Cltntcal and Experimental Dermatology 1990; 15: 134-136.
Pemphigoid gestationis and neonatal alloimmune thromboeytopenia B.ADRIAANS, H.PULLON,* A.DU VIVIER AND R.MIBASHAN* Departments of Dermatology and *Haematology, Kings College Hospital, Denmark Hill, London SE5 9RS. UK Accepted for publication 12 September 1989
Summary A patient whose second, third and fourth pregnancies were complicated by alloimmune thromboeytopenia, developed pemphigoid gestationis after the fourth pregnancy. The infant was delivered by Caesarean section at 34 weeks gestation. The pemphigoid gestationis resolved promptly after a short course of systemic corticosteroids. A possible association between these two uncommon conditions is discussed. Case report The patient's obstetric history is as follows; her first pregnancy was unplanned at the age of 17 years and she decided to have the pregnancy terminated. Her second pregnancy was unexpectedly complicated by severe alloimmune thromboeytopenia (AIT). Maternal antibodies to the platelet antigen Pl^i were demonstrated. These resulted in severe neonatal thromboeytopenia. The child developed a left-sided hemiparesis soon after delivery and development was delayed secondary to an intracranial haemorrhage. The patient became pregnant for the third time aged 23. During the third pregnancy cordocentesis performed at 26 weeks showed severe foetal thromboeytopenia (platelets 32xlO''/l). Weekly intrauterine platelet infusions were given to the foetus and the mother received a short course of intravenous IgG immunoglobulin (0-4 g/kg/day for 5 days). Unfortunately, the patient accidentally fell and the pregnancy ended in a stillbirth at 30 weeks gestation. Necropsy did not show any evidence of internal haemorrhage. In 1987, at age 25, the patient commenced her fourth pregnancy. At 29 weeks gestation, foetal blood samplings revealed severe thromboeytopenia (platelets 17xlO''/l). Weekly intra-uterine platelet transfusions were commenced using Pl\|-negative platelet concentrates and good increments in foetal platelet count were obtained.' After the sixth platelet transfusion at 34 weeks gestation, a (lorrespontlence: Dr B.Adriaans, Department of Dermatology, C^ollcgc Hospital, Denmark Hill. London .SK5 *)RS. UK.
134
21-kg female infant was delivered by Caesarean section. The baby was neurologically normal but moderately thrombocytopenic in the neonatal period. The thromboeytopenia resolved following a partial whole-blood exchange transfusion and administration of further PI\| negative platelet concentrate. All the pregnancies were from the same consort. Five days post-partum the mother developed intense pruritus over the lower part of her abdomen. A week later she developed a widespread eruption over the arms, upper trunk, lower abdomen and upper thighs (Fig. 1). Over the arms and upper trunk the eruption consisted of several erythematous papules and plaques as well as vesicles on an erythematous base. Over the lower abdomen there were confluent plaques of erythema, but no vesiculation whereas the eruption over the thighs consisted of symmetrieal areas of erythema and oedema with some intact and some ruptured blisters. Secondary impetiginization caused crust formation. The mucosal surfaces and nails were spared. Investigations Mother: normal full blood count values were present throughout the fourth pregnancy. Maternal platelet typing was as follows: homozygous PlAi-negative; HLA typing HLA-Al, A3, B7, B8, Bw6, DR3, DR4, DRw52. Paternal platelet type homozygous P1M/P1M. Maternal skin histology: the epidermis showed marked spongiosis with spongiotic vesicles. The oedematous papillary dermis stretched the rete ridges. The dermis contained a heavy inflammatory infiltrate which consisted of lymphocytes and eosinophils. There was no vasculitis. There were extravasated red blood cells in the papillary dermis and large subepidermal bullae which contained many eosinophils (Fig. 2). Direct immunofluorescence showed a strong linear band of C3 at the dermo-epidermal junction. Indirect immunofluorescence of maternal serum and human skin as substrate was positive to a titre of 1:160 for circulating IgG directed at the basement membrane zone.
PEMPHIGOID GESTATIONIS AND NEONATAL AIT
Figure I. Bullous eruption (if pemphigoid gesiationis.
Figure 2. Hl.^iopaIlll^lllg\ DJ pcniphigoid ^csuiiiiju^ (11 \ l.'-.S.i) showitig spongiosis, dermal oedema and an inflammatory infiltrate in tbe dermis.
Discussion Alloimmune thromboeytopenia is an uncommon disorder which complicates 1-2/10000 live births.^ AIT is caused by foetomaternal incompatibility for platelet-specific
135
antigens, most commonly PI.M (ZW"')^-^. The foetus inherits the antigen PI.M from the father as the mother is PlAi-negative. The antigen is present in 98"(, of the general population\ Homozygous PlAi-negative mothers may thus be sensitized by the PlAi-positive foetal platelets. The mother produces antibodies, usually IgG immunoglobulins, which are directed against the foetal platelets and ultimately damage the infant's platelets.' Unfortunately, the maternal platelet antibody titre does not predict how severely the infant is affected, as severely affected infants have been born to mothers with low antibody titres.' The diagnosis of AIT is usually only made after the birth of the first affected infant as antenatal screening does not include platelet typing of the mother. Subsequent pregnancies are usually similarly or more severely affected'' as occurred in this patient. The most serious complication of AIT is intracranial haemorrhage which may cause death or neurological sequelae in up to 25% of cases.^ Recently, attention has been given to minimizing foetal thromboeytopenia and its complications. This may be achieved with weekly administration of high-dose intravenous IgG to the mother^ or repeated in-utero platelet transfusions'' as used here. In addition, birth trauma might be minimized by delivering the foetus by Caesarean section.'" Maternal sensitization to platelet antigens and the subsequent development of alloimmune thromboeytopenia has been associated with HLA B8 and DR3."'^ Our patient carried both these antigens. After delivery our patient developed pemphigoid gestationis. The histological and immunotluorescence findings confirmed the clinical diagnosis. Pemphigoid gestationis is a rare vesicobullous disease which is characterized by the onset of extreme pruritus followed by a bullous or an urticarial eruption w ith vesicles around the edge of the erythema. Bullae may develop on clinically uninvolved skin,'' are often tense and filled with clear fluid. The disease usually starts in the second or third trimester but in about 25*^!,, of cases the disease may start post-partum. Once the disease occurs, it recurs with subsequent pregnancies and may appear earlier and be more severe in subsequent pregnancies.'^ The incidence of foetal complications from pemphigoid gestationis is not known. Some authors report no increase in the incidence of stillbirth or spontaneous abortion'"* yet others suggest an increased incidence.'''"* Holmes and Black'^ reported an increased incidence of 'small for dates' babies in patients with pemphigoid gestationis and suggested that treatment with systemic steroids during the pregnancy may adversely affect the size of the foetus. Our patient's infant weighed 2-1 kg, which is at the 10th centile for the gestational age. The birth weight was unrelated to steroid administration as our patient only received the steroids post-partum. About
136
B.ADRIAANS^/
I0"o of infants show cutaneous manifestations of pemphigoid gestationis. Our patient's haby showed no such lesions, but purpura related to thromboeytopenia was visible. There is a strong association between HLA-DR3 and the development of pemphigoid gestationis'' and 4345^0 patients with pemphigoid gestationis carry both the HLA-DR3, -DR4 markers whereas only 3% women share this antigen combination.'' Both -DR3 and -DR4 antigens have been associated with an increased incidence of other autoimmune diseases." Our patient also carried HLA-BS, another antigen associated with autoimmune diseases. Our patient with a combination of-DR3, -DR4, -US may thus have been likely to develop pemphigoid gestationis on the basis of a strong genetic predisposition. We conclude that pemphigoid gestationis and alloimmune thromboeytopenia are both diseases associated with specific HLA antigens. To date, these two conditions have not been described in the same person. Although our patient carried the antigens associated with both conditions, it is unusual that she developed both conditions. She is at risk of a recurrence of pemphigoid gestationis at an earlier stage of any subsequent pregnancy and of course any subsequent foetus is likely to be affected by alloimmune thromboeytopenia. Management in such a pregnancy would be difficult. References 1. Murphy MF, Pullon HWH et al. Management of foetal alloimmune thrcmbocytopenia by weekly in utero platelet transfusions. Vox Sangutnis 1989; {in press). 2. .Meulier-Fxkbardt C, Grubert A, Weisbeit M et al. 348 Cases of suspected neonatal alloimmune thromboeytopenia. Lancet 1989; i: 363-366. 3. Shulman NR, Marder VJ, Hillar iMC, Collier EM. Platelet and leucocyte isoantigens and tbeir antibodies. Serologic, physiologic and clinical .studies. Progress in Haematology !y()4; 4: 222-.'?04.
4. Von dem Borne AEG, Van Leeuwen Y.Y, Von Riez LK et al. Neonatal alloimmune tbromboeytopcnia: detection and ebaracterization of tbe responsible antibodies by the platelet immunofluorescence tesi. Blood 1981; 57: 649-656. 5. Oski N. Neonatal isoimmune disorders. In: Jobn Dyson, ed. Haematology of Infancy and Childhood. 3rd edition. Pbiladelphia: W.B. Saunders, 1987: 111. ii. Re/nikoR-Lticvant MF. Management of alloimmune neonatal and antenatal tbrombocytopenia. Vox Sanguinis 1988; 5: 193-201. 7. De Vries LS, Clonnell J, Bydder GM el al. Reeurrent intracranial haemorrhages in utero in an infant witb alloimmune thromboeytopenia. British Journal of Ohstetrus and Cynaecology 1988; 95: 299-302. 8. Bu.s.sel JP, Berkowitz, RL. McKarland JG et al. Antenatal treatment of neonatal atloimmunc thromboeytopenia. New England Journal of Medinne 1988; 319: 1374-1378. 9. Nicolini U, Rodeck CH, Koebenour NK et al. In-utero platelet transfusion for alloimmune thromboeytopenia. Lancet 1988; ii: 506. 10. DafTos F, Forestier F, Kaplan C, Cox W. Prenatal diagnosis and management of bleeding disorders witb fetal blood sampling. American Journal of Ohsietrics and Gynecology 1988; 158:939 946. 11. ReznikofF-l'.tievant MI', Dongb C, Lobet R. HLA-B8 antigens and anti PUi alloimmuni/ation. Tissue Antigens 1981; 18: 66-68. 12. Mueller-I'ckbardt C, .Mueller-KcLbardt G,'\Villen-Obft II
Pemphigoid gestationis and neonatal alloimmune thromboeytopenia B.ADRIAANS, H.PULLON,* A.DU VIVIER AND R.MIBASHAN* Departments of Dermatology and *Haematology, Kings College Hospital, Denmark Hill, London SE5 9RS. UK Accepted for publication 12 September 1989
Summary A patient whose second, third and fourth pregnancies were complicated by alloimmune thromboeytopenia, developed pemphigoid gestationis after the fourth pregnancy. The infant was delivered by Caesarean section at 34 weeks gestation. The pemphigoid gestationis resolved promptly after a short course of systemic corticosteroids. A possible association between these two uncommon conditions is discussed. Case report The patient's obstetric history is as follows; her first pregnancy was unplanned at the age of 17 years and she decided to have the pregnancy terminated. Her second pregnancy was unexpectedly complicated by severe alloimmune thromboeytopenia (AIT). Maternal antibodies to the platelet antigen Pl^i were demonstrated. These resulted in severe neonatal thromboeytopenia. The child developed a left-sided hemiparesis soon after delivery and development was delayed secondary to an intracranial haemorrhage. The patient became pregnant for the third time aged 23. During the third pregnancy cordocentesis performed at 26 weeks showed severe foetal thromboeytopenia (platelets 32xlO''/l). Weekly intrauterine platelet infusions were given to the foetus and the mother received a short course of intravenous IgG immunoglobulin (0-4 g/kg/day for 5 days). Unfortunately, the patient accidentally fell and the pregnancy ended in a stillbirth at 30 weeks gestation. Necropsy did not show any evidence of internal haemorrhage. In 1987, at age 25, the patient commenced her fourth pregnancy. At 29 weeks gestation, foetal blood samplings revealed severe thromboeytopenia (platelets 17xlO''/l). Weekly intra-uterine platelet transfusions were commenced using Pl\|-negative platelet concentrates and good increments in foetal platelet count were obtained.' After the sixth platelet transfusion at 34 weeks gestation, a (lorrespontlence: Dr B.Adriaans, Department of Dermatology, C^ollcgc Hospital, Denmark Hill. London .SK5 *)RS. UK.
134
21-kg female infant was delivered by Caesarean section. The baby was neurologically normal but moderately thrombocytopenic in the neonatal period. The thromboeytopenia resolved following a partial whole-blood exchange transfusion and administration of further PI\| negative platelet concentrate. All the pregnancies were from the same consort. Five days post-partum the mother developed intense pruritus over the lower part of her abdomen. A week later she developed a widespread eruption over the arms, upper trunk, lower abdomen and upper thighs (Fig. 1). Over the arms and upper trunk the eruption consisted of several erythematous papules and plaques as well as vesicles on an erythematous base. Over the lower abdomen there were confluent plaques of erythema, but no vesiculation whereas the eruption over the thighs consisted of symmetrieal areas of erythema and oedema with some intact and some ruptured blisters. Secondary impetiginization caused crust formation. The mucosal surfaces and nails were spared. Investigations Mother: normal full blood count values were present throughout the fourth pregnancy. Maternal platelet typing was as follows: homozygous PlAi-negative; HLA typing HLA-Al, A3, B7, B8, Bw6, DR3, DR4, DRw52. Paternal platelet type homozygous P1M/P1M. Maternal skin histology: the epidermis showed marked spongiosis with spongiotic vesicles. The oedematous papillary dermis stretched the rete ridges. The dermis contained a heavy inflammatory infiltrate which consisted of lymphocytes and eosinophils. There was no vasculitis. There were extravasated red blood cells in the papillary dermis and large subepidermal bullae which contained many eosinophils (Fig. 2). Direct immunofluorescence showed a strong linear band of C3 at the dermo-epidermal junction. Indirect immunofluorescence of maternal serum and human skin as substrate was positive to a titre of 1:160 for circulating IgG directed at the basement membrane zone.
PEMPHIGOID GESTATIONIS AND NEONATAL AIT
Figure I. Bullous eruption (if pemphigoid gesiationis.
Figure 2. Hl.^iopaIlll^lllg\ DJ pcniphigoid ^csuiiiiju^ (11 \ l.'-.S.i) showitig spongiosis, dermal oedema and an inflammatory infiltrate in tbe dermis.
Discussion Alloimmune thromboeytopenia is an uncommon disorder which complicates 1-2/10000 live births.^ AIT is caused by foetomaternal incompatibility for platelet-specific
135
antigens, most commonly PI.M (ZW"')^-^. The foetus inherits the antigen PI.M from the father as the mother is PlAi-negative. The antigen is present in 98"(, of the general population\ Homozygous PlAi-negative mothers may thus be sensitized by the PlAi-positive foetal platelets. The mother produces antibodies, usually IgG immunoglobulins, which are directed against the foetal platelets and ultimately damage the infant's platelets.' Unfortunately, the maternal platelet antibody titre does not predict how severely the infant is affected, as severely affected infants have been born to mothers with low antibody titres.' The diagnosis of AIT is usually only made after the birth of the first affected infant as antenatal screening does not include platelet typing of the mother. Subsequent pregnancies are usually similarly or more severely affected'' as occurred in this patient. The most serious complication of AIT is intracranial haemorrhage which may cause death or neurological sequelae in up to 25% of cases.^ Recently, attention has been given to minimizing foetal thromboeytopenia and its complications. This may be achieved with weekly administration of high-dose intravenous IgG to the mother^ or repeated in-utero platelet transfusions'' as used here. In addition, birth trauma might be minimized by delivering the foetus by Caesarean section.'" Maternal sensitization to platelet antigens and the subsequent development of alloimmune thromboeytopenia has been associated with HLA B8 and DR3."'^ Our patient carried both these antigens. After delivery our patient developed pemphigoid gestationis. The histological and immunotluorescence findings confirmed the clinical diagnosis. Pemphigoid gestationis is a rare vesicobullous disease which is characterized by the onset of extreme pruritus followed by a bullous or an urticarial eruption w ith vesicles around the edge of the erythema. Bullae may develop on clinically uninvolved skin,'' are often tense and filled with clear fluid. The disease usually starts in the second or third trimester but in about 25*^!,, of cases the disease may start post-partum. Once the disease occurs, it recurs with subsequent pregnancies and may appear earlier and be more severe in subsequent pregnancies.'^ The incidence of foetal complications from pemphigoid gestationis is not known. Some authors report no increase in the incidence of stillbirth or spontaneous abortion'"* yet others suggest an increased incidence.'''"* Holmes and Black'^ reported an increased incidence of 'small for dates' babies in patients with pemphigoid gestationis and suggested that treatment with systemic steroids during the pregnancy may adversely affect the size of the foetus. Our patient's infant weighed 2-1 kg, which is at the 10th centile for the gestational age. The birth weight was unrelated to steroid administration as our patient only received the steroids post-partum. About
136
B.ADRIAANS^/
I0"o of infants show cutaneous manifestations of pemphigoid gestationis. Our patient's haby showed no such lesions, but purpura related to thromboeytopenia was visible. There is a strong association between HLA-DR3 and the development of pemphigoid gestationis'' and 4345^0 patients with pemphigoid gestationis carry both the HLA-DR3, -DR4 markers whereas only 3% women share this antigen combination.'' Both -DR3 and -DR4 antigens have been associated with an increased incidence of other autoimmune diseases." Our patient also carried HLA-BS, another antigen associated with autoimmune diseases. Our patient with a combination of-DR3, -DR4, -US may thus have been likely to develop pemphigoid gestationis on the basis of a strong genetic predisposition. We conclude that pemphigoid gestationis and alloimmune thromboeytopenia are both diseases associated with specific HLA antigens. To date, these two conditions have not been described in the same person. Although our patient carried the antigens associated with both conditions, it is unusual that she developed both conditions. She is at risk of a recurrence of pemphigoid gestationis at an earlier stage of any subsequent pregnancy and of course any subsequent foetus is likely to be affected by alloimmune thromboeytopenia. Management in such a pregnancy would be difficult. References 1. Murphy MF, Pullon HWH et al. Management of foetal alloimmune thrcmbocytopenia by weekly in utero platelet transfusions. Vox Sangutnis 1989; {in press). 2. .Meulier-Fxkbardt C, Grubert A, Weisbeit M et al. 348 Cases of suspected neonatal alloimmune thromboeytopenia. Lancet 1989; i: 363-366. 3. Shulman NR, Marder VJ, Hillar iMC, Collier EM. Platelet and leucocyte isoantigens and tbeir antibodies. Serologic, physiologic and clinical .studies. Progress in Haematology !y()4; 4: 222-.'?04.
4. Von dem Borne AEG, Van Leeuwen Y.Y, Von Riez LK et al. Neonatal alloimmune tbromboeytopcnia: detection and ebaracterization of tbe responsible antibodies by the platelet immunofluorescence tesi. Blood 1981; 57: 649-656. 5. Oski N. Neonatal isoimmune disorders. In: Jobn Dyson, ed. Haematology of Infancy and Childhood. 3rd edition. Pbiladelphia: W.B. Saunders, 1987: 111. ii. Re/nikoR-Lticvant MF. Management of alloimmune neonatal and antenatal tbrombocytopenia. Vox Sanguinis 1988; 5: 193-201. 7. De Vries LS, Clonnell J, Bydder GM el al. Reeurrent intracranial haemorrhages in utero in an infant witb alloimmune thromboeytopenia. British Journal of Ohstetrus and Cynaecology 1988; 95: 299-302. 8. Bu.s.sel JP, Berkowitz, RL. McKarland JG et al. Antenatal treatment of neonatal atloimmunc thromboeytopenia. New England Journal of Medinne 1988; 319: 1374-1378. 9. Nicolini U, Rodeck CH, Koebenour NK et al. In-utero platelet transfusion for alloimmune thromboeytopenia. Lancet 1988; ii: 506. 10. DafTos F, Forestier F, Kaplan C, Cox W. Prenatal diagnosis and management of bleeding disorders witb fetal blood sampling. American Journal of Ohsietrics and Gynecology 1988; 158:939 946. 11. ReznikofF-l'.tievant MI', Dongb C, Lobet R. HLA-B8 antigens and anti PUi alloimmuni/ation. Tissue Antigens 1981; 18: 66-68. 12. Mueller-I'ckbardt C, .Mueller-KcLbardt G,'\Villen-Obft II
