Autoimmune blistering disease (AIBD) in pregnancy raises several complex management issues associated with underlying pathogenesis and treatment options. This article considers the effects of the disease as well as its treatment for both mother and fetus. All AIBDs can occur in pregnancy but are relatively rare. Pemphigoid gestationis is a rare AIBD that is specific to pregnancy. The article considers each AIBD in turn and then looks at treatment options for the group as a whole, as there are many issues common to all.
Autoimmune blistering disease (AIBD) in pregnancy raises several complex management issues associated with underlying pathogenesis and treatment options. This article considers the effects of the disease as well as treatment for both mother and fetus.
All AIBDs can occur in pregnancy but are relatively rare. There are two distinct clinical situations. The first is a patient with known AIBD who is considering pregnancy or who becomes pregnant. Second is a pregnant woman presenting with a blistering disease that requires diagnosis and management. Pemphigoid gestationis (PG) (formerly called herpes gestationis) is a rare AIBD that is specific to pregnancy.
The authors consider each AIBD in turn and then look at treatment options for the group as a whole, as there are many issues common to all. For each disease the effect of the illness on the pregnant woman is considered as well as the treatments, and the possible effect on the fetus and neonate of maternal illness, maternal antibodies, and maternal treatment.
Autoimmunity and immunology in pregnancy
Tendency to autoimmunity even in the absence of clinically manifest autoimmune disease can affect every aspect of pregnancy beginning with fertilization, and can contribute to maternal complications and adverse fetal outcomes. For this reason, pregnancy in women with preexisting autoimmune conditions, including AIBD, are classified as high risk. However, advances in monitoring and treatment mean that risks can now be managed more effectively, particularly if pregnancy is planned during periods of inactive or stable disease.
Pregnancy is a specific immune state: the mother must maintain tolerance of the fetus while not suppressing her own immune system and exposing herself, and the fetus, to infection. Dramatic hormonal changes occur in pregnancy both in the levels of estrogens and progesterone but also in cortisol, norepinephrine, and dehydroepiandrosterone. At the same time, and partially under the influence of these hormones, profound immunologic changes occur throughout pregnancy and during the postpartum period. These changes are required to accommodate the semi-allogeneic fetus and include immunosuppressive and immune-regulatory processes. Whereas a Th1-dominated milieu is required initially for successful implantation, later gestation requires a predominantly Th2-type pattern of cytokines. This situation appears to maintain transient tolerance to paternal antigens in pregnancy. In addition, it seems likely that the generation of specific regulatory T (Treg) cells may play an important role. Treg cells are seen to accumulate in the decidua and are likely to be present in maternal circulation. Tregs are thought to be capable of regulating coincidental autoimmune responses through the phenomenon of linked suppression. In turn, this suppression may explain why autoantibody levels decline during pregnancy for certain diseases, leading to remission of autoimmune conditions in pregnancy followed by postpartum flares (eg, Graves disease and rheumatoid arthritis). Preexisting AIBD such as pemphigus vulgaris (PV) and linear IgA have been reported to improve during pregnancy, but may flare postpartum. However, not all autoimmune conditions are seen to improve. There are reports of disease flares in most autoimmune disease, and diseases such as systemic lupus erythematosus often worsen, implying that this is a complex process.
Maternal autoimmune antibodies cross the placenta and can cause fetal disease both in utero and neonatally.
Bullous Pemphigoid
Bullous pemphigoid is almost never seen in pregnancy, as it affects an older population of people beyond child-bearing age. The rare reports that do exist show the possibility of both flaring and improving in pregnancy.
Pemphigus Vulgaris
PV may improve in pregnancy but often not until the third trimester. A recent review of publications involving 49 pregnant women with PV found that 37% presented with the disease for the first time during pregnancy.
Severe pemphigus in pregnancy may be associated with fetal prematurity and death, but it is difficult to separate the effects of treatment from those of the disease. A recent review found that adverse pregnancy outcomes (ie, neonatal pemphigus and perinatal death) occurred in up to 10% of pregnancies. Adverse outcomes do seem to be correlated more closely with poor maternal disease control, higher maternal serum, and umbilical cord blood antibody titers than with particular medications used to treat maternal PV. Therefore, treatment to cause a decrease in maternal serum autoantibody levels to limit transplacental passage of pathogenic IgG antibodies makes therapeutic sense. However, the effectiveness of such an approach during pregnancy has not been clearly established. It should be remembered that before the advent of systemic steroids PV could cause death, and therefore treatment for some patients will be both necessary and life saving. Additional immunosuppression or plasmapheresis can be used as an adjunct to prednisolone in severe disease.
In general, the baby is healthy and although neonatal PV does occur relatively frequently, this tends to be transient disease that is normally mild and treatable topically. Differing expression of desmoglein in neonatal skin accounts for the differing clinical manifestations between mother and child.
Pemphigus Foliaceus
Pemphigus foliaceus has a variable course in pregnancy. There tends to be no effect on the fetus, and neonatal pemphigus is only seen extremely rarely in the context of exceptionally high antibody titers. Desmoglein 3 is expressed throughout the epidermis including the subcorneal layers in neonatal skin, and may be protective against anti–desmoglein-1 antibodies causing disease.
Linear IgA
Linear IgA is seen to improve in pregnancy and commonly remits in the second trimester. For this reason patients may be able to stop dapsone during pregnancy. There is evidence that IgA antibodies become glycosylated during pregnancy, which may explain this remission. There may also be a role for Tregs. However, patients should be counseled about the possibility of a relapse postpartum. Disease may also recur years later even after a prolonged period of remission.
Pemphigoid Gestationis
PG is an autoimmune subepidermal bullous dermatosis uniquely associated with pregnancy. It is an extremely rare condition with an incidence estimated at 1 in 500,000 pregnancies. However, a recent review found it was the second most common AIBD diagnosed overall (PG was 9.75% with bullous pemphigoid the most common at 66% ), and in a review of pregnant women presenting to dermatology clinics it represented 4.2% of all pregnancy referrals.
PG results from a mismatch between maternal and fetus HLA with paternal antigens, inducing production of antiplacental antibodies that cross-react with the same proteins in skin. The main antigen of PG is BP180 (collagen XVII), present in both skin and placenta, exposed to the maternal immune system through an abnormal expression of major histocompatibility complex class II molecules in the placenta.
Onset of PG is typically late (second to third trimester) but can occur at any point including postpartum. Typical lesions are urticated plaques plus or minus blisters and are initially located around the periumbilicus. Itch can be severe and is the primary symptom. Differentiating from polymorphic eruption of pregnancy (PEP) can be difficult clinically prior to biopsy. However, PEP typically involves striae whereas PG does not. PG can be associated with other autoimmune disease such as Graves disease and vitiligo.
Early onset in pregnancy and presence of blisters does seem to be associated with a worse prognosis, indicating a likely need for more aggressive management. Autoantibody titer has not been shown to correlate with worse disease PG usually resolves within weeks to months after delivery but can recur with subsequent pregnancies (unlike PEP). Recurrence in future pregnancies often occurs earlier (as early as 5 weeks) but may be milder. PG may persist beyond pregnancy, albeit rarely.
PG is associated with fetal morbidity. Several studies have shown an increased risk of preterm birth, small for gestational age, and low birth weight. However, there is no reported increased fetal loss. Appropriate treatment may decrease this morbidity. BP180 antibodies show transient neonatal disease, which occurs in 2% to 3% of neonates but typically lasts less than 3 weeks, resolving rapidly and causing no permanent harm to the child.
Oral corticosteroids are the therapeutic mainstay both in pregnancy and postpartum, but several other modalities may be tried in recalcitrant disease. Antihistamines can be used for pruritus. No significant associations of adverse pregnancy outcomes with systemic corticosteroid treatment were found in a cohort of 61 women presenting to 3 different tertiary centers.
Investigations in AIBD in pregnancy
In a patient with known AIBD there may be no need for diagnostic investigation in pregnancy. However, if a pregnant woman presents with a blistering disorder then investigations must be performed to determine diagnosis, just as they would be in a nonpregnant individual. Diagnosis can be made, as in other AIBDs, by skin biopsy and direct and indirect immunofluorescence.
When undertaking a skin biopsy, chlorhexidine can safely be used for disinfection. There is no teratogenic effect described with the use of local anesthetics. However, there is a theoretic risk of prilocaine fetal methemoglobinemia or that adrenaline may reduce uterine blood flow. It is therefore prudent to consider the need for any intervention in pregnancy, including skin biopsy.
Investigations in AIBD in pregnancy
In a patient with known AIBD there may be no need for diagnostic investigation in pregnancy. However, if a pregnant woman presents with a blistering disorder then investigations must be performed to determine diagnosis, just as they would be in a nonpregnant individual. Diagnosis can be made, as in other AIBDs, by skin biopsy and direct and indirect immunofluorescence.
When undertaking a skin biopsy, chlorhexidine can safely be used for disinfection. There is no teratogenic effect described with the use of local anesthetics. However, there is a theoretic risk of prilocaine fetal methemoglobinemia or that adrenaline may reduce uterine blood flow. It is therefore prudent to consider the need for any intervention in pregnancy, including skin biopsy.
Treatment of AIBD in pregnancy
Treatment should be considered for all AIBDs in pregnancy. This strategy is challenging in that all of these diseases are rare and it is difficult to conduct controlled studies. There is limited experience of many drugs in pregnancy, and pregnant women are often excluded from trials. In addition, serious outcomes in pregnancy are rare events and reliable data do not exist. Therefore, most of the treatment options are based on case reports and clinical experience. However, experience of treatments in other diseases gives useful information. As a general rule great care must be taken prescribing in pregnancy, and use of any medication is not recommended unless the potential benefits justify the potential risks to the fetus.
Antihistamines
First-generation H 1 blockers are not associated with an increased risk of major malformations or any other adverse fetal effects. There is a large body of epidemiologic data supporting safety in pregnancy, with a meta-analysis involving more than 200,000 participants concluding that there was no increase in any type of congenital malformation. Although there is less evidence on second-generation H 1 blockers, there is no established link to adverse pregnancy outcomes. In addition, none of the antihistamines is excreted in the breast milk in any appreciable amount so as to have any adverse effects on breastfeeding.
Dapsone
Dapsone can be used for its anti-inflammatory effect. It has been used successfully either alone or as an adjunct to corticosteroids in PV and PG. Dapsone has been used widely in the treatment of leprosy and malaria. In this setting there are no reported links to adverse maternal fetal outcomes, and there are no reports of problems if conception occurs while on dapsone. There are rare reports of neonatal hemolysis and neonatal jaundice, and these should be monitored.
Corticosteroids
Although topical corticosteroids are used regularly in pregnancy, a recent systematic review concluded that the evidence is insufficient. Current evidence shows no statistically significant elevated risk of congenital abnormality, preterm delivery, or stillbirth. However, there does appear to be an association between very potent topical corticosteroids and low birth weight.
Systemic corticosteroids are widely used and are effective treatments. Dosage should be tailored to disease control, but a starting dose of 30 to 40 mg is usual for PG. Side effects in pregnant women include all those found in nonpregnant subjects. Increased blood pressure, osteopenia, osteonecrosis, and susceptibility to infection are of particular relevance in pregnancy. Pregnancy induces insulin resistance at later stages, and the resulting glucose intolerance is further enhanced by exogenous glucocorticoids, with an increased risk of gestational diabetes.
Systemic steroids have been reported to cause cleft palate in animal studies, but this is not a consistent finding in human experience. On the whole, corticosteroids do not seem to increase the risk of congenital abnormalities in humans. Growth retardation is controversial but has been reported in association with treatment of AIBD. The possible induction of hypertension in adult life by antenatal exposure to corticosteroids has not been proved in humans. Other rare adverse events reported for antenatal exposure to corticosteroids are neonatal cataract and adrenal suppression in children born to women taking high doses of steroids during pregnancy.
There are important differences between classes of steroids. Prednisone and prednisolone are 90% inactivated by the placenta, whereas glucocorticoids with fluorine at the 9α position, such as betamethasone and dexamethasone, are far less inactivated and, therefore, the least dose possible should be used for as short a time as possible for these drugs.
A single course of fluorinated corticosteroids (betamethasone or dexamethasone) given to pregnant women at risk for preterm delivery clearly reduced the risk of death, respiratory distress syndrome, and cerebral hemorrhage in preterm infants. However, evidence has accumulated on the potential harm of repeated courses of fluorinated steroids for the mother and fetus, and these should therefore not be used for disease control.
Other Immunosuppression
Cyclosporine A is an alternative immunosuppressant that seems to be safe in pregnancy. Although not used routinely in pregnancy, it may be preferable to other steroid-sparing medications. Cyclosporine A has been used to treat PG and other pregnancy dermatoses. It is known to cross the placenta in high quantities, but is rapidly cleared from the newborn and has not been shown to teratogenic, mutagenic, or myelotoxic in animal models except in very high doses. The data on the safety during pregnancy in humans are primarily derived from transplant recipients. These studies include large series and meta-analyses with cyclosporine in addition to other immunosuppressive agents. Cyclosporine did not appear to increase the rate of malformation frequency, prematurity, or low birth weight.
Azathioprine has been shown to have various teratogenic effects at high doses but not at therapeutic doses in animal studies. Available data for larger numbers of patients treated with inflammatory bowel disease suggest that mercaptopurine and the prodrug azathioprine are safe and well tolerated during pregnancy. Azathioprine has been successfully used in PV and PG in addition to prednisolone.
Mycophenolate mofetil (MMF) and tacrolimus have been shown to be teratogenic in animal studies. There is limited experience of use in pregnant humans, but current advice would be to avoid both topical and systemic tacrolimus and MMF during pregnancy.
Systemic Antibiotics
Antibiotics can be used for an anti-inflammatory effect. Erythromycin and other macrolide antibiotics are considered safe. However, tetracyclines, which are commonly used for combination treatment of AIBD, are contraindicated in pregnancy. Animal studies have revealed evidence of teratogenicity, including toxic effects on skeletal formation. There are no controlled data regarding human pregnancy. However, congenital defects and maternal hepatotoxicity have been reported. When used during tooth development (second half of pregnancy), tetracyclines cause permanent yellow-gray-brown discoloration of the teeth and enamel hypoplasia.
Related posts:
Autoimmune Blistering Diseases Part II—Diagnosis and Management
Rituximab and its Use in Autoimmune Bullous Disorders
Pemphigoid Gestationis: Current Management
Management of Linear IgA Disease
Management of Autoimmune Bullous Diseases in France: A Nationwide Network of 30 Centers
Treatment of Chronic Bullous Disease of Childhood
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