In addition to the emergence of the pregnancy-specific hormone human chorionic gonadotrophin (hCG), several other hormones are upregulated during pregnancy such as progesterone (P4), estrogens, cortisol, prolactin, leptin, vitamin D, and alpha-fetoprotein (AFP).

HCG is a placental glycoprotein hormone, that appears first during pregnancy and serves as pregnancy confirmation, peaks during the 9th−12th week of pregnancy, followed by a gradual decline until delivery, even though hCG levels during pregnancy remain high. Its major function is to maintain P4 synthesis by the corpus luteum (13). HCG promotes maternal immune tolerance and helps to ensure fetal survival (14). The hormone is able to convert naïve T cells into regulatory T cells (Treg) (15); can modulate dendritic cells (DCs) into tolerogenic antigen-presenting cells (APCs) (16, 17) and stimulate IL-10 production by B cells (18). HCG application was shown to in vivo boost the number of Treg cells and prevent abortion in mice (14) and is also injected intrauterine in IVF protocols for women with a history or implantation failure (19).

Progesterone (P4), is a member of the steroid hormone family and plays a crucial role in maintaining pregnancy, in addition to HCG (14). During the initial stages, it is secreted by the corpus luteum and, later on, by the placenta. P4 modulates the immune system via intracellular P4 receptors (PR) expressed by epithelial cells, eosinophils, macrophages, lymphocytes MCs, and DCs (20), and by the upregulation of progesterone-induced blocking factor (PIBF) and glycodelin A (a cell-surface glycoprotein expressed in endometrium/decidua, amniotic fluid, and maternal serum, with immunosuppressive properties) (14). P4 contributes to gestational tolerance by suppressing innate immunity via different mechanisms such as blocking the cytolytic action of NK cells, inducing tolerogenic DCs, and promoting Th2 polarization by preferential apoptosis of Th1 subset and increasing Th2 cytokine production (20, 21). Furthermore, P4 stimulates Treg cells by inducing Fork Head Box Protein 3 (FoxP3) expression in naïve T-cells at the feto-maternal interface, in murine pregnancies (21). P4 plays a crucial role in maintaining gestational tolerance by suppressing innate immunity and promoting Th2 polarization (20). The maternal P4 level continues to rise until about 10–12 weeks of gestation (corpus luteum), then returns to its baseline level and again starts to rise around the 32nd week of pregnancy (2nd peak-secreted by the placenta) to be maintained until conception (22). P4 levels drop during lactation (23). Occasionally, CSU-like cutaneous eruption has been reported due to excess serum P4, called progesterone hypersensitivity. The reasons for increased serum P4 include pregnancy or exposure to exogenous progesterone or increased level during the menstrual cycle (luteal phase; 3–10 days before the onset of menstruation) (24).

Estrogens, also belonging to the steroid hormone family, are of three major types, estrone (E1), estradiol (E2), and estriol (E3). Among them, E2 constitutes the major fraction in reproductive females (both pregnant and non-pregnant) and accounts for most of the classic estrogenic-induced effects. In contrast, E3 is exclusively secreted in pregnant females, by the fetoplacental unit, and comprises almost 90% of the pregnancy estrogen (20). During pregnancy, estrogen levels rise steadily until delivery due to placental secretion. Estrogens act via estrogen receptors (ERs) expressed by B and T lymphocytes, macrophages, and DCs and affect both innate and acquired immunity (14). It is generally accepted that estrogens play a role in the development of adaptive immunity such that low levels of estrogen promote pathogenic Th1/Th17 pathway while high levels (as during pregnancy) promote Th2/Treg responses. E3 downregulates innate immunity by programming DCs to become tolerogenic and anti-inflammatory (23). Many researchers have depicted the harmful role of exogenous estrogen mimickers, called endocrine-disrupting chemicals (EDCs), which act by disrupting the endocrine milieu. These substances are present in several daily use products such as plastic water bottles or food containers, which may be systemically absorbed by ingestion. Recently, the negative impact of EDCs, particularly Bisphenol A and phthalates, is being recognized on human pregnancy and fetal development by interfering with the developing embryonic epigenome (24). Rarely, premenstrual urticarial eruption has been reported in women with estrogen hypersensitivity. In such cases, removal of the exogenous estrogen results in remission e.g., discontinuation of estrogen-containing oral contraceptives or use of estrogen antagonists (leuprolide or tamoxifen) (25).

Cortisol, synthesized in the adrenal cortex and released into circulation after various physical and psychological stimuli; has strong anti-inflammatory effects. During pregnancy, maternal cortisol levels rise continuously to facilitate fetal development, followed by an abrupt drop post-partum (26). Cortisol exerts its anti-inflammatory effect by multiple pathways such as reducing the circulating levels of pro-inflammatory cytokines such as IL-2, IL-3, IL-6, IFN-γ, and TNF-α, activating tolerogenic Treg cells by enhancing the expression of high-affinity IL-2 receptor (CD25), inducing the apoptosis of T cells, and reducing the number of B cells in spleen and lymph nodes, thereby reducing IgG production (23). These effects may explain, in part, the improvement of some immunological disorders during pregnancy.

Prolactin, a polypeptide hormone, is largely produced by the lactotrophic cells of the pituitary gland and several extra-pituitary sources like mammary epithelium, ovaries, and placenta, under the influence of dopamine. Prolactin levels increase slightly during gestation with exponential rise during delivery and lactation, contrasting the abrupt reduction of sex hormones (E2, E3, and P4) post-delivery (27). Prolactin stimulates the immune system and causes aberrant activation by aiding the maturation of naïve Th0 cells to effector CD4 and CD8 cells, impairing the clonal deletion of auto-reactive B cells, and reducing the threshold for activating anergic B cells. Thus, hyperprolactinemia has been associated with several autoimmune disorders and might explain disease flare or relapse during breastfeeding (28). The effects of prolactin on CU during pregnancy remain largely unexplored, but Sabry et al. (29) reported significantly higher serum prolactin levels in a subset of CU patients (positive autologous serum skin test, ASST) and its association with disease severity. In contrast, Soliman et al. (30) did not find any relationship between serum prolactin levels and urticaria activity.

Leptin, secreted by adipocytes, primarily regulates energy metabolism, but its impact on the immune system is increasingly being recognized. Leptin promotes inflammatory responses by activating the JAK-STAT, PI3K, and MAPK pathways as its receptor mimics the IL-6 receptor (31). A recent review has highlighted the cross-talk between mast cells and adipocytes in certain situations like obesity, where adipose tissue-resident MCs release pro-inflammatory cytokines like TNF-α, under the influence of leptin, and worsen the inflammatory state (32). During pregnancy, leptin levels rise to counter the hypermetabolic state and modulate the feto-maternal immune system. The recent findings that the placenta is a relevant source of leptin and its trophoblastic effects further strengthen this view (33). Several authors have reported higher serum levels of leptin in patients with CU (34, 35), but, as of yet, pregnant CU patients have not been studied.

Vitamin D, a steroid hormone, plays an important role in modulating the immune system during pregnancy. The placenta is one of the major sites of extra-renal vitamin D synthesis and produces considerable amounts during pregnancy. Vitamin D promotes antibacterial innate immune responses and suppresses inflammatory adaptive immunity via negative effects on NK cells, T, and B cells (36). The effect on T-cells include a shift from Th1 to Th2 phenotype, in vitro suppression of Th17 axis and IL-17 secretion, and inducing the conversion of naïve T-cells into tolerogenic Treg cells, while antibody production by B-cells is suppressed by inhibiting the differentiation of plasma cells and memory cells (23). Furthermore, placental vitamin D contributes to the development of localized fetal-maternal immune tolerance (37). Vitamin D deficiency may negatively affect several immune-mediated disorders, such as psoriasis, type 1 diabetes, multiple sclerosis, rheumatoid arthritis, tuberculosis, sepsis, and systemic lupus erythematosus (23, 38). A recent systematic review concluded that adult patients with CU are at a higher risk of developing Vitamin D deficiency, and its supplementation may provide therapeutic benefit in this subset (39).

Alpha-fetoprotein (AFP) is another pregnancy-specific glycoprotein hormone secreted by the yolk sac and fetal liver. This hormone peaks between weeks 12 and 16 of pregnancy, and gradually declines thereafter. AFP may have immune regulatory effects, but conclusive evidence is lacking (40).

The human immune system is designed to recognize and eradicate possibly harmful foreign, i.e., non-self antigens. During pregnancy, paternal antigens that are expressed by the fetus are recognized as foreign, but the maternal immune system protects the fetus through several immunological changes briefly discussed here.

The key elements of pharmacotherapy of CU are H1 antihistamines and antihistamines are among the most frequently prescribed medications during pregnancy. Approximately 15% of pregnant women use antihistamines during pregnancy, particularly during the first trimester (91). Despite associations of first- and second-generation H1AHs with birth defects have been reported in older reports, detailed analysis of the findings from these reports did not show a meaningful association between antihistamines and major congenital anomalies (92, 93).

Loratadine and cetirizine are the antihistamines of choice based on the data on their safety and the recommendations in the urticaria guidelines (1, 94–98). Compared with loratadine, the use of desloratadine during pregnancy did not increase the risk of adverse pregnancy outcomes (99) and a study from Denmark showed that use of fexofenadine during pregnancy did not increase the risk of major birth defects or spontaneous abortion compared with cetirizine (100).

The use of chlorpheniramine or diphenhydramine as first-generation H1 antihistamines is not recommended as the first-line treatment due to their various side effects. They have not been associated with adverse fetal outcomes in prospective cohort trials (97). The use of H1 antihistamines during the first trimester was not found to be associated with an increased risk of major malformations or other adverse pregnancy outcomes (91). Table 2 shows the pregnancy categories of H1-antihistamines. The safety of higher than approved doses of antihistamines has not been evaluated in pregnant patients, therefore potential risks and benefits have to be discussed with the patient before implementing it.

Although the use of leukotriene antagonists for the treatment of CU is not recommended by the international guidelines due to insufficient level of evidence (1), in case of intention to use during pregnancy, it will be useful to know that montelukast has been assigned pregnancy category B and no increase in major malformations were reported with the use of this medication during pregnancy (101).

Omalizumab is a recombinant IgG1 anti-IgE monoclonal antibody which is recommended in the treatment of antihistamine resistant CSU (1). Animal data on omalizumab (reproduction studies in cynomolgus monkeys) showed no maternal toxicity when administered throughout late gestation, delivery and nursing, subcutaneously in doses up to 75 mg/kg (12-fold the maximum clinical dose) as well as no impaired male or female fertility, embryotoxicity or teratogenicity and no adverse effects on fetal or neonatal growth (102). The Xolair Pregnancy Registry (EXPECT) which was designed to compare the maternal and neonatal outcomes of asthma patients treated with omalizumab (n = 250) or conventional drugs but not omalizumab (n = 1,153) during pregnancy. The prevalence of major congenital anomalies (8.1 vs. 8.9%), live births (99.1 vs. 99.3%), premature birth (15.0 vs. 11.3%) was similar between omalizumab treated and the conventional treatment groups (103). Given that this study includes only asthmatic patients and is an observational study, it is difficult to draw definitive conclusions for the safety of omalizumab in pregnant CU patients, however, there are several case reports on the safe use of omalizumab during pregnancy in CU patients (104).

Of note, omalizumab has a very long life of elimination half-life (26 days), and omalizumab exposure of the neonate would persist for weeks after birth. This may also translate to the exposure of the fetus to omalizumab which has been given to the patient even she was not aware of her pregnancy (of note: elimination of a given drug totally from the body takes 4–5 half-lives; in case of omalizumab this would take 26 × 5 = 130 days).

Another point to remember is that although all IgG subtypes can cross the placenta, IgG1 has the greatest transplacental transfer. It is expected that the lowest omalizumab exposure occurs during the first trimester of pregnancy and the greatest during the third trimester (105).

In 2019, European Medicine Agency updated the European Public Assessment Report and stated that omalizumab might be considered for use in pregnancy (82). In antihistamine refractory, severe CU patients, omalizumab may be a reasonable choice of treatment; however, the benefit-risk ratio should be reconsidered in every pregnant case individually and should be discussed with the patient in detail.

Cyclosporine-A is the treatment recommended by the guidelines for CSU cases who do not respond to omalizumab treatment for 6 months. It is classified as category “C” in the FDA letter category system for pregnancy.

Bar Oz et al. reported in their meta-analysis which included 15 studies with 410 transplant patients that cyclosporine-A is not a major human teratogen but is associated with a trend toward increased risk of congenital malformations in the babies of transplant recipients and increased rates of prematurity (106).

Due to its side effects such as hypertension and nephrotoxicity which can potentiate gestational complications such as preeclampsia, cyclosporine-A is generally not recommended in pregnancy. It should be preserved for very severe cases only after other treatments have failed (107).

The use of systemic glucocorticosteroids (GCS) in CSU is limited only during exacerbations for short periods by the guidelines (1). GCS are generally not considered to be teratogenic but has been linked to growth retardation if fetal exposure (a median of 20 mg/day) happens during intrauterine development (108). Even though an increased risk of ~3-fold for oral clefts has been shown (109), the US National Birth Defects Prevention showed no increased risk of oral clefts with the 1st trimester use of GCS in a case-control study (110). It should be remembered that GCS use in pregnancy may lead to maternal side effects such as hypertension, gestational diabetes, and preeclampsia, and these can lead to poor pregnancy outcomes (i.e., intrauterine growth restriction, macrosomia, intrauterine fetal demise). Therefore, if possible, the use of GCS should be avoided in pregnancy, but if it must be used, it should be prescribed for severe cases at the lowest effective dose (≤ 20 mg/day prednisone) for a limited period (111, 112). Use of GCS during exacerbations of CU as short courses of 1–5 days with minimally effective dose is unlikely to cause pregnancy complications. With a short half-life and effective metabolization by 11-β-hydroxy-steroid present in the placenta, prednisone should be the steroid of choice (FDA category B). Fetal exposure is found ~10% of the maternal plasma level (113–115).

Hence the transfer rate to breast milk is minimal, second-generation antihistamines are safe to use during lactation (116). Cetirizine, loratadine, and fexofenadine are the best studied antihistamines (117, 118). Higher doses of terfenadine and loratadine showed very minimal transmission to the milk (114, 119). In refractory cases of CU who are nursing their babies, higher doses of second-generation antihistamines might be safely used since the transfer rate to breast milk is minimal (114). First-generation antihistamines might lead to infant irritability and drowsiness (120) and are better not used during lactation.

GCS are considered to be safe to use during lactation by The American Academy of Pediatrics. They recommend the use of minimal effective dose for the possible shortest duration and to prefer prednisone or prednisolone over other GCS options (121). Since low amounts of prednisolone can transfer to breast milk, delaying breastfeeding for 4 h after maternal GCS ingestion to avoid plasma level peaks occurring 1 h after ingestion is recommended (122, 123).

Montelukast is safe to use during breastfeeding given its very low levels in breastmilk. Since it is approved for use even in infants as young as 6 months of age, amounts ingested during breastfeeding by the infants are not expected to cause any adverse effects (124). A task force of respiratory experts reported that the use of these medications during breastfeeding is probably safe (125).

With a molecular weight of 145,058 Da, omalizumab is a large protein molecule and, likely, omalizumab transfer to the milk and, therefore the level in milk, is very low. It is partially destroyed in the gastrointestinal system of the infant and systemic absorption by the baby is probably minimal (126). Pregnant and nursing asthmatic patients have been followed in the EXPECT pregnancy registry for several years; 154 infants of these mothers were breastfed while their mothers were on omalizumab treatment. The results of this study showed that there is no difference in serious adverse events among the infants who received or did not receive omalizumab (102, 103). A case report of a CU patient who was treated with omalizumab during pregnancy and nursery showed that only 1/10,000 to 1/1,000 of omalizumab in the maternal serum is transferred into breast milk (127).

Cyclosporine-A transfers to the milk <1% of the mother's weight-adjusted dosage. It does not cause adverse effects on infant's growth, development, or kidney function. However, if cyclosporine-A is used during lactation, infants should be monitored for the serum levels of cyclosporine-A to rule out toxicity (128).

The considerations for pregnancy and lactation for CU medications are shown in Table 2.