J. E. Cradock-Watson

Consequences of varicella and herpes zoster in pregnancy: prospective study of 1739 cases

In a joint prospective study in Germany and the United Kingdom between 1980 and 1993, 1373 women who had varicella and 366 who had herpes zoster during the first 36 weeks of gestation were followed up. 9 cases of congenital varicella syndrome were identified, all occurring after maternal varicella during the first 20 weeks of gestation. The highest risk (2.0%) was observed between 13-20 weeks gestation, with 7 affected infants identified among 351 pregnancies (95% CI of risk 0.8-4.1%). Only 2 cases of congenital varicella syndrome were identified among 472 pregnancies in which maternal varicella occurred before 13 weeks (observed risk 0.4%, 95% CI 0.05-1.5%). Herpes zoster in infancy was reported in 10 children whose mothers had had varicella in pregnancy. No infants with clinical evidence of intrauterine infection were born to the 366 women with herpes zoster in pregnancy (upper 95% confidence limit of estimated risk 1.0%). Varicella-zoster-specific IgM antibody was found at birth in 4 of 16 (25%) infants with clinical manifestations of intrauterine infection and persistent specific IgG antibody in 5 of 7 infants tested. The corresponding rates in asymptomatic infants whose mothers had varicella were 12% (76/615) and 7% (22/335) respectively. No serological evidence of intrauterine infection was found in infants who mothers had herpes zoster in pregnancy. In 97 pregnant women, varicella occurred after post-exposure prophylaxis with anti-varicella-zoster immunoglobulin. No cases of congenital varicella syndrome or zoster in infancy occurred in this group. Our estimates provide a sound basis for counselling women with varicella in pregnancy. Although the risk of congenital varicella syndrome is small, the outcome for the affected infant is so serious that a reliable method of prenatal diagnosis would be valuable. In the long term, prevention of maternal varicella would be an option if a safe and effective vaccine were to become routinely available.

CONSEQUENCES OF CONFIRMED MATERNAL RUBELLA AT SUCCESSIVE STAGES OF PREGNANCY

Over a thousand women with confirmed rubella infection at different stages of pregnancy were followed up prospectively. Two-thirds of the women were multiparous. Pregnancy continued in 40%, and the infants were followed up after birth both clinically and serologically. The frequency of congenital infection after maternal rubella with a rash was more than 80% during the first 12 weeks of pregnancy, 54% at 13-14 weeks, and 25% at the end of the second trimester. The infection rate then rose again to reach a high figure in the last month. Follow-up was to 2 years of age--the findings in infected children being compared with those in children who had escaped infection. Rubella defects occurred in all infants infected before the 11th week (principally congenital heart disease and deafness) and in 35% of those infected at 13-16 weeks (deafness alone). No defects attributable to rubella were found in 63 children infected after 16 weeks. Continued surveillance of cases of confirmed rubella during pregnancy is recommended as an additional way of monitoring the effect of rubella vaccination.

OUTCOME OF CONFIRMED PERICONCEPTIONAL MATERNAL RUBELLA

61 pregnant women in whom confirmed rubella occurred from 5 weeks before to 6 weeks after the last menstrual period (LMP) were followed up prospectively. In 39, the pregnancy was terminated and the fetal tissues or mixed products of conception were examined for rubella virus. In 22, the pregnancy continued to term and cord serum was tested for specific IgM antibody. No evidence of intrauterine infection was found in 38 pregnancies in which the mothers rash appeared before, or within 11 days after, the last menstrual period. The shortest interval at which fetal infection occurred was when the rash appeared 12 days after the last menstrual period. All 10 pregnancies in which the rash appeared 3-6 weeks after the last menstrual period resulted in fetal infection: 4 of these pregnancies went to term, and all 4 infants were damaged. The risk to the fetus when rubella occurs before the mothers last menstrual period is probably negligible.

Outcome of asymptomatic infection with rubella virus during pregnancy

We have tried to detect prenatal infection in 34 infants whose mothers were re-infected with rubella virus during pregnancy and in six infants whose mothers had primary subclinical rubella during pregnancy. Two methods of assessment were used: first, serum obtained soon after birth was tested for IgM antibody; secondly, serum obtained after the age of 8 months was tested for specific IgG. The 34 women with re-infections had increases in IgG antibody titre but no IgM response. No evidence of prenatal infection was found in 33 of their 34 infants. One infant was found to have IgG antibody at the age of 11 months. This infant was IgM-negative at birth and had a rubelliform rash at the age of 5 1/2 months; it therefore probably contracted post- rather than pre-natal infection. Fetal infection from maternal re-infection during pregnancy is probably rare. The six women with primary subclinical rubella produced both IgG and IgM classes of antibody. Three of their six infants showed serological evidence of intrauterine infection. One, infected when its mother was 8 weeks pregnant, had clinical evidence of congenital rubella. Primary subclinical rubella during pregnancy therefore carries a significant risk of fetal infection. Because of the difference in outcome, great care should be taken to distinguish between primary infection and re-infection when investigating symptomless increases in antibody titre after contact with rubella during pregnancy.

Specific immunoglobulin responses after varicella and herpes zoster

The indirect immunofluorescence technique has been used to titrate the specific immunoglobulins in 200 sera from 64 patients with varicella, and 195 sera from 67 patients with herpes zoster. IgG and IgM antibodies were detected in all patients with varicella, and IgA in 59 (92%). All three classes of antibody appeared 2--5 days after the onset of the rash, increased virtually simultaneously and reached maximum titres during the second and third weeks. IgG then declined slowly, but never became undetectable and was still present in five subjects who were retested after 2--4 years; it was present in 88 out of 100 healthy young adults and probably persists indefinitely after varicella. IgA and IgM antibodies declined more rapidly and were not detected in specimens taken more than a year after the illness. IgA, however, may possibly persist in some cases since low titres were found in 8 out of 88 young adults who possessed IgG antibody and had presumably had varicella in the past. IgA responses were significantly weaker in children under the age of 6 years than in older children and adults. Six out of 67 patients with zoster were tested at various times before the onset of the rash: IgG antibody was detected in all. IgG was present in all sera taken after the onset of the rash, increased rapidly after 2--5 days, reached maximum titres during the second and third weeks and then declined slowly. IgA antibody was detected in 66 patients (99%) and IgM in 52 (78%); both types of antibody followed transient courses, as in varicella. Maximum titres of IgG and complement-fixing antibodies were greater after zoster than after varicella, but the differences were not significant. IgA and IgM titres in young adults with zoster were significantly lower than in older patients, and also lower than in young adults with varicella. Increases in varicella-zoster antibody in patients with herpes simplex virus infections consisted mainly of IgG, sometimes IgA, but never IgM.

HUMAN ANTI-CHICKENPOX IMMUNOGLOBULIN IN THE PREVENTION OF CHICKENPOX

Human anti-chickenpox immunoglobulin (zoster immune globulin, ZIG) was largely ineffective in preventing infection in forty-three high-risk contacts of chickenpox. Twenty-nine of these non-immune infants and children who had been in close contact with cases of varicella became infected, and symptoms developed in twenty-four. Since ZIG may modify chickenpox it should continue to be given to high-risk contacts until the availability of a simple and sensitive test makes it possible to identify those who are susceptible. However, ZIG is not necesary for infants whose mothers have chickenpox or zoster five or more days before delivery, since all such infants (eleven) had varicella-zoster antibody at birth.

Laboratory diagnosis of rubella: past, present and future.

Fifty years ago in New South Wales the late Sir Norman Gregg [1] described congenital cataracts in 78 babies, 67 of whose mothers had had clinical rubella in early pregnancy; he concluded that the disease in the mother caused the abnormality in the baby. Gregg [1–3] and Swan [4, 5] and their colleagues reported that deafness, heart disease and microcephaly were also major components of the congenital rubella syndrome. The need to prevent this tragic outcome stimulated intensive work on laboratory diagnosis and vaccine development, leading to the isolation of rubella virus in 1962 and then to methods for antibody detection. These complementary advances established the two traditional pillars of virological diagnosis and opened the way to immunization, with the result that some countries are now on the verge of eliminating a disease which for over 100 years was regarded as no more than a mild and harmless exanthem of childhood.

A comparison of antibody capture radio- and enzyme immunoassays with immunofluorescence for detecting IgM antibody in infants with congenital rubella

IgM antibody capture radioimmunoassay (MACRIA) and enzyme immunoassay (MACEIA) were compared with immunofluorescence (IF) for detecting specific IgM antibody in 99 sera from 76 infants with confirmed congenital rubella, and 61 sera from a comparative group of 59 infants who had miscellaneous abnormalities but in whom congenital rubella was not confirmed. All of 35 specimens collected from confirmed cases within 12 weeks of birth were positive by all three methods and all but one of 17 specimens collected after the age of 18 months were uniformly negative. At intermediate ages discrepancies occurred in 18 specimens, of which eight were positive and 10 negative by IF. Three of these 18 specimens were negative by both antibody capture procedures but showed weak fluorescence; the other 15 were negative by MACEIA, but positive by MACRIA which appears to be the more sensitive of the antibody capture methods. Sera from five infants in the comparative group were clearly positive by all three methods. These five infants were probably congenitally infected with rubella. Sera from the other 54 infants were negative, except for one that gave a weakly positive result by MACRIA alone. Antibody capture procedures offer several advantages over previous methods for detecting IgM antibody. Although MACRIA was found to be slightly more sensitive than MACEIA, the greater stability of the enzyme label, together with the possibility of both visual and quantitative assessment, could make MACEIA the method of choice for detecting rubella-specific IgM.

Fetal infection resulting from maternal rubella after the first trimester of pregnancy.

We have tried to measure the incidence of prenatal infection in 304 infants whose mothers had had rubella at various times after the first 12 weeks of pregnancy. Two methods of assessment were used: first, serum obtained soon after birth was tested for specific IgM antibody; secondly, serum obtained after the age of eight months was tested for specific IgG. When maternal rubella occurred 12-16 weeks after the last menstrual period specific IgM antibody was detected in 28 out of 50 infants (56%). The proportion fell progressively to 12% after maternal rubella at 24-28 weeks, rose to 19% after rubella at 28-36 weeks and then to 58% when the illness occurred during the last month of pregnancy. In all, IgM antibody was detected in 77 out of 260 infants (29%). The fetus can thus be infected at any time during the second and third trimesters of pregnancy, but the risk varies at different stages.The figures for the prevalence of IgG antibody were greater throughout, because some infants had IgG who had previously lacked specific IgM. After maternal rubella at 12-16 weeks IgG antibody persisted in 22 out of 31 infants (71%). The proportion fell to 28% after rubella at 24-28 weeks and then increased progressively to 94% after rubella during the last month. In all, IgG antibody persisted in 94 out of 190 infants (49%). The true rate of fetal infection probably lies between the rates estimated from the presence of IgM antibody and the subsequent prevalence of IgG.Infants whose mothers had rubella at any time during pregnancy should be examined regularly for possible evidence of damage.

Antibody titres in women six to eight years after the administration of RA27/3 and Cendehill rubella vaccines.

Titres of haemagglutination-inhibiting antibody have been measured repeatedly in young women during a period of 6-8 years after the administration of RA27/3 and Cendehill attenuated rubella vaccines. Mean antibody titres were initially 217 after RA27/3 and 159 after Cendehill, but the difference diminished after the first year. Antibody titres were subsequently well maintained in both groups and did not reveal any need for regular revaccination. Mean titres in the Cendehill group were partly maintained by symptomless reinfection which was commoner after Cendehill than after RA27/3. Significant falls in titre were equally common after both vaccines, but low titres of 30 or less were more frequent in subjects who had received Cendehill. Mean neutralizing antibody titres were initially 15.4 after RA27/3 vaccine and 9 after Cendehill. Titres remained higher after RA27/3 for 3 years, but the difference then diminished and became insignificant during the fifth year. Revaccination of women with low antibody titres produced significant increases in 69% of subjects when standard RA27/3 vaccine was used; a special preparation of RA27/3 of higher potency produced a similar number of rises (70%) but elicited higher titres and might occasionally be useful for revaccinating women who are likely to come into contact with rubella. Challenge with RA27/3 vaccine produced weaker responses in women who had experienced natural infection than in those whose antibody was vaccine-induced. Rises in antibody titre after revaccination consisted mainly of IgG, but traces of IgM antibody were detected in one vaccinee who had recently experienced natural reinfection and in 1 woman with naturally acquired antibody who had been challenged with high titre RA27/3 vaccine.