Management of Psoriasis During Preconception, Pregnancy, Postpartum, and Breastfeeding: A Consensus Statement

ACTAS Dermo-Sifiliográficas 112 (2021) 225---241 CONSENSUS DOCUMENT Management of Psoriasis During Preconception, Pregnancy, Postpartum, and Breastfeeding: A Consensus Statement夽 I. Belinchón,a,∗,1M. Velasco,b,1M. Ara-Martín,cS. Armesto Alonso,d O. Baniandrés Rodríguez,eL. Ferrándiz Pulido,fM. García-Bustinduy,g J.A. Martínez-López,hN. Martínez Sánchez,iA. Pérez Ferriols,jE. Pérez Pascual,k R. Rivera Díaz,lR. Ruiz-Villaverde,mR. Taberner Ferrer,nA. Vicente Villa,o J.M. Carrascosap aServicio de Dermatología, Hospital General Universitario de Alicante-ISABIAL-UMH, Alicante, Spain bServicio de Dermatología, Hospital Universitario Arnau de Vilanova, Valencia, Spain cServicio de Dermatología, Hospital Clínico Lozano Blesa, Zaragoza, Spain dServicio de Dermatología, Hospital Universitario Marqués de Valdecilla, Santander, Spain eServicio de Dermatología, Hospital Universitario Gregorio Mara˜ nón, Madrid, Spain fServicio de Dermatología, Hospital Universitario Virgen Macarena, Sevilla, Spain gServicio de Dermatología, Hospital Universitario de Canarias, Santa Cruz de Tenerife, Spain hServicio de Reumatología, Hospital Universitario Fundación Jiménez Díaz, Madrid, Spain iServicio de Ginecología-Obstetricia, Hospital Universitario La Paz, Madrid, Spain jServicio de Dermatología, Hospital General de Valencia, Valencia, Spain kServicio de Ginecología-Obstetricia, Hospital General Universitario de Alicante-ISABIAL, Alicante, Spain lServicio de Dermatología, Hospital Universitario 12 de Octubre, Madrid, Spain mServicio de Dermatología, Hospital Universitario San Cecilio, Granada, Spain nServicio de Dermatología, Hospital Son Llàtzer, Palma de Mallorca, Spain oServicio de Dermatología, Hospital Sant Joan de Déu, Esplugues de Llobregat, Barcelona, Spain pServicio de Dermatología, Hospital Universitario Germans Trias i Pujol, Badalona, Barcelona, Spain Received 17 April 2020; accepted 2 October 2020 KEYWORDS Psoriasis; Fertility; Pregnancy; Abstract Objective: To develop evidenceand experience-based recommendations for the management of psoriasis during preconception, pregnancy, postpartum, and breastfeeding. Methods: The nominal group technique and the Delphi method were used. Fifteen experts (12 dermatologists, 2 of whom were appointed coordinators; 1 rheumatologist; and 2 夽Please cite this article as: Belinchón I, Velasco M, Ara-Martín M, Armesto Alonso S, Baniandrés Rodríguez O, Ferrándiz Pulido L et al. Consenso sobre las actuaciones a seguir durante la edad fértil, el embarazo, el posparto y la lactancia en pacientes con psoriasis. Actas Dermosifiliogr. 2021;112:225---241. ∗Corresponding author. E-mail address: belinchon [email protected] (I. Belinchón). 1Both authors contributed equally to this work. 1578-2190/© 2020 AEDV. Published by Elsevier Espa˜ na, S.L.U. This is an open access article under the CC BY-NC-ND license (http:// creativecommons.org/licenses/by-nc-nd/4.0/). I. Belinchón, M. Velasco, M. Ara-Martín et al. Postpartum; Breastfeeding; Delphi process; Recommendations gynecologists) were selected to form an expert panel. Following a systematic review of the literature on fertility, pregnancy, postpartum, and breastfeeding in women with psoriasis, the coordinators drew up a series of preliminary recommendations for discussion by the panel at a nominal group meeting. The experts defined the scope, sections, and intended users of the statement and prepared a final list of recommendations. Consensus was obtained using a Delphi process in which an additional 51 dermatologists rated their level of agreement with each recommendation on a scale of 1 (total disagreement) to 10 (total agreement). Consensus was defined by a score of 7 or higher assigned by at least 70% of participants. Level of evidence and strength of recommendation were reported using the Oxford Center for Evidence-Based Medicine categories. The final statement was approved by the expert panel. Results: The resulting consensus statement includes 23 recommendations on preconception (fertility and contraception), pregnancy (planning, pharmacological management, and follow-up), and breastfeeding (management and follow-up). Consensus was achieved for all recommendations generated except one. Conclusions: These recommendations for the better management of psoriasis in women of childbearing age could improve outcomes and prognosis. © 2020 AEDV. Published by Elsevier Espa˜ na, S.L.U. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). PALABRAS CLAVE Psoriasis; Fertilidad; Embarazo; Posparto; Lactancia; Método Delphi; Recomendaciones Consenso sobre las actuaciones a seguir durante la edad fértil, el embarazo, el posparto y la lactancia en pacientes con psoriasis Resumen Objetivo: Desarrollar recomendaciones basadas en la mejor evidencia y experiencia sobre el manejo de pacientes con psoriasis durante la edad fértil, el embarazo, el posparto y la lactancia. Métodos: Se siguió la metodología de grupos nominales y Delphi. Se seleccionó un grupo director de expertos (12 dermatólogos ---- d e los cuales 2 fueron los coordinadores---- , 1 reumatólogo, 2 ginecólogos). Se realizó una revisión sistemática de la literatura sobre fertilidad, embarazo, posparto y lactancia en pacientes con psoriasis. Con esta información los coordinadores generaron una serie de recomendaciones preliminares. Todo ello se presentó y discutió con el resto de expertos en una reunión de grupo nominal donde se definió el alcance, los usuarios, los apartados del documento, y donde se generaron las recomendaciones definitivas. El grado de acuerdo con las recomendaciones se votó siguiendo la metodología Delphi, que se extendió a 51 dermatólogos más, según una escala de 1 (total desacuerdo) a 10 (total acuerdo), definiéndose el acuerdo como una puntuación ≥ 7 por al menos el 70% de los participantes. El nivel de evidencia y el grado de recomendación se clasificaron según el modelo del Center for Evidence Based Medicine de Oxford. El documento completo final fue aprobado por el panel de expertos. Resultados: Se generaron 23 recomendaciones sobre el periodo pre-concepcional (fertilidad y anticoncepción), el embarazo (planificación, manejo farmacológico y seguimiento) y la lactancia (manejo y seguimiento). Todas las recomendaciones menos una alcanzaron el nivel de acuerdo definido. Conclusiones: En los pacientes con psoriasis en edad fértil estas recomendaciones pueden mejorar el manejo, los resultados y el pronóstico. © 2020 AEDV. Publicado por Elsevier Espa˜ na, S.L.U. Este es un art´ ıculo Open Access bajo la licencia CC BY-NC-ND (http://creativecommons.org/licenses/by-nc-nd/4.0/). Introduction Psoriasis is a very common disease1,2 with 2 peaks in incidence----one between age 15 and 30 years and the other between 50 and 60 years----although the disease first manifests before age 40 years in more than 75% of cases.3,4 In clinical practice, a large percentage of patients are of reproductive age, and psoriasis and/or its treatments can affect fertility, pregnancy, postpartum, and breastfeeding and vice versa.5 --- 8 Owing to its severity, or to pain or embarrassment in the case of genital involvement, psoriasis may be associated with fertility problems, both in men and in women.9---11 Some treatments of psoriasis, including tazarotene and acitretin,12,13 are potentially teratogenic and are therefore contraindicated during pregnancy. It has also been reported that the disease worsens in 40% to 80% of patients a few weeks after delivery14 and that the children of mothers who have been in treatment with monoclonal antibodies that cross the placenta during the third trimester are at greater risk of infection and, therefore, require specific monitoring and management.15 Awareness of these problems and a suitable approach to preventing them or treating them early and efficiently should form part of the knowledge and skills of health 226 ACTAS Dermo-Sifiliográficas 112 (2021) 225---241 professionals involved in the management of affected patients.16 In addition, these problems are very relevant for psoriasis patients themselves.16 The objective of this consensus statement is to generate a series of recommendations aimed at improving management of patients of reproductive age with psoriasis. The statement covers fertility, pregnancy, postpartum, and breastfeeding. We believe that the recommendations are of considerable interest for health professionals involved in treating patients with psoriasis, namely, dermatologists, gynecologists, primary care physicians, and nurses. Methods Study Design This document was promoted by the Psoriasis Working Group of the Spanish Academy of Dermatology and Venereology (Academia Espa˜ nola de Dermatología y Venereología [AEDV]). The consensus statement was drafted following the nominal group technique and the Delphi method, with the help of a systematic review of the literature.17 The project was managed in full agreement with the principles set out in the Declaration of Helsinki and in line with current norms of Good Clinical Practice. Selection of Participants The participants selected formed a multidisciplinary group comprising 12 dermatologists (2 of whom were the coordinators), 1 rheumatologist, and 2 gynecologists with experience and interest in the subject area. With help from methodologists, the coordinators defined the objectives, scope, users, and sections of the document. It was decided to address 3 broad areas: (a) reproductive age; (b) pregnancy and postpartum; and (c) breastfeeding and perinatal care. Systematic Review of the Literature and Preliminary Recommendations A systematic review of the literature was performed to assess fertility, delivery, and breastfeeding in patients with psoriasis. An expert documentalist designed the search strategies for the PubMed, EMBASE, and Cochrane library databases (from baseline to November 2018) using Medical Subject Headings and free text terms. In order to be included, studies had to fulfil the following criteria: (1) they had to include patients with psoriasis; (2) they had to provide data on pregnancy, breastfeeding, and postpartum (e.g., prevalence, interventions, prognoses); and (3) they had to be a meta-analysis, systematic review of the literature, randomized clinical trial, or observational study. Two reviewers independently selected articles and collected data. Finally, a secondary search for articles was carried out. The quality of the studies was evaluated using the 2011 classification of the Oxford Centre for Evidence-Based Medicine.18 This information enabled the coordinators to generate a series of preliminary recommendations. Meeting of the Nominal Group The objectives, scope, users, and sections of the document were confirmed at the meeting of the nominal group. The results of the systematic literature review were then presented and discussed, as were the provisional recommendations. Finally, the definitive recommendations were established. Delphi Process The definitive recommendations were assessed using the Delphi process to establish the level of agreement (LA) with them. This stage was carried out online. The recommendations were sent to the expert panel and to 120 dermatologists. The vote was based on a Likert-type scale ranging from 1 (completely disagree) to 10 (completely agree). Agreement was defined as a score of ≥ 7 from at least 70% of the participants. The recommendations with an LA < 70% were evaluated and, if applicable, re-edited and voted on in a second Delphi round. It was possible to include new recommendations in the first Delphi round. Edition of the Final Document The definitive document was drafted based on the systematic review of the literature, the decisions of the nominal group, and the Delphi process. In addition to the LA, each of the recommendations was assigned a level of evidence (LE) and a grade of recommendation (GR) according to the recommendations for evidence-based medicine of the Oxford Centre for Evidence-Based Medicine.18 The final version of the document was sent to the experts for a concluding evaluation and comments. Results Systematic Review of the Literature and Delphi Process After elimination of duplicates, 610 references were recovered. Of these, 49 were eventually included (Fig. 1 and other results in Appendix A, Supplementary material). A total of 23 recommendations were generated. The Delphi response rate was 50%. In the first Delphi round, the LA was sufficient for all recommendations but one. The recommendation for which a sufficient LA was not reached was excluded. The results are shown in Table 1. Preconception Preconception Counseling Recommendation 1. Preconception counseling should be offered to all psoriasis patients of reproductive age (both men and women) (LE 2b; GR B; LA 82%). Preconception counseling should always be offered so that patients with psoriasis can make informed decisions together with the dermatologist and also to avoid, as far as possible, unnecessary delays in conception. 227 I. Belinchón, M. Velasco, M. Ara-Martín et al. Table 1 Definitive Recommendations and Results of the Delphi Process. # Recommendation Mean SD Median P25 P75 Min Max %≥7 1 Preconception counseling should be offered to all psoriasis patients of reproductive age (both men and women) 8.23 2.82 9 7.5 10 1 10 82% 2 The panel recommends regular assessment of the desire to become pregnant 8.66 2.82 9 8 10 1 10 87% 3 The panel advises evaluating and recommending, if applicable, an effective contraceptive method for as long as a pregnancy is not desirable 7.89 2.12 9 7 10 1 10 73% 4 The panel recommends referring the patient to a gynecologist for reproductive health counseling 6.23 1.41 6 5 8.5 1 10 46% 5 Planning for pregnancy should include an assessment of the gynecologic and dermatologic history, a laboratory analysis, assessment of current psoriasis and its treatment, assessment of comorbidities, and possible contraindications to pregnancy 8.64 4.24 9 8 10 1 10 93% 6 The panel recommends that patients be informed on an individual basis about maternal-fetal risk factors in pregnancy and about all aspects of follow-up of pregnancy, including postpartum 7.98 1.41 9 7.25 10 1 10 81% 7 The panel recommends that psoriasis be as well controlled as possible before the patient tries to become pregnant 7.62 2.83 9 7 9 1 10 78% 8 The panel recommends establishing the most effective and safest drug profile possible during pregnancy. This should be tailored to the individual patient 9.41 2.12 10 9 10 1 10 98% 9 Potentially teratogenic topical agents (anthralin, tazarotene, topical psoralen---UV-A) should be discontinued once pregnancy is confirmed. Topical drugs with a more favorable safety profile should be considered 9.6 1.41 10 9.75 10 5 10 98% 10 Potentially teratogenic systemic agents (acitretin, systemic retinoids, systemic psoralen---UV-A, apremilast, dimethyl fumarate, methotrexate) should be discontinued before conception. Drugs with a better safety profile should be considered 9.56 2.12 10 10 10 5 10 97% 11 In the case of women receiving biologic therapy, the panel recommends that this be maintained during the first and second trimesters. Together with the patient, the clinician should evaluate the risks and benefits of continuing these drugs during the third trimester. Patients taking certolizumab pegol can continue the drug throughout pregnancy only if it is considered clinically necessary 8.48 4.24 9 8 10 1 10 88% 12 Patients with psoriasis who require standard systemic treatment and/or biologics to control their disease must be followed up closely by an obstetrician once the pregnancy is confirmed 8.88 0.13 10 8 10 2 10 92% 13 The panel recommends strict follow-up and monitoring of pregnant women with psoriasis 8.10 1.41 9 7 10 1 10 83% 14 In the case of a flare-up, the panel recommends treating each case on an individual basis, taking into account type and severity, week of gestation, and available therapeutic options 9.75 0.10 10 10 10 8 10 100% 15 The panel recommends encouraging cooperation between specialties (e.g., dermatology, obstetrics, pediatrics) 9.50 0.12 10 9 10 5 10 98% 228 ACTAS Dermo-Sifiliográficas 112 (2021) 225---241 Table 1 (Continued) # Recommendation Mean SD Median P25 P75 Min Max %≥7 16 Emollients can be prescribed during breastfeeding 9.74 0 10 10 10 7 10 100% 17 With respect to topical treatments for psoriasis during breastfeeding, tazarotene is contraindicated. Other topical agents can be used providing that the benefits outweigh the risks, at minimum doses, and for as short a period as possible. The area of the nipple and areola should be avoided 9.16 0.71 10 9 10 3 10 97% 18 Topical PUVA is not recommended during breastfeeding. Narrowband UV-B phototherapy can be used 9.18 0.70 10 9 10 2 10 95% 19 Systemic corticosteroids can be used during breastfeeding as long as the benefits outweigh the risks They should be administered at minimum doses and for as short a time as possible 8.33 0.34 9 7.75 10 2 10 80% 20 Oral retinoids, apremilast, dimethyl fumarate, methotrexate, and ciclosporin A are not recommended during breastfeeding 9.16 3.54 10 9 10 1 10 95% 21 Certolizumab pegol has been approved for use during breastfeeding. For all other biologics, the panel recommends assessing the risks and benefits in each case 9.38 0.71 10 9 10 5 10 93% 22 Once the pregnancy has come to term, standard follow-up should be resumed in the dermatology clinic as soon as possible 8.91 1.41 10 9 10 2 10 88% 23 The newborn does not require special care, except if the mother has been exposed to biologics that cross the placenta and have been maintained beyond the second trimester 8.83 0.71 10 9 10 1 10 87% Table 2 Areas to Be Covered in Preconception Counseling. # Area 1 Genetic counseling (heritability of psoriasis) 2 Impact of psoriasis and its treatment on fertility 3 Use of contraceptives (when and types) 4 Impact of psoriasis and its treatment (as well as the risk of not treating) during pregnancy (for mother and fetus) and postpartum 5 Impact of pregnancy and postpartum on psoriasis 6 Planning for pregnancy (e.g., justification, alternatives, and modifications of treatment before conception and during pregnancy, visit schedule, tests, vaccinations) 7 Measures for puerperium and breastfeeding 8 Management of the unexpected pregnancy Psoriasis is not a contraindication for gestation, although pregnancy can affect psoriasis; in turn, psoriasis (and its treatment) may be a risk factor for the course of the pregnancy.4,14,19---25 Preconception counseling (Table 2) ranges from information on the impact of the disease on fertility and pregnancy to the approach to an unexpected pregnancy and genetic counseling.26,27 This in turn should be adjusted to the patient’s characteristics and involve the partner where possible. Preconception counseling should be repeated periodically. While psoriasis is not a frequently reported problem, its severity or the consequences of genital involvement (pain or embarrassment) mean that it may be associated with fertility problems.9,22,25,28---36 Some of the drugs used to treat psoriasis may also affect fertility, although this has not been demonstrated.10,37---40 Recommendation 2. The panel recommends regular assessment of the desire to become pregnant (LE 5; GR D; LA 87%). This recommendation applies to all patients of reproductive age (both sexes), especially those who are receiving or who are candidates for long-term systemic treatment. Recommendation 3. The panel recommends evaluating and recommending, if applicable, an effective contraceptive method panel for as long as pregnancy is not desirable (LE 2b; GR B; LA 73%). We should recommend the use of effective contraceptive methods to both men and women, for as long as a pregnancy is not envisaged or when it is preferable to postpone it (e.g., owing to the severity of the disease, initiation of a teratogenic treatment). Combined hormonal contraception is the most efficacious method,41 except in the case of a contraindication.42 How229 I. Belinchón, M. Velasco, M. Ara-Martín et al. Table 3 Planning the Pregnancy. # Action 1 Complete gynecologic and obstetric history Number of previous pregnancies (to term or not), route of delivery, number of induced and spontaneous abortions History of preeclampsia, HELLP syndrome, arterial hypertension, or thrombosis in previous pregnancies History of delayed growth or low birth weight Previous fertility problems 2 Identification and evaluation of comorbidities Metabolic syndrome (obesity, arterial hypertension, diabetes mellitus, hypercholesterolemia) Smoking and drinking Depression Other, depending on the patient 3 Characteristics and severity of psoriasis (current and past) Duration of psoriasis Type Location Severity 4 Absolute and relative contraindications to pregnancy 5 Estimation of the risk of maternal-fetal complications during pregnancy Individualized Age, activity, and damage caused by the disease itself and drugs Complications during previous pregnancies 6 Treatments Drugs used in the 3-36 months before deciding to become pregnant Time since the last dose of drugs that are contraindicated in pregnancy 7 Complementary tests Standard laboratory work-up (complete blood count, urine, biochemistry) Other, depending on the patient 8 Re-evaluation of treatment options In the case of clinical remission, maintenance of nonteratogenic drugs 9 Information Complications during pregnancy, puerperium, and breastfeeding Disease course Plan for action in the case of complications of the underlying disease and/or pregnancy Schedule for check-ups Abbreviations: HELLP, hemolysis, elevated liver enzymes, low platelet count. ever, the panel recommends tailoring the method to the individual case and referring the patient to a gynecologist or primary care if necessary. While assisted reproduction is considered a gynecologic area, dermatologists who care for patients undergoing this process should be aware of the general aspects of the procedures in order to be able to provide appropriate information. The LA for the recommendation formulated with respect to this area (Recommendation 4, Table 1) was insufficient (see Discussion). Planning for Pregnancy Recommendation 4. The panel recommends referring the patient to a gynecologist for reproductive counseling (LE 5; GR D; LA 46%). Recommendation 5. Planning for pregnancy should include an assessment of the gynecologic and dermatologic history, a laboratory analysis, assessment of current psoriasis and its treatment, assessment of comorbidities, and possible contraindications to pregnancy (LE 5; GR D; LA 93%). Recommendation 6. The panel recommends that patients be informed on an individual basis about maternal-fetal risk factors in pregnancy and about all aspects of follow-up of the pregnancy, including postpartum (LE 5; GR D; LA 81%). Recommendation 7. The panel recommends that psoriasis is controlled as well as possible before the patient tries to become pregnant (LE 2b; GR B; LA 78%). Pregnancy can affect psoriasis, and this (and its treatment) may be a risk factor for the course of the pregnancy.4,14,19---25 Control of psoriasis and preconception use of drugs with a low risk for the fetus make it possible to reduce the risk of maternal-fetal complications. Therefore, it is essential to plan the pregnancy and ensure collaboration with a gynecologist and primary care physician. Planning (Tables 3 and 4) should involve a personalized preconception assessment covering the patient’s complete gynecologic and obstetric history, contraindications for pregnancy, and risk factors for maternal-fetal complications,22,25 including the drugs used before and during pregnancy (Table 5). 230 ACTAS Dermo-Sifiliográficas 112 (2021) 225---241 Table 4 Risk Factors for Maternal-Fetal Complications in Patients With Psoriasis. Previous Bad Obstetric History Severe preeclampsia HELLP syndrome Previous recurrent miscarriage . . . Dependent on the Patient or on Psoriasis Age > 40 y Family history of preeclampsia Personal history of preeclampsia, multiple pregnancies, nulliparity, or diabetes Obesity or arterial hypertension at the beginning of pregnancy Moderate to severe psoriasis Comorbidity Exposure to Teratogenic Drugs Between 6 and 36 mo before conception Abbreviation: HELLP, hemolysis, elevated liver enzymes, low platelet count. Psoriasis improves in 33%-60% of women during pregnancy,4,14,19 remains unchanged in 25%, and worsens in 25%.14 However, 40%-88% experience a flare-up after delivery.4,6,14,19,24,43---45 Data on the effect of psoriasis in pregnancy, childbirth, and the newborn are somewhat controversial.5,25,34,46---48 Some studies associate poor results specifically with patients who have moderate to severe psoriasis.7,48 At present, there are no data suggesting an association between psoriasis and the development of congenital malformations,7,49 and while findings are heterogeneous, there does seem to be an association between psoriasis and the development of diabetes and gestational arterial hypertension.7,48 Finally, it is also essential to ensure that psoriasis is inactive for 3-4 months, using nonteratogenic drugs. If this is not possible, then the lowest degree of activity possible should be sought on an individual basis. Pregnancy and Follow-up Pregnancy Recommendation 8. The panel recommends establishing the most effective and safest pharmacological profile possible during pregnancy. This should be tailored to the individual patient (LE 5; GR D; LA 98%). Knowledge of safety of medications is one of the pillars of effective and safe medical and obstetric care (Table 5). However, we lack sufficient evidence to provide robust, explicit recommendations for all drugs.9,50,51 Therefore, during pregnancy, drugs should be prescribed with caution, after performing a meticulous evaluation of the risks and benefits for each patient and taking informed decisions, which should be agreed with the patient.40 Topical Drugs Recommendation 9. Potentially teratogenic topical agents (anthralin, tazarotene, topical psoralen---UV-A [PUVA]) should be discontinued once pregnancy is confirmed. Topical drugs with a more favorable safety profile should be considered (LE 3a; GR C; LA 98%). The panel also considers it important to assess the riskbenefit ratio on an individual basis. In the case of topical drugs with a more favorable safety profile, these should be prescribed at the lowest dose possible over as small an area as possible for as short a time as possible. Occlusive dressings should be avoided (Table 5). The only association reported for topical corticosteroids is between low birth weight and the use of highand veryhigh-potency corticosteroids, especially when the duration of exposure and cumulative dose are considerable.15,52 Topical calcineurin inhibitors15 and calcipotriol have been shown to be safe. However, maternal vitamin D deficiency can be associated with a teratogenic risk. As for coal tar, there are no data to suggest teratogenicity or poor pregnancy outcome in humans, although cases of malformation have been reported in animals.15,53,54 A moderate amount of topical salicylic acid (9%-25%) can be absorbed systemically, and it has been reported that use of this agent during the first trimester could be associated with an increased risk of gastroschisis.15,55 It is important to note that phototherapy with narrowband UV-B radiation is safe during pregnancy.56 While teratogenicity and poor pregnancy outcome have not been reported with anthralin, this agent should be suspended 4 weeks before conception.15 As for topical tazarotene, it is estimated that 6% is absorbed systemically57,58; in addition, systemic absorption may increase owing to individual factors, such as damage to the skin barrier. Although there are no data pointing to embryopathy, this drug is contraindicated during pregnancy. Similarly, topical PUVA drugs are not recommended during pregnancy.15 Systemic Drugs Recommendation 10. Potentially teratogenic systemic agents (acitretin, systemic retinoids, systemic PUVA, apremilast, dimethyl fumarate, methotrexate) should be discontinued before conception. Prescription of topical and/or systemic and/or phototherapy with a better safety profile should be considered (LE 3a; GR C; LA 97%). No cases of congenital malformations or other relevant problems have been reported for systemic corticosteroids.59---61 Acitretin is a potent teratogen in humans.62,63 It can be detected in blood 2 months after the last dose, although in some circumstances, such as the presence of alcohol, it can be converted to etretinate and be detected for 120 days. Therefore, it is usually recommended to suspend this drug for up to 2 years before conception. Cases should be managed on an individual basis.15,64,65 Other oral retinoids, such as alitretinoin and isotretinoin are also contraindicated during pregnancy.39,40 Potential associations between systemic PUVA agents and teratogenic complications remain unclear15,66,67; therefore, these agents are contraindicated during pregnancy. Narrowband UV-B phototherapy, on the other hand, has proven to be safe during pregnancy.56 No data are currently available on the teratogenic potential of apremilast in humans, although abortion and low birth weight have been reported in animals; consequently, its use 231 I. Belinchón, M. Velasco, M. Ara-Martín et al. Table 5 Safety of Commonly Used Dermatologic Drugs With Respect to Fertility and Pregnancy. Drug MR FR FDA AEMPS and Other Data Ref [0,1-6]Topical Corticosteroids U U B-C -No data on effect on the fetus or on other pregnancy outcomes in humans -If corticosteroids are necessary, topical agents should not be used extensively during pregnancy, that is, in large amounts, or over long periods, or over wide areas. Occlusive dressings should be avoided 98---100,116 Calcineurin inhibitors -Pimecrolimus -Tacrolimus U U C -No data on the effect on the fetus or on other pregnancy outcomes -Do not use during pregnancy, except when the potential benefit outweighs the potential risk for the fetus 117---120 Calcipotriol U U C -Animal studies have revealed cases of cleft palate and lack of lung maturation - No data on the effect on the fetus or on other outcomes of pregnancy in humans - Do not use during pregnancy, except when the potential benefit outweighs the potential risk for the fetus 104 Anthralin U U C -No animal or human data -Experts recommend suspending treatment for 4 wk before conception and avoiding it during pregnancy -AEMPS: not mentioned Coal tar U U C - Animal studies have revealed cases of cleft palate and lack of lung maturation -During pregnancy, the product should be used intermittently, at low concentrations and over a reduced body surface area. Coal tar should be avoided during the first trimester 53,54,101 Salicylic acid U U C -Experts recommend avoiding this agent at high doses (> 3%) and in large amounts (e.g., > 20 g/d). Occlusive dressings should also be avoided -AEMPS: not mentioned Retinoids (tazarotene) U U X -No data for humans -Contraindicated during pregnancy -AEMPS: not mentioned 13 Topical PUVA U U C - No data for humans -Experts recommend avoiding the drug during pregnancy -AEMPS: not mentioned 67 NBUVB U U --- -Few data in humans (occasional case reports) -Experts consider that it can be used during pregnancy -AEMPS: not mentioned 56 [0,1-6]Systemic Corticosteroids B-C -AEMPS: No need to interrupt if administered at standard doses 59,60 Acitretin U U X -Teratogenic in humans -AEMPS: Contraindicated during pregnancy 12 Other retinoids U U X -Teratogenic in humans -AEMPS: Contraindicated during pregnancy 39,40 PUVA U U C -Possible teratogenic effect -Experts recommend avoiding the drug during pregnancy -AEMPS: not mentioned 15,66,67 232 ACTAS Dermo-Sifiliográficas 112 (2021) 225---241 Table 5 (Continued) Drug MR FR FDA AEMPS and Other Data Ref NBUVB U U --- -Not associated with teratogenicity -AEMPS: not mentioned 56 Apremilast U U C -No data for humans -Cases of miscarriage reported in animals -AEMPS: Contraindicated during pregnancy 15 Dimethyl fumarate U U C -No data for humans -Experts recommend not using the drug during pregnancy -AEMPS: Contraindicated during pregnancy 9 Methotrexate D U X -Cases of miscarriage and congenital malformations reported in animals. This effect seems to be dose-dependent in humans and is associated mainly with high drug doses -AEMPS: Contraindicated during pregnancy 109 Ciclosporin A U U C -Case reports of low birth weight and preterm birth -AEMPS: Use if benefits outweigh risks 73---75 Infliximab U U B -No data showing an association with teratogenicity or poor pregnancy outcomes -AEMPS: Use if benefits outweigh risks 83,121 Adalimumab U U B -No data showing an association with teratogenicity or poor pregnancy outcomes -AEMPS: Use if benefits outweigh risks 15,83 Etanercept U U B - No data showing an association with teratogenicity or poor pregnancy outcomes -AEMPS: Not recommended 84 Certolizumab pegol U U B -Data similar to those for the general public -Approved by the EMA for use during pregnancy 81,82,122,123 Brodalumab U U B -Few data for humans -AEMPS: Preferably avoid 113 Secukinumab U U B -No data showing an association with teratogenicity or poor pregnancy outcomes -AEMPS: Preferably avoid 89 Ustekinumab U U B -Lack of data for humans -AEMPS: Preferably avoid 78,87,88,124 Ixekizumab U U B -Few data in humans -AEMPS: Preferably avoid 15 Guselkumab U U B -Few data in humans -AEMPS: Preferably avoid 125 Abbreviations: AEMPS, Agencia Espa˜ nola del Medicamento y Productos Sanitarios (Spanish Agency of Medicines and Medical Devices); D, doubtful; FDA, Food and Drug Administration; FR, fetal risk; MR, maternal risk; NBUVB, narrowband UV-B phototherapy; PUVA, psoralen---UV-A; U, unknown. is contraindicated in pregnancy.15 Similarly, the lack of data in humans for dimethyl fumarate means that this agent is not recommended.9 Animal data show that, in addition to causing abortion, methotrexate is a teratogenic drug. However, various observational studies suggest that defects are induced with doses of methotrexate greater than 10 mg/wk and that the critical period would be 6-8 weeks after conception.68---72 This drug is currently contraindicated in pregnancy and should be suspended 3 months before conception. Finally, ciclosporin A has been associated with a greater risk of low birth weight and preterm birth in pregnant women who have received solid organ transplants, but not with a greater risk of congenital abnormalities.73---75 Biologic Therapy Recommendation 11. In the case of women receiving biologic therapy, the panel recommends that this be maintained during the first and second trimesters. Together with the patient, the clinician should evaluate the risks and benefits of continuing these drugs during the third trimester. Patients taking certolizumab pegol can continue the drug throughout pregnancy only if it is considered clinically necessary (LE 3a; GR C; LA 88%). 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