Psoriasis is a chronic, complex, multifactorial inflammatory disease that affects both sexes equally. The mean age of onset in women is around 28 years, and 75% of female patients develop psoriasis before they are 40 years old, meaning that the majority of women are in their childbearing years at the time of diagnosis.1 The fact that psoriasis is associated with comorbid conditions, such as diabetes, metabolic syndrome, and cardiovascular disease, and that several studies have linked psoriasis in pregnancy to certain modifiable risk factors, such as overweight, smoking, depression, and maintenance of systemic inflammation, gestational, perinatal, and neonatal complications are a possibility in pregnant women with psoriasis.2 Understanding the above factors is crucial for the adequate management of psoriasis in pregnancy and for ensuring satisfactory outcomes during pregnancy, delivery, and the postpartum period.

The literature contains scant information on the prognosis of pregnancy in women with psoriasis, or on associated risk factors and comorbidities or therapeutic management. Most of the information available is based on case reports and series and data from pregnancy registries,3 whose purpose is to collect information on pregnancy and related complications and help identify possible teratogenic effects and evaluate the safety of exposure to particular drugs during pregnancy.

The aim of this review is to provide up-to-date information and to review the literature on the interrelationship between psoriasis and pregnancy and on current treatment recommendations for this special situation. Due to space constraints, biologic agents will be dealt with in a second part of this review.

We performed a systematic literature search to identify relevant studies. Our search yielded 362 publications using the terms “psoriasis and pregnancy” and 243 publications using the terms “psoriasis treatment and pregnancy”. We then searched for each treatment used in psoriasis in combination with the terms “pregnancy” and “lactation”. All of the references were scanned individually.

The maternal immune system undergoes physiological changes during pregnancy to achieve immune tolerance towards paternal antigens expressed by fetal cells and thereby prevent rejection of the fetus. These changes, which occur both at the maternal-fetal interface and in the systemic circulation, are influenced by the effect of estrogens, progesterone, and cortisol, whose blood levels gradually increase over the course of pregnancy, giving rise to a change in helper T (TH) cell polarization that potentiates the humoral TH2 response and inhibits the cell-mediated TH1 response.4 Cytokines play a key role in the regulation of physiological and pathological processes such as pregnancy and psoriasis. During pregnancy, multiple cytokines are produced by different types of maternal and fetal cells in the uterus and the fetoplacental unit; the cells involved are not only immune system cells, but also other types of cells such as maternal decidual cells and fetal trophoblasts. The close relationship between the embryo and the endometrium and the placenta and the decidua is mediated by steroid hormones5 and diverse cytokines and chemokines, thereby ensuring sufficient cross-talk to ensure successful maintenance of pregnancy.6 During the formation of placenta, there is a clear tendency towards the formation of TH2 cytokines. Levels of these cytokines appear to progressively decrease during the second and third trimesters of pregnancy as the placenta completes its formation. In the third trimester, and particularly in the last weeks of pregnancy, the balance of cytokines is once again reversed towards a predominance of TH1 cells, which stimulate labor and protect both the mother and fetus against infection during and after birth.1,2

Numerous molecules are involved in implantation, and defective molecules rarely have a significant effect due to the complementary and compensatory action of other cytokines.7 Cytokine balance at the time of implantation is practically neutral. To date 2 molecules have been identified as playing a crucial role in implantation: interleukin (IL) 1, which is primarily produced by activated macrophages, and leukemia inhibitory factor, which is crucial for implantation and inhibits the differentiation of embryonic stem cells; it is produced by TH2 lymphocytes and the endometrial endothelium.6

An adequate cytokine environment is crucial during the early stages of embryo implantation and subsequent invasion of maternal uterine vessels by trophoblast cells, and it would appear that TH2 lymphocytes promote trophoblast anchorage, thereby favoring maintenance of pregnancy.8 TH2 cells produce cytokines such as IL-4, IL-5, and IL-13, which, through the activation of B cells and the production of antibodies, are responsible for the pathogenesis of several diseases such as lupus erythematosus.9 TH1 cells, on the other hand, produce proinflammatory IL-2 cytokines, interferon (IFN) γ, tumor necrosis factor (TNF), and IL-12, which are involved in cell-mediated tissue damage in certain autoimmune diseases, such as rheumatoid arthritis, Crohn disease, and psoriasis, among others.10 IFN-γ is the main mediator of the TH1 response, as it has a considerable inhibitory effect on TH2 response. These molecules are directly embryotoxic and complicate fetoplacental development through multiple mechanisms. Il-10 is an anti-inflammatory cytokine produced by TH1 and TH2 lymphocytes, and it downregulates proinflammatory cytokine production by TH1 lymphocytes and macrophages, favoring a TH2 response.11

In placenta, prostaglandin D2 and its metabolite, the cyclopentenone 15-deoxy-Delta(12,14)-prostaglandin J2 (15dPGJ2), acting through prostanoid D (DP1) receptors and the chemotactic TH2 receptor, CRTH2 or DP2, promote local accumulation of TH2 cells at the maternal-fetal interface12 and exert an anti-inflammatory effect through the inhibition of nuclear factor κB and the nuclear peroxisome proliferator-activated receptor (PPAR) by 15DPGJ2.13

The immune changes that take place during pregnancy, which favor TH2 activity, could explain why certain autoimmune diseases that involve TH1 cytokines, such as psoriasis and rheumatoid arthritis, tend to improve during pregnancy, while those involving TH2 cytokines, such as lupus erythematosus, tend to worsen.14

Likewise, multiple cytokine network dysregulation can lead to complications during pregnancy such as spontaneous abortion, premature birth, preeclampsia, and intrauterine growth restriction. Increased secretion of IFN-γ and IL-10, for example, has been associated with an increased risk of premature birth, while increased production of IL-6 and IL-1 at the implantation site has been linked to recurrent miscarriage.15

TNF has a dual, almost paradoxical, role in embryo development, as it is a potent activator of both apoptotic and antiapoptotic signaling cascades. It now seems clear that this cytokine not only promotes embryo destruction in the event of severe structural abnormalities, but also stimulates protective mechanisms that prevent against abnormalities that could compromise normal fetal development. In fact, several TNF single nucleotide polymorphisms (SNPs) have been associated with heart defects (tetralogy of Fallot or ventricular septum defect) and lower limb abnormalities.16 SNPs represent the minimum level of genetic differentiation between individuals, and in this post-genomic era, they are being increasingly used to identify genetic markers in complex diseases. As the regulatory regions of many genes are poorly characterized, attempts have been made to characterize coding area variations. TNF, however, provides a unique opportunity to study the distribution of SNPs in a genetic area where the regions involved in transcriptional regulation are well characterized.17

Hormonal changes during pregnancy play an important role in improving psoriasis, as they induce a state of immunological tolerance. Estrogens have both immunosuppressive and immunostimulatory functions. Maternal estrogens stimulate the production of IL-2, IL-10, and IFN-γ and inhibit the production of TNF in peripheral mononuclear cells. Three forms of estrogen are known: estradiol and estrone, which are derived from androgen and fetal precursors, and estriol, which is derived from fetal precursors. Estradiol and estrone predominate in early pregnancy, while estriol predominates in late pregnancy.18 Progesterone is primarily immunosuppressive, as it decreases proliferative T cell–responses and is a key factor in uterine immunosuppression. Because progesterone concentrations increase to a much greater extent than estrogens in pregnancy, it has been postulated that this change in the estrogen-progesterone ratio might be responsible for changes to the immune system during pregnancy. The shift towards the TH2 response in pregnancy occurs both in systemic circulation and at the fetal-maternal interface; progesterone inhibits the production of TH2 cytokines and induces TH2 activity, thereby contributing to adequate development of pregnancy.19 Prolactin and human placental lactogen also appear to have immunosuppressive functions, although their immunomodulatory role seems to be less well-established.5

In addition to contributing to TH2 polarization, hormonal changes during pregnancy appear to directly affect keratinocytes. It was recently demonstrated that these cells possess estrogen and progesterone receptors, which are specifically located in the cytoplasm of suprabasal keratinocytes.20 Progesterone receptor immunoreactivity is not related to hormones but rather to inflammation in the epidermis and dermis.20 Considering that progesterone acts as an immunosuppressant, it could be postulated that its receptor might be induced by unknown cytokines that would cause progesterone to increase or decrease the inflammatory process. This is an interesting field of research.

Although pregnancy has an unpredictable effect on psoriasis, it is generally accepted that between 30% and 40% of women with psoriasis experience clinical improvements during pregnancy and a worsening of disease between week 4 and 6 postpartum; between 40% and 90% of women can experience a significant disease flare in the immediate postpartum period.21 One retrospective study of 91 pregnant women with psoriasis reported improvements in 56% of patients, worsening in 26%, and no changes in 17.6%.22

In another study, improvements were noted in 55% of pregnant women with psoriasis, worsening in 23%, and no noticeable changes in 21%.5 In the postpartum period, 9% of the patients experienced improvement, 65% experienced worsening, and 26% experienced no clinical changes in disease activity.

In most cases, the improvements observed in psoriasis during pregnancy occurred in the first 2 trimesters, both in the pregnancies studied and subsequent pregnancies.5

Boyd et al.14 postulated that improvements in psoriasis during pregnancy might be associated with hormone-mediated suppression of the immune system, with a key role played by progesterone, not only at the immunological level, but also through a direct effect on keratinocytic proliferation. This hypothesis contrasts with the results of the study by Murase et al.,5 in which improvements in psoriasis during pregnancy were linked to high levels of estrogen, with no correlation observed with progesterone levels.

The systemic inflammation that occurs in different immune-mediated diseases, such as rheumatoid arthritis, lupus erythematosus, inflammatory bowel disease, and moderate to severe psoriasis, may lead to poor prognosis and disease progression, with a particular risk of preterm birth and low birth weight.23 Increased levels of diverse proinflammatory cytokines (IL-6 and TNF) and inflammation biomarkers (C-reactive protein) in both maternal serum and cord blood during the pregnancy of women with psoriasis have been shown to result in preterm birth or small-for-gestational-age neonates.23 The coexistence of inflammation biomarkers (high-sensitivity C-reactive protein) and placental dysfunction (low levels of placental growth factor), which have been associated with trophoblast implantation defects, preeclampsia, and intrauterine growth restriction, have been linked to a 6- to 7-fold increase in the risk of premature birth.24 Cytokine imbalance can lead to endothelial dysfunction, resulting in systemic and placental vascular disease through the induction of platelet aggregation, intermittent vasospasm, and activation of the coagulation system.25 It has been postulated that placental vascular disease contributes to low birth weight, which is also a complication of preeclampsia, which, in turn, is associated with inflammatory activity and a subsequent increase in the same cytokines as in psoriasis.25

Several studies have attempted to link psoriasis and psoriasis severity to the development of gestational, fetal and/or perinatal complications. One case-control study of 145 pregnant women with psoriasis found a statistically significant association with several complications, such as hypertension, recurrent miscarriage, and cesarean delivery.26 Cohen-Barak et al.27 conducted a retrospective study in which they compared 68 pregnancies in 35 women with moderate to severe psoriasis with 237 pregnancies in 236 healthy controls to investigate the association between disease severity and gestational and/or fetal complications. They found that compared with the controls, women in the psoriasis group had significantly higher mean (SD) rates of spontaneous abortions (0.42 [0.58] vs 0.26 [0.63], P=.002), induced abortions (0.32 [0.60] vs 0.06 [0.25], P=.001), and large-for-gestational age neonates (3375 [543] vs 3247 [460] g, P=.03). They also found that pregnant women with psoriasis had a higher rate of pregnancy-induced hypertensive diseases (7.4% vs 2.1%, P<.05), premature membrane rupture (16% vs 5.5%, P<.008), and fetal macrosomia (13% vs 4.2%, P=.02). No significant associations were observed between gestational, fetal, or perinatal complications and either disease duration or use of systemic therapy during pregnancy.

Yang et al.28 conducted an extensive study of the Taiwanese population to investigate the correlation between psoriasis severity and the risk of gestational and/or fetal complications. They compared 1483 pregnant women with psoriasis (classified as mild or severe) with 11 704 pregnant women without psoriasis. Of the women with psoriasis, 645 (44.1%) had been treated with phototherapy or systemic therapy in the 2 years prior to delivery and were included in the severe disease subgroup. The authors found that these women had a greater odds (odds ratio, 1.40; 95% CI, 1.04-1.89) of giving birth to low-birth weight infants than those without psoriasis. Although the data were adjusted for comorbidities such as diabetes mellitus and cardiovascular disease, the impact of systemic therapy during pregnancy could not be excluded. Nonetheless, the authors observed an increased risk of complications, such as preterm birth, low birth weight, cesarean delivery, and preeclampsia in pregnant women who received systemic treatment, and therefore concluded that the intrinsic risk could be only attributable to the systemic inflammation caused by psoriasis. Mild psoriasis was not found to be significantly associated with an increased risk of complications (Table 1).

Bandoli et al.2 investigated whether pregnant women with psoriasis had an excess of potentially modifiable risk factors for adverse pregnancy outcomes. They analyzed data from the Organization of Teratology Information Specialists (OTIS) Autoimmune Diseases in Pregnancy Project and compared the prevalence of certain risk factors between 170 pregnant women with psoriasis and 158 controls. Of the women with psoriasis, 128 had received biologic therapy at some moment during pregnancy. The authors found that patients with psoriasis, especially those with moderate to severe disease, were more likely to be overweight or obese prior to pregnancy (P<.0001), to smoke during the first trimester (P<.0001), and to be diagnosed with depression (P<.03). They also observed that the women with psoriasis were less inclined to be taking vitamin or folic acid supplements at the time of conception (P=.004).

The association between different psoriasis-related comorbidities and pregnancy- and delivery-related complications are summarized below25:

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  Hypertension during pregnancy has been associated with low birth weight secondary to placental insufficiency, increased perinatal mortality, and preterm birth.

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  Diabetes mellitus has been associated with fetal macrosomia, postnatal hypoglycemia, and congenital malformations, such as transposition of the great vessels.

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  Obesity has been associated with macrosomia, certain congenital abnormalities, hypoglycemia, and low Apgar scores.

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  Smoking has been associated with low birth weight, placental complications, and cleft palate.

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  Alcohol consumption during pregnancy may result in fetal alcohol syndrome and low birth weight.

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  Depression may be linked to a higher risk of preterm birth, low birth weight, and spontaneous abortions.

In a retrospective study, Lima et al.23 compared 162 pregnancies in 122 women with psoriasis with 501 pregnancies in 290 healthy women to investigate the association with the development of complications such as preterm birth (<37 weeks) and low birth weight (<2500g). They performed univariate and multivariate analyses, and adjusted for demographic factors (race, educational level, social background, number of previous pregnancies, etc.), associated comorbidities, and disease severity. The women with psoriasis had an increased risk of preterm birth and low birth weight in the univariate analysis (OR, 1.89; 95% CI, 1.06-3.39), and the association remained statistically significant in the multivariate analysis. No association was found between psoriasis and rate of spontaneous abortion, cesarean delivery, or preeclampsia.

As more information becomes available, we will gain a better understanding of the reciprocal relationship between pregnancy and psoriasis and the prevalence of potentially modifiable risk factors. This increased knowledge will help to optimize pregestational care in women with psoriasis and reduce the risk of gestational complications and fetal damage.

In the next section, we will review the scientific evidence available on the use of different treatments for psoriasis during pregnancy.

There is scant scientific evidence on the exact effect of certain drugs on embryonic and fetal development in pregnant women with psoriasis as clinical trials cannot be performed in this population for ethical reasons. Some of the current guidelines are based on retrospective studies and data from women who were taking a particular drug before knowing that they were pregnant.

When treating a pregnant woman with psoriasis, it is important to evaluate the severity and extent of disease, the potential risk to the fetus, the expected benefits of treatment, and the availability of safe and effective alternatives.

The authors declare that they have no conflicts of interest.