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Rubella during pregnancy
Comments
o n C u r r e n t Literature
RUBELLA DURING PREGNANCY Since 1941, when G r e g g 1 first reported the relationship between Germ a n measles (rubella) in the p r e g n a n t w o m a n a n d the occurrence of congenital m a l f o r m a t i o n in her offspring, the physician has been faced with the v e r y practical p r o b l e m of management in the p a t i e n t who has had k n o w n exposure to rubella d u r i n g p r e g n a n c y , or who develops clinical manifestations of this disease e a r l y in p r e g n a n c y . The rubella s y n d r o m e in offspring of w o m e n who have experienced G e r m a n measles d u r i n g p r e g n a n c y is well established, and has been verified by a n u m b e r of careful clinical studies. On the basis of G r e g g ' s retrospective studies a n d those of some o t h e r observers, the incidence of m a l f o r m a t i o n seems ext r e m e l y high. F o r example, G r e g g reported an 80 to 90 per cent incidence of congenital m a l f o r m a t i o n where rubella c o m p l i c a t e d the first t r i m e s t e r of p r e g n a n c y ; a 21 to 78 per cent incidence following infection in the second t r i m e s t e r ; and f r o m zero to 20 per cent in the t h i r d trimester. G r e g g ' s studies were retrospective in type, o r i g i n a t i n g w i t h the d a m a g e d infant. In recent y e a r s prospective studies have been u n d e r t a k e n with the result t h a t these high incidence r a t e s have been altered significantly. Such prospective studies, w i t h subsequent e x a m i n a t i o n of the n e w b o r n infant, indicate t h a t m a t e r n a l rubella infection in the first t r i m e s t e r m a y be followed b y congenital m a l f o r m a t i o n in 10 to 12 p e r cent of the cases followed. A p p a r e n t l y , there is v e r y little risk of the rubella s y n d r o m e resulting if exposure to rubella or clinical
manifestations of the disease occur d u r i n g the second or the t h i r d trimester. G r e e n b e r g and his associates 2 have been i n t e r e s t e d for some time in the f r e q u e n c y of defects as e v a l u a t e d by the prospective t y p e of study. Recently, one g r o u p r e p o r t e d b y them comprised 104 cases of m a t e r n a l rubella occurring in the first three months of p r e g n a n c y ; of these 104 cases, there were 48 in which therapeutic abortion w a s considered advisable; in ten cases of the 104, it was not possible to follow the patient. In the r e m a i n i n g 46 cases, 28 of the m o t h e r s gave birth to normal i n f a n t s ; 12 mothers had s p o n t a n e o u s misc a r r i a g e ; three infants were stillborn; and three i n f a n t s developed congenital m a l f o r m a t i o n s : t h a t is, three of 31 liveborn infants, or a b o u t 10 per cent. A t the E i g h t h I n t e r n a t i o n a l Congress of P e d i a t r i c s in Copenhagen, in August, 1956, L u n d s t r 5 m 3 r e p o r t e d extensive survey studies of the prospective type. His findings are in accord with those f r o m other such studies, t h a t is, m a l f o r m a t i o n s occurring a f t e r rubella infection in the first t r i m e s t e r of p r e g n a n c y in f r o m 9 to 12 p e r cent. In a control g r o u p of p r e g n a n t women, c o m p a r a b l e numerically, who did not acquire rubella, the incidence of m a l f o r m a t i o n w a s only 1.6 per cent. On the basis of this u n u s u a l l y well-organized survey, risk of fetal d a m a g e f r o m rubella cont r a c t e d in the first t r i m e s t e r was estimated as a ratio of 6:1 as comp a r e d with t h a t in u n c o m p l i c a t e d pregnancy. 237
258
THE JOURNAL OF PEDIATRICS
In spite os this re-evaluation of the incidence of letal damage, which has been the result of the prospective type of study rather than the retrospective approach employed earlier, the problem remains and is invariably a difficult one for the clinician to handle, requiring thoughtful consideration in each individual case. In the May, ]958, issue of Neurology, an unusual case report appears which is pertinent in this connection. This report, from the National Institute of Neurologic Diseases and Blindness by Dekaban, O'Rourke, and Cornman, 4 describes in detail the case of an 8-year-old boy who was damaged severely as a result of rubella infection in the mother. This boy was the firstborn of a young mother who developed severe rubella at the end of the fourth week of gestation, and had to be confined to bed for one week. Description of the clinical course of the mother's rubella would indicate that this was an unusually severe disease. The infant was born with multiple defects, giving evidence of a " v e r y profound disturbance of embryonic development." Of the fifteen pathologic lesions generally recognized as the result of maternal rubella infection early in pregnancy, this child showed eleven characteristic clinical manifestations, including cataract, congenital heart, deafness, mental and physical retardation, etc. In reviewing the literature pertinent to this case, the authors were impressed by the "occurrence of more severe abnormalities during the earliest stages of pregnancy and the substantial decline of incidence of malformation after two to three months of gestation. ''4 It appeared worthwhile to them " t o analyze the frequency with which the abnormalities in various organs are encountered relevant to the different stages of gestation."4 Accordingly, these authors selected for analysis 108 cases from published reports of patients who developed rubella during pregnancy, and-whose history as to the stage of pregnancy when the
disease occurred was considered to be reliable. On analyzing these 108 cases in detail, it became apparent that the highest incidence of three major abnormalities, cataract, congenital heart disease, and deafness, occurred when rubella complicated the first four weeks of pregnancy. Fetuses exposed to maternal rubella between the fifth and tenth weeks of gestation still showed frequent occurrence of these malformations. From the tenth week on, there appeared to be a rapid decline in fetal susceptibility, so that the incidence reached a low level after fourteen weeks of gestation. No instances of congenital abnormality were encountered when exposure of the fetus to rubella occurred after 20 weeks of gestation. From these findings, which are presented graphically in an objective figure, emphasizing the importance of the time-exposure relationship, the authors concluded that the highest incidence of three of the most important congenital anomalies, cataract, deafness, and congenital heart disease, occurred when rubella complicated the pregnancy within the first five weeks of gestation. A re-evaluation of the rubella problem from the standpoint of prevention was attempted recently by Krugman and Ward, ~ whose interest in this subject has extended over a period of years. Equivocal results concerning the efficacy of gamma globulin in the prevention of rubella prompted these authors to study the levels of neutralizing antibody in ordinary gamma globulin, in convalescent rubella plasma, and in gamma globulin prepared from plasma of patients convalescent from rubella. In this unusually clear-cut study, a serum pool previously shown to contain active rubella virus was used as a basis for serum-virus neutralization tests in human subjects. Four groups of individuals, six in each group, were inoculated intramuscularly with appropriate mixtures of active virus and "serum: active virus from the
COMMENTS ON CURRENT LITERATURE
original rubella serum pool plus normal human serum free from rubella antibodies; active virus plus ordinary gamma globulin ; active virus mixed with convalescent-phase plasma; and a mixture of active virus with convalescent gamma globulin. In the group receiving active rubella virus plus normal human serum as inoeulum, five of the six individuals developed clinical rubella. Of the group who received rubella virus plus gamma globulin, one of the six developed clinical rubella; of the group receiving as inoculum a mixture of active virus and convalescent-phase serum, one of six developed rubella; and in the group receiving active virus plus rubella convalescent-phase gamma globulin, none of the six showed signs of clinical rubella. These results show clearly the presence of neutralizing antibody to the virus of rubella in ordinary gamma globulin, in convalescentphase plasma, and in convalescentphase gamma globulin, and under the conditions of this study, can be interpreted as indicating the relative efficacy of these preparations in the prevention of clinical manifestations of the disease. That the rubella antibody level to be found in ordinary gamma globulin varies widely from sample to sample has been well recognized for a number of years. In one of the epidemic studies made by Korns, ~ this range of variability was considerable: from no protection against German measles to a significant reduction in its occurrence in susceptible contacts. Thus, in attempting to answer the question of gamma-globulin prophylaxis on exposure, Krugman and W ar d ~ recommend that as soon after exposure as possible, all pregnant women in the first trimester who have no known history of rubella be given at least 20 ml. of gamma globulin intramuscularly. If rubella convalescent-phase gamma globulin is available, a dosage of ]0 ml. administered intramuscularly is considered adequate. Early
259
administration of gamma globulin in adequate amount is important, since rubella can occur without rash, and since damage to the fetus may be out of proportion to the clinical manifestations observed in the mother. The probable risk of injury to the developing infant would be less in a mother who receives immune substance early and in an adequate amount. With respect to the advisability of therapeutic abortion in women who develop clinical rubella during pregnancy, the conscientious physician is often faced with a difficult decision. As Krugman and W a r d 5 point out, this important decision must be based on many factors, and each case must be individualized carefully. It would seem, however, on the basis of the statistical analysis by Dekaban and his associates 4 that in the very early weeks of pregnancy, before the fourth week, the fetus is extremely susceptible to serious damage from rubella infection in the mother, and actually the damage may be done before the mother is aware that she is pregnant. Patients in this category would appear to be likely candidates for therapeutic abortion. From the sixth to the eighth weeks of gestation, the decision as to whether this therapeutic procedure is indicated could be answered in the negative more easily. Certainly patients who develop rubella beyond the twelfth week of gestation would not be advised to terminate the pregnancy. In general, the most satisfactory approach to the problem at present seems to be as follows: A woman b~ early pregnancy with no previous history of rubella who has known exposure to the disease should receive immune substance early and in large amount. In most parts of the world the antibody-containing blood product readily available would be gamma globulin: dosage, 20 ml. intramuscularly. Convalescent-phase plasma or convalescent-phase gamma globulin are preferred to ordinary gamma
260
THE JOURNAL OF PEDIATRICS
globulin, and should be used whenever they are available: approximate dosage, 10 ml. intramuscularly. The advisability of exposing young girls to rubella merits reiteration, especially since one a t t a c k of this benign disease of childhood is followed, as a rule, by durable immunity which will protect them throughout the childbearing period. Safe measures for active immunization against rubella, undeveloped as yet, would seem to offer a promising means of control in the future. Despite the general consensus that the risk of congenital malformation following maternal rubella is less than earlier estimates made some years ago would indicate this risk is still a real one, often with tragic consequences for the individual and his family. Careful studies such as those being reported c u r r e n t l y are of value in helping the clinician to make a wise decision. RUSSELL J . BLATTNER
REFERENCES 1. Gregg, ~. M. : Congenital Cataract Following German Measles in the Mother~ Tr. Ophth. Soc. Australia 3: 35, 1941. 2. Greenberg, M., Pellitteri, O., and Barton, J.: Frequency of Defects in Infants Whose Mothers Had Rubella During Pregnancy, J. A. M. A. 165: 675, 1957. 3. LundstrSm, R.: Rubella During Pregnancy: Its Effect Upon Perinatal Mortality, Incidence of Congenital Abnormalities and Immaturity: Preliminary Report, Aeta paediat. 41: 583, 1952. Rubella During Pregnancy, In V I I I International Congress of Paediatrics, Copenhagen, Denmark, Aug. 1956, Abst. No. 172, p. 95; Discussion, p. 316. Berlingska Boktryckeriet, Lurid, Sweden, 1956. 4. Dekaban, A., O'Rourke, J., and Cornman, T.: Abnormalities in Offspring Related to 1V[aternal Rubella During Pregnancy, Neurology 8: 387, ]958. 5. Krugman, S., and Ward, R.: Rubella: Demonstration of Neutralizing Antibody in Gamma Globulin and Re-Evaluation of the Rubella Problem, New England J. Med. 259: 16, ]958. 6. I(orns, R. F.: Prophylaxis of German Measles With hnmune Serum Globulin, J. Infect. Dis. 90: 183, 1952.
o n C u r r e n t Literature
RUBELLA DURING PREGNANCY Since 1941, when G r e g g 1 first reported the relationship between Germ a n measles (rubella) in the p r e g n a n t w o m a n a n d the occurrence of congenital m a l f o r m a t i o n in her offspring, the physician has been faced with the v e r y practical p r o b l e m of management in the p a t i e n t who has had k n o w n exposure to rubella d u r i n g p r e g n a n c y , or who develops clinical manifestations of this disease e a r l y in p r e g n a n c y . The rubella s y n d r o m e in offspring of w o m e n who have experienced G e r m a n measles d u r i n g p r e g n a n c y is well established, and has been verified by a n u m b e r of careful clinical studies. On the basis of G r e g g ' s retrospective studies a n d those of some o t h e r observers, the incidence of m a l f o r m a t i o n seems ext r e m e l y high. F o r example, G r e g g reported an 80 to 90 per cent incidence of congenital m a l f o r m a t i o n where rubella c o m p l i c a t e d the first t r i m e s t e r of p r e g n a n c y ; a 21 to 78 per cent incidence following infection in the second t r i m e s t e r ; and f r o m zero to 20 per cent in the t h i r d trimester. G r e g g ' s studies were retrospective in type, o r i g i n a t i n g w i t h the d a m a g e d infant. In recent y e a r s prospective studies have been u n d e r t a k e n with the result t h a t these high incidence r a t e s have been altered significantly. Such prospective studies, w i t h subsequent e x a m i n a t i o n of the n e w b o r n infant, indicate t h a t m a t e r n a l rubella infection in the first t r i m e s t e r m a y be followed b y congenital m a l f o r m a t i o n in 10 to 12 p e r cent of the cases followed. A p p a r e n t l y , there is v e r y little risk of the rubella s y n d r o m e resulting if exposure to rubella or clinical
manifestations of the disease occur d u r i n g the second or the t h i r d trimester. G r e e n b e r g and his associates 2 have been i n t e r e s t e d for some time in the f r e q u e n c y of defects as e v a l u a t e d by the prospective t y p e of study. Recently, one g r o u p r e p o r t e d b y them comprised 104 cases of m a t e r n a l rubella occurring in the first three months of p r e g n a n c y ; of these 104 cases, there were 48 in which therapeutic abortion w a s considered advisable; in ten cases of the 104, it was not possible to follow the patient. In the r e m a i n i n g 46 cases, 28 of the m o t h e r s gave birth to normal i n f a n t s ; 12 mothers had s p o n t a n e o u s misc a r r i a g e ; three infants were stillborn; and three i n f a n t s developed congenital m a l f o r m a t i o n s : t h a t is, three of 31 liveborn infants, or a b o u t 10 per cent. A t the E i g h t h I n t e r n a t i o n a l Congress of P e d i a t r i c s in Copenhagen, in August, 1956, L u n d s t r 5 m 3 r e p o r t e d extensive survey studies of the prospective type. His findings are in accord with those f r o m other such studies, t h a t is, m a l f o r m a t i o n s occurring a f t e r rubella infection in the first t r i m e s t e r of p r e g n a n c y in f r o m 9 to 12 p e r cent. In a control g r o u p of p r e g n a n t women, c o m p a r a b l e numerically, who did not acquire rubella, the incidence of m a l f o r m a t i o n w a s only 1.6 per cent. On the basis of this u n u s u a l l y well-organized survey, risk of fetal d a m a g e f r o m rubella cont r a c t e d in the first t r i m e s t e r was estimated as a ratio of 6:1 as comp a r e d with t h a t in u n c o m p l i c a t e d pregnancy. 237
258
THE JOURNAL OF PEDIATRICS
In spite os this re-evaluation of the incidence of letal damage, which has been the result of the prospective type of study rather than the retrospective approach employed earlier, the problem remains and is invariably a difficult one for the clinician to handle, requiring thoughtful consideration in each individual case. In the May, ]958, issue of Neurology, an unusual case report appears which is pertinent in this connection. This report, from the National Institute of Neurologic Diseases and Blindness by Dekaban, O'Rourke, and Cornman, 4 describes in detail the case of an 8-year-old boy who was damaged severely as a result of rubella infection in the mother. This boy was the firstborn of a young mother who developed severe rubella at the end of the fourth week of gestation, and had to be confined to bed for one week. Description of the clinical course of the mother's rubella would indicate that this was an unusually severe disease. The infant was born with multiple defects, giving evidence of a " v e r y profound disturbance of embryonic development." Of the fifteen pathologic lesions generally recognized as the result of maternal rubella infection early in pregnancy, this child showed eleven characteristic clinical manifestations, including cataract, congenital heart, deafness, mental and physical retardation, etc. In reviewing the literature pertinent to this case, the authors were impressed by the "occurrence of more severe abnormalities during the earliest stages of pregnancy and the substantial decline of incidence of malformation after two to three months of gestation. ''4 It appeared worthwhile to them " t o analyze the frequency with which the abnormalities in various organs are encountered relevant to the different stages of gestation."4 Accordingly, these authors selected for analysis 108 cases from published reports of patients who developed rubella during pregnancy, and-whose history as to the stage of pregnancy when the
disease occurred was considered to be reliable. On analyzing these 108 cases in detail, it became apparent that the highest incidence of three major abnormalities, cataract, congenital heart disease, and deafness, occurred when rubella complicated the first four weeks of pregnancy. Fetuses exposed to maternal rubella between the fifth and tenth weeks of gestation still showed frequent occurrence of these malformations. From the tenth week on, there appeared to be a rapid decline in fetal susceptibility, so that the incidence reached a low level after fourteen weeks of gestation. No instances of congenital abnormality were encountered when exposure of the fetus to rubella occurred after 20 weeks of gestation. From these findings, which are presented graphically in an objective figure, emphasizing the importance of the time-exposure relationship, the authors concluded that the highest incidence of three of the most important congenital anomalies, cataract, deafness, and congenital heart disease, occurred when rubella complicated the pregnancy within the first five weeks of gestation. A re-evaluation of the rubella problem from the standpoint of prevention was attempted recently by Krugman and Ward, ~ whose interest in this subject has extended over a period of years. Equivocal results concerning the efficacy of gamma globulin in the prevention of rubella prompted these authors to study the levels of neutralizing antibody in ordinary gamma globulin, in convalescent rubella plasma, and in gamma globulin prepared from plasma of patients convalescent from rubella. In this unusually clear-cut study, a serum pool previously shown to contain active rubella virus was used as a basis for serum-virus neutralization tests in human subjects. Four groups of individuals, six in each group, were inoculated intramuscularly with appropriate mixtures of active virus and "serum: active virus from the
COMMENTS ON CURRENT LITERATURE
original rubella serum pool plus normal human serum free from rubella antibodies; active virus plus ordinary gamma globulin ; active virus mixed with convalescent-phase plasma; and a mixture of active virus with convalescent gamma globulin. In the group receiving active rubella virus plus normal human serum as inoeulum, five of the six individuals developed clinical rubella. Of the group who received rubella virus plus gamma globulin, one of the six developed clinical rubella; of the group receiving as inoculum a mixture of active virus and convalescent-phase serum, one of six developed rubella; and in the group receiving active virus plus rubella convalescent-phase gamma globulin, none of the six showed signs of clinical rubella. These results show clearly the presence of neutralizing antibody to the virus of rubella in ordinary gamma globulin, in convalescentphase plasma, and in convalescentphase gamma globulin, and under the conditions of this study, can be interpreted as indicating the relative efficacy of these preparations in the prevention of clinical manifestations of the disease. That the rubella antibody level to be found in ordinary gamma globulin varies widely from sample to sample has been well recognized for a number of years. In one of the epidemic studies made by Korns, ~ this range of variability was considerable: from no protection against German measles to a significant reduction in its occurrence in susceptible contacts. Thus, in attempting to answer the question of gamma-globulin prophylaxis on exposure, Krugman and W ar d ~ recommend that as soon after exposure as possible, all pregnant women in the first trimester who have no known history of rubella be given at least 20 ml. of gamma globulin intramuscularly. If rubella convalescent-phase gamma globulin is available, a dosage of ]0 ml. administered intramuscularly is considered adequate. Early
259
administration of gamma globulin in adequate amount is important, since rubella can occur without rash, and since damage to the fetus may be out of proportion to the clinical manifestations observed in the mother. The probable risk of injury to the developing infant would be less in a mother who receives immune substance early and in an adequate amount. With respect to the advisability of therapeutic abortion in women who develop clinical rubella during pregnancy, the conscientious physician is often faced with a difficult decision. As Krugman and W a r d 5 point out, this important decision must be based on many factors, and each case must be individualized carefully. It would seem, however, on the basis of the statistical analysis by Dekaban and his associates 4 that in the very early weeks of pregnancy, before the fourth week, the fetus is extremely susceptible to serious damage from rubella infection in the mother, and actually the damage may be done before the mother is aware that she is pregnant. Patients in this category would appear to be likely candidates for therapeutic abortion. From the sixth to the eighth weeks of gestation, the decision as to whether this therapeutic procedure is indicated could be answered in the negative more easily. Certainly patients who develop rubella beyond the twelfth week of gestation would not be advised to terminate the pregnancy. In general, the most satisfactory approach to the problem at present seems to be as follows: A woman b~ early pregnancy with no previous history of rubella who has known exposure to the disease should receive immune substance early and in large amount. In most parts of the world the antibody-containing blood product readily available would be gamma globulin: dosage, 20 ml. intramuscularly. Convalescent-phase plasma or convalescent-phase gamma globulin are preferred to ordinary gamma
260
THE JOURNAL OF PEDIATRICS
globulin, and should be used whenever they are available: approximate dosage, 10 ml. intramuscularly. The advisability of exposing young girls to rubella merits reiteration, especially since one a t t a c k of this benign disease of childhood is followed, as a rule, by durable immunity which will protect them throughout the childbearing period. Safe measures for active immunization against rubella, undeveloped as yet, would seem to offer a promising means of control in the future. Despite the general consensus that the risk of congenital malformation following maternal rubella is less than earlier estimates made some years ago would indicate this risk is still a real one, often with tragic consequences for the individual and his family. Careful studies such as those being reported c u r r e n t l y are of value in helping the clinician to make a wise decision. RUSSELL J . BLATTNER
REFERENCES 1. Gregg, ~. M. : Congenital Cataract Following German Measles in the Mother~ Tr. Ophth. Soc. Australia 3: 35, 1941. 2. Greenberg, M., Pellitteri, O., and Barton, J.: Frequency of Defects in Infants Whose Mothers Had Rubella During Pregnancy, J. A. M. A. 165: 675, 1957. 3. LundstrSm, R.: Rubella During Pregnancy: Its Effect Upon Perinatal Mortality, Incidence of Congenital Abnormalities and Immaturity: Preliminary Report, Aeta paediat. 41: 583, 1952. Rubella During Pregnancy, In V I I I International Congress of Paediatrics, Copenhagen, Denmark, Aug. 1956, Abst. No. 172, p. 95; Discussion, p. 316. Berlingska Boktryckeriet, Lurid, Sweden, 1956. 4. Dekaban, A., O'Rourke, J., and Cornman, T.: Abnormalities in Offspring Related to 1V[aternal Rubella During Pregnancy, Neurology 8: 387, ]958. 5. Krugman, S., and Ward, R.: Rubella: Demonstration of Neutralizing Antibody in Gamma Globulin and Re-Evaluation of the Rubella Problem, New England J. Med. 259: 16, ]958. 6. I(orns, R. F.: Prophylaxis of German Measles With hnmune Serum Globulin, J. Infect. Dis. 90: 183, 1952.