, these were removed from model 3. Post hoc analysis (adjustment for pelvic inflammatory diseases and endometriosis) was performed on EP only.
Characteristic	Crude† OR (95% CI)	Model 1‡ OR (95% CI)	Model 2§ OR (95% CI)	Model 3‖ OR (95% CI)
Women without psoriasis vs women with psoriasis
Spontaneous abortion (6.66% vs 6.92%)	1.05 (0.95–1.15)	1.03 (0.93–1.13)	1.02 (0.90–1.16)	1.04 (0.92–1.17)
EP (1.50% vs 1.87%)	1.25 (1.06–1.50)	1.24 (1.03-1.49)	1.35 (1.07–1.70)	1.34 (1.06–1.68)
IUFD (0.25% vs 0.19%)	0.75 (0.42–1.32)	0.74 (0.42–1.31)	0.74 (0.40–1.38)	0.74 (0.40–1.39)
Stillbirth (0.14% vs 0.16%)	1.14 (0.61–2.13)	1.14 (0.61–2.12)	0.77 (0.34–1.72)	0.76 (0.34–1.70)
Live birth (91.45% vs 90.87%)	—	—	—	—
Women without psoriasis vs women with mild psoriasis
Spontaneous abortion (6.66% vs 6.89%)	1.04 (0.94–1.15)	1.02 (0.93–1.13)	1.03 (0.92–1.17)	1.05 (0.93–1.18)
EP (1.50% vs 1.80%)	1.21 (1.00–1.46)	1.19 (0.99–1.44)	1.30 (1.03–1.65)	1.29 (1.02–1.64)
IUFD (0.25% vs NA)	0.71 (0.39–1.28)	0.70 (0.39–1.27)	0.69 (0.36–1.32)	0.69 (0.36–1.33)
Stillbirth (0.14% vs NA)	1.16 (0.63–2.20)	1.17 (0.63–2.19)	0.79 (0.36–1.78)	0.78 (0.35–1.76)
Live birth (91.45% vs 90.97%)	—	—	—	—
Women without psoriasis vs women with moderate-to-severe psoriasis
Spontaneous abortion (6.66% vs 7.96%)	1.25 (0.75–2.08)	1.25 (0.75–2.09)	0.78 (0.37–1.66)	0.79 (0.37–1.68)
EP (1.50% vs 3.98%)	2.77 (1.37–5.64)	2.77 (1.36–5.63)	2.79 (1.15–6.79)	2.70 (1.11–6.60)
IUFD (0.25% vs NA)	2.07 (0.29–14.80)	2.07 (0.30–14.79)	2.29 (0.32–16.38)	2.29 (0.32–16.39)
Stillbirth (0.14% vs 0.00%)	—	—	—	—
Live birth (91.45% vs 87.56%)	—	—	—	—

PsA subanalysis

A total of 291 (0.06%) women had PsA, of which 171 (58.76%) had an overlapping psoriasis diagnosis. Amongst these women, 127 had mild and 44 had moderate-to-severe psoriasis. The risk of EP was 2-fold in women with PsA compared with women without (regardless of psoriasis diagnosis; crude OR, 2.12) and increased further when adjusting for other risk factors (model 2: OR 2.48; model 3: OR, 2.41).

Conclusion

This study showed that psoriasis was associated with an increased risk of EP. Women with moderate-to-severe psoriasis and PsA had the highest risk of EP. Psoriasis was not associated with an increased risk of spontaneous abortion, intrauterine fetal death, or stillbirth. Johansen, et al. speculate that this association may be due to women with severe psoriatic disease being more susceptible to tubal implantation due to a predominance of T helper type 17 cells (drivers of systemic inflammation), a reduced activity of regulatory T cells, and a microenvironment in the fallopian tubes that is permissive of embryo implantation. The shared immunopathologic pathway with inflammatory bowel disease, which is also associated with an increased risk of EP, strengthens the hypothesis that psoriasis is associated with an increased risk of EP.

Although the study included data from nationwide registries of high quality, validity, and completeness, it was limited by recall, interview, and questionnaire biases. Additionally, information on clinical measurements, including body surface area, psoriasis area severity index, and lifestyle factors (such as alcohol and exercise), were not available. Therefore, further clinical studies exploring the association between antipsoriatic treatment and the inflammatory state and severity of the disease are warranted. In addition, studies of the causality between psoriasis and EP, the pathophysiologic mechanism of psoriasis inflammation, and APOs are needed to confirm the finding of this study. With EP being a leading cause of maternal morbidity and mortality in the first trimester of pregnancy, the authors call for particular care for women of reproductive age with psoriasis.