Vaccine, Lyme Disease in Pregnancy and Breastfeeding
Fetal Risk Summary
Lyme disease vaccine (recombinant OspA) contains an outer surface protein of Borrelia burgdorferi sensu stricto (lipoprotein OspA) that is noninfectious (1,2). The recombinant OspA protein is expressed in Escherichia coli and then purified. Only the LYMErix vaccine is licensed for use in the United States (2). The vaccine (30 g/0.5 mL) is administered IM on a three-dose schedule of 0, 1, and 12 months.
Lyme disease is a tickborne infection caused by the spirochete B. burgdorferi, with an incubation period from infection to onset of rash (erythema migrans) of 714 days (range 330 days) (2). The disease is characterized by rash, fever, malaise, fatigue, headache, myalgia, and arthralgia (2). Without adequate antibiotic treatment, chronic disease of the nervous system, musculoskeletal system, or the heart may occur.
No cases describing the use of Lyme disease vaccine in pregnancy have been located. Moreover, animal reproductive tests have not been conducted with the vaccine.
A 1985 case report described a woman who developed Lyme disease during the 1st trimester of pregnancy (3). She received no antibiotic therapy for her disease (3). She delivered a 3000-g, male infant at an estimated 35 weeks' gestation who developed respiratory distress shortly after birth. Studies revealed a dilated, poorly contractile left ventricle, aortic valvular stenosis, patent ductus arteriosus, and coarctation of the aorta (3). The infant died at age 39 hours. Cardiovascular malformations found at autopsy were tubular hypoplasia of the ascending aorta and aortic arch, marked endocardial fibroelastosis, and a persistent left superior vena cava draining into the coronary sinus (3). No signs of infection, such as inflammation, necrosis, or granuloma formation, were found in the heart or other organs, but a few spirochetes similar to the Lyme disease spirochete were found in the spleen, renal tubules, and bone marrow. Evaluation of the mother was consistent with Lyme disease, and she was successfully treated with tetracycline therapy.
A second case of fetal death associated with Lyme disease was published in 1987 (4). A 24-year-old woman with an apparent onset of infection (annular erythematous patch noted near her left knee followed by pain and swelling in the knee) near the time of conception delivered a 2500-g stillborn infant at term. Serologic studies of maternal blood were positive for B. burgdorferi in two of three samples. At autopsy, the only malformation found was an atrioventricular canal ventricular septal defect (4). Spirochetes immunologically consistent with B. burgdorferi were recovered from the fetal liver, myocardium, adrenal gland, and subarachnoid space of the midbrain. The authors concluded that the fetus had died near term of overwhelming spirochetosis (4).
The outcomes of 19 pregnancies of women with documented Lyme disease were described in 1986 (5). Eight of the pregnancies were followed prospectively, and 11 were identified retrospectively. Among the 17 women with erythema chronicum migrans (ECM), eight had the onset of disease in the 1st trimester, seven in the 2nd trimester, and two in the 3rd trimester. The onset of infection could not be determined in the remaining two, but one developed facial palsy in the 1st trimester and the other developed arthritis in the 3rd trimester. Normal outcomes occurred in 14 pregnancies, seven with onset of illness in the 1st trimester, four in the 2nd trimester, two in the 3rd trimester, and one with unknown time of onset. Six of the women (3 in 1st trimester; 1 in 2nd trimester; 2 in 3rd trimester) did not receive antibiotic therapy, but all delivered apparently normal infants, although two had transient problems. One of these, a 2100-g infant delivered prematurely, developed hyperbilirubinemia at 4 days of age but has had otherwise-normal development through 9 years of age. Another, delivered 7 days after onset of maternal ECM and meningitis, had hyperbilirubinemia and a generalized, petechial, vesicular rash at 5 days of age. Viral and bacterial blood and skin cultures were negative; tests for B. burgdorferi were not available at that time. The rash faded within 1 week during treatment with penicillin. The remaining three pregnancies had abnormal outcomes as described below (time of onset of maternal illness shown in parentheses): (1st trimester) intrauterine fetal death at 16 weeks; no congenital abnormalities; no inflammation noted in fetal tissues; culture and indirect immunofluorescence assay of placenta and fetal tissues were negative (2nd trimester) syndactyly (type 1) of second and third toes (2nd trimester) full-term, healthy male infant at birth, developed cortical blindness and developmental delay at 8 months of age; diagnostic studies were negative; no serum antibodies to B. burgdorferi found at 1 year of age; mother had a previous child with trisomy 18 None of the five adverse outcomes described above can be directly attributed to maternal Lyme disease (5). At least one is known to be a fairly common genetic defect (i.e., syndactyly), and two were minor, transient adverse effects (5). Moreover, no cardiovascular anomalies were observed, but because only eight cases with ECM occurred in the 1st trimester, the power of this study to detect such defects is limited (5).
Two reports from the same group of investigators, one published in 1993 and the other in 1995, examined the effects of maternal exposure to Lyme disease and pregnancy outcome (6,7). A total of 2,014 women were enrolled in the first study at their first prenatal visit (6). Of these, 11 were seropositive for Lyme disease, but information on the presence of congenital malformations was available for only 10 of their infants. Among these 10 newborns, one infant had a major defect (multiple major anomalies with VATER association [vertebral defects, imperforate anus, tracheoesophageal fistula, and radial and renal dysplasia]) (6). Two other infants had minor malformations: metatarsus adductus and stomach reflux. Other outcome data included no spontaneous abortions and a mean birth weight of 3650 g. None of these outcomes differed significantly from the group without Lyme disease exposure (i.e., with no significant titer and negative clinical history) (6).
In the second study, no difference in the incidence of total congenital malformations (odds ratio [OR] 0.87; 95% confidence interval [CI] 0.701.06) was observed in the infants of mothers in an endemic hospital cohort (N=2,504) compared with the infants of mothers in a control hospital (N=2,507) (7). The total number represented 81% of all eligible infants. However, the rate of cardiac malformations (most commonly ventricular septal defect [VSD]) was significantly higher in the endemic cohort (OR 2.40; 95% CI 1.254.59). Although the incidence of total minor malformations was no different between the groups, three minor defects (hemangiomas, polydactyly, and hydrocele) were significantly higher (p<0.05) in the control group. Only the difference in polydactyly could be explained by demographic variations (7). A comparison of mean birth weights between the cohorts found no significant differences.
In the endemic cohort, 22 of the mothers had Lyme disease before pregnancy (7). Among their 23 offspring (1 set of twins), there were two major malformations: multiple heart defects (infant died), and hydrocele and laryngomalacia. Six mothers contracted the disease during pregnancy and one of their infants had a major defect (hypospadias). Three infants with major malformations (VSD, vesicoureteral block with reflux, and hypospadias) and five with minor defects (inguinal hernia, laryngomalacia, hemangioma, genu varum, and metatarsus adductus) were observed in the mothers (N=67) who had reported a tick bite during pregnancy. Of the 20 infants born from mothers who had immunoglobulin G antiB. burgdorferi antibodies in their cord blood (all infants were tested), one had a minor defect (cryptorchidism). Within the endemic cohort, there were no differences between those who had possible exposure to Lyme disease or who had positive cord serology compared with those who were not exposed and had negative serology in terms of mean birth weight or the rate of major or minor abnormalities (7).
A 1999 retrospective case-control study compared 796 children with a diagnosis of congenital cardiac anomaly with 704 children from the same region without cardiac defects (8). Records of all of the children were obtained from a medical center in a suburban area where Lyme disease is endemic. All had been born in the study area. No statistical differences in the frequencies of maternal conditions and exposures between the two groups were found for cigarette smoking, alcohol use, conception while using contraceptives, the use of fertility drugs, the use of electric blankets or heated waterbeds, vaginal bleeding during pregnancy, occupational exposure to video display terminals, asthma, upper respiratory tract infections, or thyroid disorders. More study mothers had high blood pressure (6.7% vs. 3.5%, p=0.007), whereas more controls had occupational exposure to X-ray films or anesthesia (6.1% vs. 9.1%, p=0.03). There were no statistical differences between the groups in Lyme disease during pregnancy (or 3 months, 1 year, or at anytime before conception) or in those who had received a tick bite during pregnancy (or 3 months, 1 year, or at anytime before conception). The authors concluded that there was no increased risk of congenital heart defects when maternal Lyme disease was contacted before or during pregnancy (8). However, their study could not exclude a risk to a fetus from undiagnosed and untreated Lyme disease (8).
Although there is concern that maternal Lyme disease may infect the fetus as other spirochetal infections (e.g., syphilis) do (5,9), the risk for this, based on the above studies, appears to be low. In addition, a survey published in 1994 found no cases of clinically significant nervous system disease attributable to transplacentally acquired Lyme disease that had been recognized among pediatric neurologists in regions of the United States in which Lyme disease was endemic (10). The regions surveyed included all or portions of Connecticut, Massachusetts, Minnesota, New Jersey, New York, Rhode Island, and Wisconsin. Some adult neurologists were also contacted in Connecticut. One pediatric neurologist was following three children with congenital Lyme disease, but none of the mothers of these children met the Centers for Disease Control and Prevention's diagnostic criteria for Lyme disease (10). The authors concluded that either congenital neuroborreliosis was not occurring or that the incidence was extremely low in endemic areas (10).
In summary, the occurrence of Lyme disease during pregnancy presents a serious but apparently small risk to the fetus. The greatest fetal risk may be in cases where the mother does not receive appropriate antibiotic treatment. The data to support this conclusion are limited and controversial. Because there have been no reports on the use of Lyme disease vaccine during gestation, the fetal risk from the vaccine is unknown. However, because Lyme disease itself may cause fetal harm and the vaccine is noninfectious, vaccination of women of childbearing age who are at risk for acquiring the disease may be the safest course. Although the direct risk to a fetus appears to be low, the Advisory Committee on Immunization Practices recommends that pregnant women not receive the vaccine because its safety during pregnancy has not been established (2). If a pregnant woman receives the vaccine, health care professionals are encouraged to register the case with the SmithKline Beecham Pharmaceuticals vaccination pregnancy registry by calling (800) 366-8900, extension 5231 (1).
Breast Feeding Summary
No reports describing the use of Lyme disease vaccine during lactation have been located. DNA of the spirochete B. burgdorferi has been detected in the breast milk of two women by polymerase chain reaction (PCR) (11). Breast milk samples from three healthy controls were nonreactive. Both women with reactive samples had Lyme disease as characterized by the presence of erythema migrans, and both had PCR-positive urine samples. One of the nursing infants was hospitalized at 6 months of age because of fever and vomiting. The cause of the symptoms was undetermined, but they resolved spontaneously after a few days. The urine of the infant and mother were tested 1 year later, and both were nonreactive.
- Product information. LYMErix. SmithKline Beecham Pharmaceuticals, 2001.
- CDC. Recommendations for the use of Lyme disease vaccine. Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR 1999;48(RR-7):117.
- Schlesinger PA, Duray PH, Burke BA, Steere AC, Stillman T. Maternal-fetal transmission of the Lyme disease spirochete, Borrelia burgdorferi. Ann Intern Med 1985;103:678.
- MacDonald AB, Benach JL, Burgdorfer W. Stillbirth following maternal Lyme disease. NY State J Med 1987;87:6156.
- Markowitz LE, Steere AC, Benach JL, Slade JD, Broome CV. Lyme disease during pregnancy. JAMA 1986;255:33946.
- Strobino BA, Williams CL, Abid S, Chalson R, Spierling P. Lyme disease and pregnancy outcome: a prospective study of two thousand prenatal patients. Am J Obstet Gynecol 1993;169:36774.
- Williams CL, Strobino B, Weinstein A, Spierling P, Medici F. Maternal Lyme disease and congenital malformations: a cord blood serosurvey in endemic and control areas. Paediatr Perinat Epidemiol 1995;9:32030.
- Strobino B, Abid S, Gewitz M. Maternal Lyme disease and congenital heart disease: a case-control study in an endemic area. Am J Obstet Gynecol 1999;180:7116.
- Shapiro ED. Lyme disease in children. Am J Med 1995;98(Suppl 4A):69S73S.
- Gerber MA, Zalneraitis EL. Childhood neurologic disorders and Lyme disease during pregnancy. Pediatr Neurol 1994;11:413.
Schmidt BL, Aberer E, Stockenhuber C, Klade H, Breier F, Luger A. Detection of Borrelia burgdorferi DNA by polymerase chain reaction in the urine and breast milk of patients with Lyme borreliosis. Diagn Microbiol Infect Dis 1995;21:1218.