麻豆传媒

"Medical Journeys" is a set of clinical resources reviewed by physicians, meant for the medical team as well as the patients they serve. Each episode of this journey through a disease state contains both a physician guide and a downloadable/printable patient resource. "Medical Journeys" chart a path each step of the way for physicians and patients and provide continual resources and support, as the caregiver team navigates the course of a disease.

More research is needed about the treatment of chronic urticaria in "special populations," including pregnant and lactating women, children, and the elderly. For example, there is still much to be learned about the safety and efficacy of the medications recommended for chronic urticaria in these vulnerable patients.

"Overall, the considerations are the same, except we tend to run into the limitations of therapy more often," Jonathan Silverberg, MD, PhD, MPH, of George Washington University School of Medicine and Health Sciences in Washington, D.C., told 麻豆传媒. "In the pediatric and geriatric population, and in pregnant women, we're certainly concerned about safety to a much larger extent."

In women with chronic urticaria, dramatic changes in sex hormones during pregnancy can affect the severity and duration of disease, even after delivery. Conversely, changes in disease activity can impact pregnancy, sometimes leading to mood changes such as anxiety and depression. Still, many questions remain, and physicians have been left to navigate the knowledge gaps by weighing the pros and cons of various treatments against the potential impact of no treatment.

"To date, well-designed clinical trials comparing the efficacy and safety of all modern second-generation H1-antihistamines in urticaria are largely lacking," noted the most recent (2021) . "It should be pointed out that the possible negative effects of increased levels of histamine receptor binding occurring in urticaria have also not been studied in pregnancy."

The document -- a joint initiative of the European Academy of Allergology and Clinical Immunology; the Global Allergy and Asthma European Network; the European Dermatology Forum; and the Asia Pacific Association of Allergy, Asthma and Clinical Immunology -- recommends adopting the same overall urticaria management strategy for women who are pregnant or lactating. Initial therapy consists of standard doses of non-sedating second-generation antihistamines, including bilastine (Blexten), cetirizine (Zyrtec), desloratadine (Clarinex), ebastine (Ebast), fexofenadine (Allegra), levocetirizine (Xyzal), loratadine (Claritin), and rupatadine (Rupafin).

Not recommended, the guideline notes, are astemizole (Hismanal) and terfenadine (Seldane), since both can have cardiotoxic effects in conjunction with ketoconazole and erythromycin.

The guideline authors noted that although there was not enough data to make an evidence-based recommendation on which second-generation antihistamine to use, loratadine is the preferred agent, followed by desloratadine, cetirizine, and levocetirizine.

In patients who don't respond to standard doses of second-generation antihistamines, the overall recommendation is to increase the dose up to four-fold. "This approach can only be carefully suggested in pregnancy since safety studies have not been done," the guideline noted.

'A Cautious Approach'

Regarding patients who are pregnant or lactating, a advised a cautious approach: "Pharmacological treatment should be considered with maximum advisable effect and minimum dose, especially in the first trimester."

The of pregnant women with chronic inducible urticaria (CinDU) or CinDU and chronic spontaneous urticaria (CSU) came to a similar conclusion: "The least amount of treatment needed to achieve minimal disease activity should be used," the researchers said, adding that the pros and cons of the potential side effects of treatment should be weighed against the risks to the mother and fetus of inadequately treated disease.

In that study, out of 288 pregnancies in 288 women, 28.9% had a two-fold increase in disease exacerbation during pregnancy, as did 37.4% of women after delivery. The risk factors for worsening symptoms included mild urticaria without angioedema prior to pregnancy, lack of treatment during pregnancy, and a history of worsening symptoms in a previous pregnancy.

"These considerations should be discussed with the patient and an informed and shared decision should be made," the team wrote in a subsequent . About 15% of pregnant women use antihistamines, particularly during the first trimester.

"We do have to be careful," Silverberg said, pointing out that even cetirizine -- which is an active metabolite of hydroxyzine, a first-generation anti-histamine -- can have effects on the central nervous system.

The safety of recommended first-line second-generation antihistamines can be a concern during pregnancy, agreed Jenny Murase, MD, of the University of California, San Francisco and director of Medical Dermatology Consultative Services and Patch Testing for the Palo Alto Foundation Medical Group. "You need to be judicious about the use of antihistamines and the dose in patients who are pregnant," she told 麻豆传媒.

Infants born to mothers taking high doses of antihistamines during pregnancy may develop tremulousness, irritability, poor feeding, and diarrhea, noted Murase , who specializes in the treatment of urticaria during pregnancy and lactation. These symptoms are thought to be manifestations of antihistamine withdrawal, she said, citing a case in which an infant born to a woman who self-medicated with 150 mg of hydroxyzine daily developed tonic-clonic seizures.

The use of antihistamines around the time of delivery is another concern, Murase said. One of infants born to mothers who used any antihistamine within 2 weeks of delivery showed a significantly increased risk of retinopathy of prematurity compared with infants in the general population (22% vs 11%, respectively). The use of intravenous antihistamines can also have oxytocin-like effects and stimulate uterine contractions.

Warning About First-Generation Antihistamines

Importantly, the use of first-generation antihistamines such as chlorpheniramine (Chlor-Trimeton), dimenhydrinate (Dramamine), cyproheptadine (Periactin), tripelennamine (Pyribenzamine), dexchlorpheniramine (Polaramine), hydroxyzine (Vistaril), diphenhydramine (Benadryl), and clemastine (Tavegyl) should be avoided during pregnancy and lactation. These older antihistamines, which have pronounced anticholinergic and sedative effects, interact with alcohol and other drugs, including analgesics, interfere with REM sleep, and can impair performance of complex sensorimotor tasks such as driving.

First-generation H1-antihistamines may also be associated with an increased risk of dementia. And while all H1-antihistamines are excreted in breast milk in low concentrations, nursing infants occasionally develop sedation from the transmission of first-generation H1-antihistamines in breast milk.

Next Steps for Those Refractory to Antihistamines

For patients who are refractory to antihistamines, the guideline recommends adding omalizumab (Xolair), an injectable monoclonal anti-immunoglobulin E antibody that can cross into the placenta, especially during the second and third trimesters. Again, the overall recommendation is to increase the dosage up to four-fold as needed. "The use of omalizumab in pregnancy has been reported to be safe, and to date, there is no indication of teratogenicity," the guideline states.

So what does the evidence show? From 2006-2017, the Observational Study of the Use and Safety of Xolair during Pregnancy (EXPECT) registry enrolled more than 300 pregnant women exposed to omalizumab to evaluate its safety during pregnancy. Most were treated for moderate to severe asthma. In 2020, results from a from the study from a subgroup of 30 pregnant women treated with omalizumab for H1-antihistamine-resistant CSU showed no evidence of an increased risk of major congenital anomalies or thrombocytopenia. Notably, more than 98% of participants were exposed to omalizumab during the first trimester of pregnancy, and 83.0% during all three trimesters.

"Treatment options for pregnant women with CSU are limited in patients who do not respond to high-dose antihistamines, as immunosuppressants are contraindicated during pregnancy," the EXPECT researchers said. Given the observational nature of the EXPECT registry and the low number of patients in their post-hoc analysis, however, "an absence of increased risk with omalizumab cannot be definitively established," the team said.

A 2024 of real-life data from 29 women with chronic urticaria treated with omalizumab before and during pregnancy showed that the biologic did not appear to have any negative effects on maternal or fetal outcomes. The results are in line with those from the EXPECT study, the authors said. Once again, the lack of published real-life data prevented them from drawing any firm conclusions about the risks associated with the use of omalizumab for CSU during pregnancy.

Murase explained that because the risk of major congenital malformations is highest in the first trimester, it doesn't make sense for there to be any change in the risk of congenital malformations with any of the biologics because they don't cross the placenta in the first trimester. It is "highly unlikely" that the transplacental passage of omalizumab in the third trimester will have harmful effects on the fetus, but we just don't know, Murase noted.

The guideline recommends that further treatment for recalcitrant urticaria during pregnancy be determined on an individual patient basis. Physicians are advised to give preference to "medications that have a satisfactory risk-to-benefit ratio in pregnant women and neonates with regard to teratogenicity and embryotoxicity."

Although the advice is to use cyclosporine in severe recalcitrant urticaria following 6 months of omalizumab, the document emphasizes that cyclosporine in pregnancy is associated with an increased risk of preeclampsia, preterm delivery, and low birth weight. "Whether the benefits of cyclosporine are worth the risks in pregnant women will have to be determined on a case-by-case basis," the guideline states.

Read previous installments in this series:

Part 1: Urticaria/Hives: The Search Continues for Causes

Part 2: Keys to Diagnosis of Urticaria

Part 3: Chronic Spontaneous Urticaria and Autoimmunity

Part 4: Case Study: Terrible Recurrent Itchy Wheals All Over This Woman's Body

Part 5: Managing Comorbidities in Chronic Urticaria

Part 6: What's New in the Treatment of Chronic Urticaria?