The physiology and drug metabolism of women during pregnancy are different from those in general, and the sensitivity of the fetus to drugs persists during pregnancy, so the safety of their medication use is very important. This article summarizes the characteristics of medication use in pregnant women and the recommended medications and precautions for some common dermatologic diseases in pregnancy, to provide reference for dermatologists in clinical use.
In clinical work, when facing patients with dermatological diseases in pregnancy, it is often difficult for physicians to make a choice of medication because of the high risk of adverse drug reactions or potential harm to the mother and fetus from the therapeutic drugs. Only by learning to use medications appropriately based on a full understanding of their effects on pregnancy can the benefits to the pregnant woman and fetus be maximized. We would like to make some suggestions on the dermatological use of drugs for women during pregnancy.
1. The effects of drugs on each stage of pregnancy and the principles of drug use
(1) Early Pregnancy.
Within 2 weeks after fertilization, drugs have “all” or “none” effect on the embryo. If the drug damage is serious, it can cause very early miscarriage; if it is partially damaged, the damaged cells can be repaired and the embryo can continue to develop without any abnormality. Therefore, if you have taken a small amount of drugs for a short period of time during this period, there is no need to be overly concerned. The key is that during the 3-12 weeks after fertilization, the embryo and fetal organs are in a highly differentiated and rapidly developing stage, and drugs may affect this process and lead to malformation of some systems and organs. Therefore, the first 3 months of pregnancy is a critical period for the formation of important organs of the fetus, and it is also the most sensitive period to be damaged by teratogenic factors. Unnecessary drugs should be avoided as much as possible during this period.
(2) Middle and late pregnancy.
After the 4th month of pregnancy, the sensitivity of drugs to teratogenicity decreases in the middle and late stages, but the fetus’ teeth, nervous system and reproductive system continue to differentiate and develop, and the adverse effects of drugs still exist. In addition, the teratogenicity of some drugs to the fetus does not manifest in the neonatal period, but shows up after several years. For example, the use of pregnancies with enestradiol causes vaginal adenocarcinoma in adolescent girls. Therefore, medications should also be used with caution in the middle and late stages of life, and the choice should be made on the basis of weighing the pros and cons of the indications for their use. There are few drugs that are absolutely safe during pregnancy.
The U.S. Food and Drug Administration (FDA) classifies drugs that are dangerous to pregnancy into five classes: Class A is the safest class because animal studies and clinical observations have not shown any harm to the fetus; Class B is the safest class because animal studies have shown harm to the fetus but clinical studies have failed to confirm it; or Class C is the safest class because animal studies have confirmed teratogenic or embryocidal effects on the fetus but there is no clinical data to verify it. Class D is a class with certain clinical data indicating harm to the fetus but with certain efficacy, which can be considered but should be applied with caution if the pregnant woman has a serious disease or is threatened with death and there is no alternative drug.
When a pregnant woman has indications of clinically necessary medication, it is recommended to follow the following principles: it is better to choose A and B. Avoid using class C and D during early pregnancy; class X drugs are prohibited; if the condition is urgent and drugs that are sure to be harmful to the fetus are to be used, the pregnancy should be terminated; avoid combined medication if the single drug is effective; avoid using new drugs that are still difficult to determine whether they have adverse effects on the fetus if there are old drugs with sure efficacy; avoid using large doses if the small dose is effective Avoid using large doses if they are effective.
2. Pregnancy medication for common diseases in dermatology
(1) Allergic diseases
Among the commonly used antihistamines, the first generation of H1 receptor antagonists Cyproheptadine and chlorpheniramine are class B drugs and can be used during pregnancy. Diphenhydramine (Class B) was once considered the drug of choice for the treatment of pruritus during pregnancy. The incidence of cleft palate and urogenital malformations in infants may be increased with early pregnancy use of the drug has been reported and is prohibited in early pregnancy. Doxepin (FDA unclassified), which is thought to be associated with fetal intestinal obstruction, cardiac abnormalities, respiratory distress, muscle spasms, and seizures in infants, should be avoided, especially near delivery.
Cetirizine, a second-generation H1 receptor antagonist, is a class B drug, and small-sample prospective clinical studies have confirmed that there is no increased risk to the fetus with the use of cetirizine during pregnancy. It is recommended to avoid its use in early pregnancy and is not contraindicated in mid to late pregnancy (preterm abortion can occur in the last 2 weeks of pregnancy). No adverse effects have been observed in animal reproductive toxicity studies with levocetirizine (Class B); there is no clinical data on its use in pregnant women and its use is not recommended. The safety of loratadine (Grade B) for adverse reactions in pregnancy, including cleft palate, auricular hypoplasia, microphthalmia, deafness, malformations and diaphragmatic hernia, has not been established, although the relationship with the drug is not obvious, and its use is recommended only when very necessary. Fexofenadine (Class C), for which no safety trial data are available for use in pregnant women, should be avoided.
Cimetidine, an H2 receptor antagonist, is a class C drug and its use during pregnancy is controversial. It is an antiandrogenic agent and should be avoided during pregnancy to exclude the theoretical risk of feminization of the male fetus.
Systemic use of glucocorticoids is classified as Class C by the FDA. Studies have found that systemic hormone use can increase the incidence of labyrinthine palate, placental insufficiency, intrauterine growth arrest, and neonatal weight loss. Teratogenic effects in humans have not been demonstrated, but application in early pregnancy should still be avoided. If the condition requires it, short-term courses and oral administration can be used when the benefits outweigh the disadvantages. The effects of different types of hormones on the pregnant woman and the fetus vary. Prednisone, which does not easily pass through the placenta, is preferred during pregnancy. Short-term use of prednisone 40-80 mg/d has no increased risk of congenital malformations, and prednisone at 10 mg/d or lower is not contraindicated, but may be associated with low birth weight babies. There is no significant relationship between topical glucocorticoids and fetal risk during pregnancy, and usually short-term topical glucocorticoids are not associated with congenital malformations. Due to the lack of clinical trials in pregnant women, the use of topical hormonal agents should be limited as much as possible for safety reasons, especially to avoid the use of large amounts of topical glucocorticoids during pregnancy.
(2) Acne.
Topical topical medications azelaic acid, metronidazole, erythromycin, and clindamycin are all class B drugs and can be selected for relatively safe use during pregnancy, as appropriate. Animal experiments with benzoyl peroxide (Class C) have shown that this drug has toxic side effects on the fetus (teratogenic or stillbirth), and controlled studies in pregnant women have not been conducted; the advantages and disadvantages to the fetus need to be fully weighed before using this drug. Retinoic acid (Class C) can cause congenital malformations in the fetus when used in early pregnancy and should be avoided. Adapalene (Class C), like other retinoic acids, is not recommended for use during pregnancy. Tazarotene (Class X) is teratogenic and is contraindicated in pregnant and lactating women and in women with recent childbearing desires. A serum or urine pregnancy test must be performed within 2 weeks prior to initiation of tazarotene gel treatment in women of childbearing potential and confirmed as a negative pregnancy test before starting treatment on day 2 or 3 of the next normal menstrual cycle. An effective method of contraception must be used before, during, and for a period of time after treatment has been discontinued.
Oral tetracyclines (Class D) are contraindicated during pregnancy. Animal studies have shown embryotoxic effects with tetracyclines in early pregnancy. Bone development in the fetus and young children can be inhibited in mid and late pregnancy. Tetracyclines can also cause liver damage and have toxic effects on the liver of both the pregnant woman and the fetus.
Erythromycin (class B) is not considered to cause fetal malformation and no adverse effects on the offspring have been found, but this drug can enter the fetal circulation through the placenta and it is advisable to weigh the pros and cons when applying it. In addition, oral administration of isotretinoin (grade X) can cause fetal malformation, so it should be used with caution in women of childbearing age.
(3) Bacterial infection
Penicillin, cephalosporins, erythromycin and azithromycin are clinically relatively safe for use during pregnancy (Class B). Penicillins and cephalosporins have minimal effect on the fetus and are safe for use in all stages of pregnancy, except for possible allergy in pregnant women. Clarithromycin (Class C) is associated with cardiovascular defects and embryotoxicity in animals at high doses and is recommended to be prohibited. Quinolones (Grade C) have been found to cause cartilage destruction in animal studies and are not recommended as first-line agents during pregnancy. Tetracycline (Class D) is dangerous for use in mid to late pregnancy and can affect fetal tooth staining and enamel hypoplasia. Sulforaphane (Class C) is associated with an increased risk of neonatal eosinophilic encephalopathy and G-6-PD deficiency hemolysis and is available in early pregnancy and contraindicated in late pregnancy. Erythromycin and neomycin can be used topically in pregnancy, and small doses of clindamycin and mupirocin, as well as bacitracin and polymyxin, are not harmful to the fetus. Topical sulfur is not contraindicated in pregnancy.
(4) Viral infections.
Acyclovir (class B) has no effect on embryos in animal studies, but toxic doses can cause stillbirths, growth retardation and malformations in mice. In an epidemiologic trial on the use of acyclovir in 749 pregnant women systematically administered acyclovir, no increased teratogenic risk was found. Its use in disseminated herpes simplex infection helped to reduce mortality, and there was no clear indication for recurrent HSV infection. Valacyclovir (class B) and famciclovir (class B) have not been found to be teratogenic in animal studies and should be used only when really necessary on balance.
Physical therapy for genital warts, such as cryotherapy, is relatively safe. Topical treatment of genital warts or perianal warts with imiquimod, which is FDA classification B, can cause weight loss in seals and delay bone development in mice at toxic doses, and there is a lack of adequate controlled studies in pregnant women.
(5) Fungal infections.
Terbinafine (Class B) has shown no adverse effects in fetal toxicity and fertility animal studies, either orally or topically, but has not been studied in controlled trials in pregnant women. During pregnancy, it should not be used if the benefits of taking the drug do not outweigh the risks.
Itraconazole (Class C) has shown fetotoxicity and teratogenicity in animal studies, and there is limited information on its use in pregnant women. It has the lowest risk of teratogenicity in humans compared to azole antifungals such as fluconazole and ketoconazole, but itraconazole should be avoided during pregnancy. Clinical malformations including skeletal, genitourinary tract, cardiovascular and ocular malformations as well as chromosomal abnormalities and multisite malformations have been reported, but the relevance of these cases to the drug has not been established.
Fluconazole (Class C) has been associated with miscarriage, increased stillbirths, rib malformations, and cleft palate at high doses in animal studies, and controlled studies have not been performed in pregnant women. Ketoconazole (Grade C) has been associated with teratogenicity in humans and animals and is avoided, especially in early pregnancy. Ashwagandha (Grade C) has been reported to cause skeletal and cardiac malformations in infants when given during pregnancy and is avoided.
Topical treatment of antifungal infections during pregnancy is currently considered relatively safe. Miconazole, clotrimazole and myclobutanil can be used topically in the vagina during pregnancy.