Original Article
Outcome after Maternal Varicella Infection in the First 20 Weeks of Pregnancy
N Engl J Med 1994; 330:901-905March 31, 1994
- Abstract
Background
Infection with the varicella-zoster virus during pregnancy can produce an embryopathy characterized by limb hypoplasia, eye and brain damage, and skin lesions. The risk is greatest when infection occurs during the first 20 weeks of pregnancy, but the magnitude of the risk is uncertain.
Methods
We studied 106 women with clinically diagnosed varicella infection in the first 20 weeks of pregnancy and compared the outcomes with those in 106 age-matched, nonexposed controls.
Results
Among the women with varicella, there was a trend toward more elective terminations of pregnancy (14 percent, vs. 7.5 percent among the controls; P = 0.1), corresponding to a significantly higher perception of teratogenic risk (P = 0.03). The proportions of miscarriages and live births and the mean birth weights were similar in the two study groups; there were more premature births ( ≤ 37 weeks) among the women with varicella infection (14.3 percent vs. 5.6 percent, P = 0.05). Congenital defects occurred in four infants born to the women with varicella (varicella embryopathy, hydrocephalus, meningocele and clubfeet, and hammer toe) and two infants born to the controls (ventricular septal defect and hip dislocation). The risk of varicella embryopathy after infection in the first 20 weeks was 1.2 percent (95 percent confidence interval, 0 to 2.4 percent). When we pooled our results with those from other prospective studies, the mean risk of embryopathy after infection with varicella-zoster virus in the first trimester was 2.2 percent (95 percent confidence interval, 0 to 4.6 percent).
Conclusions
The absolute risk of embryopathy after maternal varicella infection in the first 20 weeks of pregnancy is about 2 percent.
Media in This Article
Table 1
Stages of Pregnancy of 120 Pregnant Women Infected with Varicella-Zoster Virus.Table 2
Obstetrical Characteristics of the Group Contracting Varicella in the First 20 Weeks of Pregnancy and the Control Group.Article Activity
- Article
More than 80 percent of children have had chickenpox by 10 years of age, and more than 85 percent of adults who report that they have not had chickenpox are actually seropositive for antibodies to the varicella-zoster virus. Yet, because some seronegative women reach their childbearing years without ever having had the disease, they may have a primary infection while pregnant and their fetus may be infected. The effects on maternal health can range from mild chickenpox exanthem to severe, life-threatening illness with viral pneumonitis1,2. Between 0.5 and 0.7 per 1000 pregnancies (0.05 to 0.07 percent) are complicated by infection with varicella-zoster virus3.
The features of the congenital varicella syndrome include scarring with a dermatomal distribution, eye defects (cataracts, microphthalmia, and chorioretinitis), hypoplasia of bone and muscle of a limb (generally on the same side as the scarring), and neurologic abnormalities (mental retardation, microcephaly, and dysfunction of bowel or bladder sphincters). Although the embryopathy has been well described in case reports,4-9 the magnitude of risk remains unclear. On the basis of clinical and immunologic criteria, the incidence of fetal infection and subsequent development of intrauterine varicella after maternal infection has been estimated to be 25 percent,6 and in only half of these cases will the disorder be symptomatic. Although isolation of the virus or measurement of fetal IgM remains the ultimate goal of prenatal diagnosis, such techniques are not routinely used. Therefore, a solid estimate of fetal risk is essential to counseling women who become infected with this highly contagious agent.
It has been suggested on the basis of case reports that varicella embryopathy occurs between the 8th and 20th weeks of pregnancy,4 perhaps when the virus is most likely to damage the developing neural tissues and cause degeneration of nerves serving a specific anatomic locale7 and possibly before the production of fetal IgM antibodies specific for the virus.
Although the reported risks of embryopathy after maternal infection with varicella-zoster virus range from 0 percent7 to 9.2 percent6 above the base-line level of risk, this range is derived from small studies. The objective of our multicenter study was to document outcomes in a large group of women infected with the virus during the first 20 weeks of pregnancy and compare them with those in age-matched women without infection. In addition, we wished to quantify our impression that women exposed to varicella perceive the risk of teratogenetic abnormality to be high and that they may therefore be more likely to terminate an otherwise wanted pregnancy.
Methods
All information from telephone calls and clinic-intake forms for women who contacted one of the four study centers (Teratogen Information Services) between September 1986 and July 1992 for counseling after clinical diagnosis of varicella infection in pregnancy was retrieved from the respective computerized data bases. At all participating centers, the women were advised that the absolute risk of embryopathy due to varicella-zoster virus infection after exposure during the first trimester was small (<5 percent). Data on all cases involving exposure during pregnancy were collected. Between 8 and 12 months after the expected date of delivery, a trained interviewer from each center contacted each woman by telephone and completed a standardized follow-up form that asked about pregnancy outcome, birth weight, and perinatal and neonatal complications. Investigators at one center (Motherisk Program, Toronto) corroborated details listed on the form by requesting written documentation from the child's physician or from the hospital if the child was admitted for care. Investigators at the three other centers (Pregnancy Healthline, Philadelphia; Pregnancy Riskline, Salt Lake City; and Pregnancy Risk Information Service, Camden, N.J.) recorded data in a manner similar to that of the first center; they also obtained details on postnatal follow-up by making telephone calls (Philadelphia, Salt Lake City, and Camden) or by mailing follow-up cards (Philadelphia). Each patient was matched for age (within one year) with a woman not exposed to varicella who attended the Motherisk Program on the same day as the patient to receive counseling about exposure to a nonteratogenic agent (e.g., dental x-rays, acetaminophen, or penicillins). Women with a documented family history of genetic diseases were not considered as potential controls.
The proportions of birth defects in the infants of the varicella and control groups were compared by Fisher's exact test. Additional characteristics (gravidity, parity, previous miscarriages and elective abortions, gestational age at delivery, and birth weight) were compared by paired Student's t-test. Currently, the tendency to terminate pregnancy and the perception of teratogenic risk are routinely measured at the Toronto center only; thus, data on these variables are derived solely from patients who agreed to complete this portion of the clinic form with a counselor at this center. Such measurements are quantified with a visual-analogue scale previously described and validated10,11. This is a 10-cm horizontal line with a vertical mark at the left (0 cm, 0 percent), the middle (5 cm, 50 percent), and the right (10 cm, 100 percent); a patient who marked the extreme left end perceived no risk of teratogenic abnormality from her exposure or did not intend to terminate the pregnancy, and a patient who marked the extreme right end perceived a birth defect as an inevitable result of her exposure or fully intended to terminate the pregnancy. The perception or tendency for those who marked in between these extremes was quantified by measuring (in centimeters) the distance from 0 cm. The patients marked the visual-analogue scale both before counseling and after the medical facts had been explained to them; thus, the investigator gained insight into what they knew or misperceived. The patients' perceptions of the risk after infection and their tendency to terminate pregnancy were compared with the controls' perceptions and tendency by Wilcoxon's signed-rank test. Values for continuous variables are expressed as means ±SD with 95 percent confidence intervals, and values for discontinuous variables as percentages.
Results
A total of 120 women with varicella were studied, of whom 106 (88 percent) had varicella during the first 20 weeks of pregnancy (Table 1Table 1
Stages of Pregnancy of 120 Pregnant Women Infected with Varicella-Zoster Virus.) (81 women were studied at Toronto, 25 at Philadelphia, 12 at Camden, and 2 at Salt Lake City). Although different forms were used by the four centers, all data were collected prospectively. The diagnosis of varicella and zoster infection was confirmed by a clinician in all patients.Characteristics of Patients Infected during the First 20 Weeks of Pregnancy
There was no significant difference between the patients with varicella and the controls in gravidity, parity, number of previous miscarriages, or number of elective abortions (Table 2Table 2
Obstetrical Characteristics of the Group Contracting Varicella in the First 20 Weeks of Pregnancy and the Control Group.). Nine of the patients with varicella (8 percent) believed that they had been infected in childhood (serologic reports were not available), 31 (29 percent) stated that they had never had varicella, and 67 (63 percent) could not remember or information about their status was not available. Of the 23 patients for whom the source of infection was known, 20 contracted varicella after contact with a child and 3 after contact with an adult. Five patients (5 percent) received varicella-zoster immune globulin after exposure and subsequently had varicella, and 49 (46 percent) did not receive this treatment; the status of 53 patients (50 percent) was unknown, or the information was not collected. Twenty-five patients did not receive any treatment during their infection; 31 (55 percent) were treated with one or more agents (22 patients received acetaminophen, 8 diphenhydramine, 2 acyclovir, 1 amoxicillin, 1 metronidazole, 1 promethazine, and 1 hydroxyzine). One patient received acyclovir for 3 days, starting at 15.5 weeks of pregnancy (800 mg every six hours), and another received this drug for 1 week, starting at 2 weeks of pregnancy (800 mg daily). Neither patient was reported to have any complication of their pregnancy.Perception of Risk and Inclination to Terminate Pregnancy
Among 34 patients counseled in the Motherisk clinic, the mean perceived risk of a major malformation was 26 percent before counseling and 13 percent after counseling (P = 0.001); among the controls these risk estimates were 22 percent and 7 percent, respectively (P<0.001). This reduction of the perceived risk reflects the beneficial effect of our intervention, since after counseling, the risks perceived by both groups were closer to the known base-line risk of birth defects in the general population. Similarly, the scores for the inclination to terminate pregnancy that were recorded before counseling differed significantly from those recorded after counseling, in both the varicella group (35 percent vs. 22 percent, P = 0.03) and the control group (17 percent vs. 7 percent, P = 0.05).
Outcome of Pregnancy
There was no significant difference between the varicella group and the control group in the rate of live births (79 percent [95 percent confidence interval, 75 to 83 percent] vs. 85 percent [95 percent confidence interval, 81 to 88 percent], P = 0.3) or miscarriages (5.7 percent [95 percent confidence interval, 3.5 to 7.9 percent] vs. 7.5 percent [95 percent confidence interval, 4.9 to 10 percent], P = 0.6). There was a nonsignificant trend in the varicella group to report elective termination more often (14.2 percent [95 percent confidence interval, 11 to 18 percent], vs. 7.5 percent [95 percent confidence interval, 4.9 to 10 percent] in the control group; P = 0.1) (Table 3Table 3
Pregnancy Outcome in the Varicella and Control Groups.). All spontaneous abortions in the varicella group occurred within the first 15 weeks of gestation (two events at 8 weeks, one at 9 weeks, one at 10 weeks, and two at 12 weeks). All elective terminations were performed before 17 weeks of pregnancy, for various reasons (three procedures were carried out because of the perceived risk of abnormality due to varicella, one because of prenatal diagnosis of sickle cell disease, one because the pregnancy had resulted from rape, and three for personal or social reasons; information was not available on seven of the procedures).Of the 86 live-born infants delivered in the varicella group, 1 neonate had features consistent with varicella embryopathy, for an incidence of 1.2 percent (95 percent confidence interval, 0 to 2.4 percent). This infant weighed 1125 g and was delivered by cesarean section at 35 weeks of gestation; the mother had been exposed to varicella-zoster virus at 11 weeks of pregnancy, received varicella-zoster immune globulin 4 days later, then contracted mild varicella with lesions, headache, and malaise at 13 weeks. The initial maternal serum alpha-fetoprotein concentration was elevated at 15.7 weeks of pregnancy, to 3.7 multiples of the median, and rose to 5.3 multiples of the median 2 weeks later. Ultrasonograms obtained after 17.7 weeks revealed intrauterine growth retardation. The infant had punctate skin lesions at birth that resembled old chickenpox scars; progressive respiratory distress and hepatic failure developed, and the infant died on the 22nd day of life. Postmortem examination revealed extensive hepatic fibrosis and syncytial giant-cell formation. Ascitic fluid was positive for antibody to varicella-zoster virus, but no virus was identified on study with the polymerase chain reaction.
When the infant with embryopathy was excluded from analysis, the proportion of birth defects was similar in the two study groups and fell within the base-line risk in the general population of nonexposed pregnant women (varicella group vs. control group, 2.3 percent [95 percent confidence interval, 0.7 to 3.9 percent] vs. 2.2 percent [95 percent confidence interval, 0.7 to 3.7 percent]; P = 1). In the varicella group, a twin was born with meningocele and clubfeet, and another child had hammer toe. In the control group, one child had hip dislocation, and another had a small ventricular septal defect.
Diagnostic Tests
In 41 of the 106 patients exposed to varicella, fetal ultrasonography was performed before 20 weeks of pregnancy; in the rest the procedure was not carried out, or it was unknown whether ultrasonography was performed. The fetuses of 38 patients were normal, those of 2 patients had intrauterine growth retardation after the mothers had varicella at 5.5 and 13 weeks, and that of 1 patient died at 8 weeks of gestation (the fetal death was documented on the follow-up form as a blighted ovum) after the mother had had varicella at 4 weeks. In only two patients was serum alpha-fetoprotein measured after varicella was diagnosed: the mother of the infant with varicella syndrome, described above, and a mother participating in a clinical study in which alpha-fetoprotein measurement was a routine procedure. In no case was cordocentesis or the polymerase chain reaction performed to measure fetal antibody or to identify the virus in fetal tissue.
Perinatal Characteristics
There was a trend toward more premature births ( ≤ 37 weeks) among the patients who contracted varicella in the first 20 weeks than among the controls (14.3 percent [95 percent confidence interval, 10.5 to 18.1 percent] vs. 5.6 percent [95 percent confidence interval, 3.2 to 8 percent], P = 0.05). There was no significant difference between the infants of patients with varicella infection and those of the controls in birth weight (3336 ±735 vs. 3413 ±559 g, P = 0.6) or gestational age at delivery (38.8 ±3.2 vs. 39.6 ±2.2 weeks, P = 0.2).
Characteristics of Patients Infected after 20 Weeks of Pregnancy
Of the 14 patients who became infected with varicella-zoster virus after 20 weeks of pregnancy, 3 were exposed between weeks 21 and 24, 3 between weeks 25 and 28, 4 between weeks 29 and 32, 3 between weeks 33 and 36, and 1 between weeks 37 and 40. Thirteen patients contracted varicella. In the 14th patient, who reported having had varicella in childhood, zoster developed in the 24th week of pregnancy. Her child had recurrent apnea and mild hypotonia of the upper and lower extremities; extraventricular obstructive hydrocephalus was diagnosed at six months of age. Only 1 patient, who contracted varicella in the 32nd week of pregnancy, received varicella-zoster immune globulin; 10 patients did not receive it, and the status of 4 patients regarding this treatment was unknown. Two patients were treated with acetaminophen and diphenhydramine, one with calamine lotion, and one with hydroxyzine. All 14 patients had live-born infants. There was no significant difference in birth weight between the infants of the patients with infection and those of the controls (3471 ±372 vs. 3191 ±630 g, P = 0.2); however, the infants of the patients were born a mean of 1.7 weeks later than those of the controls (40 ±1 vs. 39 ±2.1 weeks, P = 0.04). Seven infants were delivered vaginally (two with forceps), and four by cesarean section; the type of delivery was not noted for three infants.
An infant whose mother contracted varicella six days before delivery received 1.25 ml of varicella-zoster immune globulin four hours after birth and became infected with varicella on the second day of life; starting on day 3, he received 30 mg of acyclovir intravenously every eight hours for two days, then 50 mg every eight hours for five days. The course of his disease was uneventful. Another infant, whose mother contracted varicella 10 days before delivery, was noted to have a few chickenpox lesions at birth and was placed in intensive care for observation for the first week of life; an incarcerated right inguinal hernia was repaired at five months of age. A mother who had shingles at 24 weeks gave birth to a 3380-g infant at 38 weeks who had mild dilatation of the cerebral ventricles, extraventricular obstructive hydrocephalus, and mild hypotonia. At follow-up examination at one year, this infant had not had either varicella or zoster.
Discussion
Epidemiologic studies of teratogenicity in humans have typically involved pregnant women exposed to drugs, chemicals, or infectious agents in the first trimester or, more specifically, during the period of organogenesis. However, the adverse outcomes described in case reports4 suggest that the period of risk to the fetus from maternal infection with varicella-zoster virus extends beyond this window so that infants ultimately born with varicella embryopathy contract the infection during the first 20 weeks of gestation. We followed 106 women infected in this period and estimated the incidence of varicella embryopathy to be 1.2 percent (95 percent confidence interval, 0 to 2.4 percent). This low risk of embryopathy suggests that for unknown reasons, the ability of the virus to cross the placenta and infect the fetus is limited. The case presented in this study may be atypical in that respiratory distress has not been consistently reported in cases of congenital varicella embryopathy4. However, the progressive intrauterine growth retardation, hepatic failure, and punctate lesions at birth suggest that exposure occurred in utero. If this atypical case did not result from such exposure, then the risk of varicella embryopathy in this cohort is even lower than our calculated risk of 1.2 percent.
Confirming intrauterine infection with varicella-zoster virus should be the first step in assessing fetal risk. Several tools can be used for this purpose. Ultrasonography may detect the more obvious structural abnormalities of the embryopathy, such as limb hypoplasia, progressive intrauterine growth retardation, and microcephaly; however, signs such as cataracts, chorioretinitis, optic atrophy, motor or sensory deficits, and sphincter dysfunction are not likely to be diagnosed until after birth. In our prospective study, sonography identified two infants with progressive intrauterine growth retardation and one fetus that died in utero (blighted ovum). A fetal antibody response confirms exposure to virus in utero; however, since the value of testing for fetal IgG is limited by the passive transfer of maternal antibody, it may be more prudent to measure fetal IgM specific for varicella-zoster virus, whose concentration increases from a mean of 6 mg per deciliter before 28 weeks of gestation to 11 mg per deciliter at term12. However, elevated levels of IgM may become normal before term, so that a diagnosis of infection in utero may be missed. In none of the infants in our study was fetal IgM assayed by cordocentesis or measured in amniotic fluid; thus, our findings may be limited in that we do not know the true number of infected fetuses. Although cordocentesis is used by physicians in several countries to detect fetal infection with toxoplasmosis, the risk-benefit ratio of this procedure is still controversial. It is unlikely this test will become widely used in the near future to detect varicella infection, which has a substantially lower rate of embryopathy.
Congenital infection, without embryopathy, is more likely when infection occurs after 20 weeks of pregnancy. The one case of extraventricular obstructive hydrocephalus in our study could have been due to varicella-zoster infection; however, no definitive conclusion can be drawn, since follow-up serologic data were not available. Neonatal infection should be considered if a mother contracts varicella during the last three weeks of pregnancy. The severity of infection in the newborn is related to the time of onset of infection in the mother during pregnancy. The illness may be mild, with a few cutaneous lesions (as in the patients in our study who contracted varicella 6 and 10 days before delivery), or it may be severe, with fever, hemorrhagic rash, and generalized visceral involvement. Severe illness has been associated with a mortality rate of about 30 percent, with death due to severe pulmonary disease; however, since these data are relatively old, they may not reflect the progress in the critical care of sick infants.
Confirmation of a causal relation between varicella-zoster virus infection in the first trimester and varicella embryopathy is not easy since much of the literature on this prenatal infection consists of case reports, which by nature are quite selective. Such case reports have worried both the public and health professionals. The media are quick to publish the results of a positive study or association but are less enthusiastic about describing the absence of an association. This bias against the negative result has been well documented13 and may have devastating effects on the field of teratology. Nonetheless, case reports are of value and can lead scientists to search for similar case reports and initiate more rigorous studies of a proposed association.
Our multicenter, controlled, prospective study compared the overall risks to reproduction of varicella infection during pregnancy. When we combined our data with those from previous, uncontrolled studies6,7,14 and one controlled but small study15 of fetal risk after maternal varicella-zoster virus infection in the first trimester, we found an aggregate mean rate16 of congenital varicella embryopathy of 2.2 percent (95 percent confidence interval, 0 to 4.6 percent; range, 0 to 9.1 percent) (Table 4Table 4
Published Prospective Studies Measuring Fetal Risk after Maternal Infection with Varicella-Zoster Virus during the First Trimester.).Until recently, the study by Paryani and Arvin,6 which found the fetal risk of congenital varicella to be 9 percent, probably led to an increase in the perceived fetal risk after maternal varicella, and this trend may have been reflected in the measurements of the risk perceived by our patients. However, since the denominator population in that study6 was only 11 infants, few conclusions can be drawn about the true fetal risk. Our study of 106 women (with 86 live-born infants) infected with varicella in the first 20 weeks of pregnancy suggests that the risk of embryopathy is only 1.2 percent. When our data are combined with those of all other prospective studies, the weighted average risk associated with maternal infection after the first trimester is still low, at 2.2 percent. The relatively higher perceived risk, even after counseling for varicella-zoster infection, may reflect a need for improved communication with the patient. Perceived risk is a multidimensional concept, and it varies greatly from patient to patient. Despite our explanations of findings from published studies,6,7,14,15 persons other than the patient, such as her physician, her prenatal counselor, or a public health nurse, may influence her perception of risk. Misinterpretation and misperception of the facts in the medical literature may lead women exposed to varicella-zoster virus to perceive the risk of a major malformation as unjustifiably high and consequently have a greater tendency to terminate pregnancy.
Source Information
From the Motherisk Program, Hospital for Sick Children, Toronto (A.L.P., M.L., J.G., F.B.-L., E.J., G.K.); Pregnancy Healthline, Pennsylvania Hospital, Philadelphia (B.S., A.D.); Pregnancy Risk Information Service, Camden, N.J. (C.Z.); Pregnancy Riskline, University of Utah, Salt Lake City (M.F.); and the Department of Genetics, North York Hospital, Toronto (W.M.).
Address reprint requests to Dr. Koren at the Division of Clinical Pharmacology, Hospital for Sick Children, 555 University Ave., Toronto, ON M5G 1X8, Canada.
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