106: Lyme Disease

Lyme disease was first reported in 1977, following an unusual cluster of adults and children with oligoarticular arthritis in a certain neighborhood of Lyme, Connecticut. Subsequently, a multisystem disease was described and attributed to the spirochete Borrelia burgdorferi. Lyme disease manifests as a spectrum of skin, musculoskeletal, cardiac, and neurologic findings. It is a vector-borne disease following the bite of an Ixodes tick—usually the black-legged Ixodes scapularis, commonly known as the deer tick. The species Ixodes includes additional subspecies (eg, I. pacificus, I. dammini, and I. ricinus) that contribute to a worldwide distribution of the disease and is known to be endemic in North and South America, Europe, Asia, Africa, and Australia. Prenatal exposure to B. burgdorferi and the development of gestational borreliosis can result in maternal Lyme disease with placentitis and transplacental infection of the fetus and newborn.

In 2009, more than 38,000 cases of Lyme disease were reported to the Centers for Disease Control and Prevention. In the United States, 44 continental states reported cases of Lyme disease, with an incidence of 12.71 in 100,000 nationwide. No specific data for the number of pregnancy-related Lyme disease is available. Estimates for active infection after exposure to a deer-tick bite are only 1–3%. Presumably the number of infected pregnant women in the United States is small.

1. Transmission. The Ixodes tick lives a 2-year life cycle consisting of 3 life stages: larval, nymph, and adult. The preferred reservoirs for the larval and nymph tick are the white-footed field mouse and for the adult tick it is the white-tailed deer. The larval stage emerges from eggs in early summer and feeds on previously infected mice from which they acquire the B. burgdorferi spirochete. The infected nymph stage emerges the next spring and is the most likely source of human infection because the activity of the feeding nymph corresponds to the outdoor activity of humans in spring and summer. The adult tick may infect before laying eggs in summer and dying soon after.

2. Human spirochetemia. Following the tick bite, the incubation period of the spirochetes is 1–32 days with a median of 11 days, followed by the first clinical signs of disease. The disease is characterized by “early” and “late” manifestations. Early disease is in 2 stages. Spirochete dissemination is presumed to be facilitated by the surface of the organism binding to human plasminogen and subsequently binding to integrins, matrix glycosaminoglycans, and extracellular matrix proteins. These complexes may explain the propensity of the spirochetes to localize to collagen fibrils in the extracellular matrices of the heart, nervous system, and bone joints. Late Lyme disease occurs months to a year or more after dissemination.

3. Placentitis and transplacental disease. Before 1990, a number of case reports had confirmed the transplacental passage of B. burgdorferi by way of identification of spirochetes in placental tissues, umbilical vessels, and fetal brain, heart, spleen, kidneys, bone marrow, liver, and adrenal glands. In 1989, MacDonald reported finding 13 cases of transplacental transmission of B. burgdorferi by way of fetal tissue cultures or immune serology.

4. Newborn disease secondary to B. burgdorferi remains undefined. A number of reviews have documented fetal demise, stillbirths, preterm births, and newborns with hyperbilirubinemia, petechial rashes, respiratory distress, and various birth defects, all thought to be related to gestational borreliosis. The most frequently studied newborn condition has been a variety of congenital heart defects, but none have been confirmed as a clinical syndrome unique to infants of mothers with documented gestational borreliosis.

Maternal Lyme disease is a result of exposure to deer ticks in known endemic areas of the United States or other endemic areas of the world. Once an expectant mother presents with a history of outdoor exposure or has dogs or cats in the home, a known tick embedment, or cutaneous lesions consistent with early disease, prompt antibiotic therapy lessens the risk for transplacental transmission of spirochetes. There are no other known predilections to Lyme disease related to pregnancy.

1. Maternal

   1. Early localized. The cutaneous stage begins with a papule at the site of the tick bite, becoming an annular erythematous migrating rash (also known as erythema migrans) with central clearing. Rash may last 3–4 weeks and is nonpruritic and painless. The early stage is often accompanied by low-grade fever, evanescent arthralgias, myalgia, fatigue, headache, and neck muscle stiffness.

   2. Early disseminated. This is most often characterized by multiple erythema migrans, several weeks after the tick bite. This stage is accompanied by worsening fatigue, severe malaise, and migratory musculoskeletal pain. Systemic disease affecting target organs becomes more apparent, namely as mono- or pauciarticular arthritis, and cardiac manifestations, such as heart block. Nervous system involvement can include lymphocytic meningitis or cranial nerve palsies.

   3. Late Lyme disease. Months after exposure to disease, arthralgias and pauciarticular arthritis persist and recur. The knees are the most often affected joint with marked swelling, but with pain that is less than that of rheumatoid-type arthritis. On rare occasions, chronic neurologic conditions of encephalopathy, peripheral neuropathy, demyelination, or dementia have been reported.

2. Neonatal

   1. No specific clinical presentation of Lyme disease in the newborn or neonatal period has been described. Of importance is the maternal history of disease and whether or not she has been adequately treated. Placental pathology in suspect cases may offer information that would prompt testing and perhaps treatment for at-risk neonates.

   2. Congenital Lyme disease as a clinical entity has been reviewed and found not to be substantive. In particular, congenital heart defects have been reviewed in large follow-up studies of mothers with positive B. burgdorferi serology. Williams et al reported in 1999 a cohort study of >5000 cord blood serologic surveys within a highly endemic area for Lyme disease (New York State). They did not find any correlation of congenital heart defects or other major or minor malformations attributable to positive maternal or cord blood serology. In 2001, Elliott et al reported a search of the world literature for teratogenic effects of gestational Lyme disease. They concluded that no effect was found, and any otherwise adverse pregnancy outcome was of low risk in the face of adequately treated gestational borreliosis. More recently, Walsh et al searched the worldwide literature for obstetric associations to Lyme disease with these conclusions:

      1. Women who are seropositive at conception have no increased incidence of adverse pregnancy.

      2. Women who develop a confirmed diagnosis of Lyme disease in pregnancy should receive appropriate antimicrobial treatment.

      3. Women with Lyme disease in pregnancy and who have been appropriately treated have shown no association with specific adverse fetal outcomes.

Laboratory testing for Lyme disease should follow if careful history taking and physical examination strongly suggest active disease.

1. Early localized disease. Diagnosis is made largely on clinical grounds (history of exposure, rash, and symptoms). Serologic tests are not recommended secondary to late development of antibodies to B. burgdorferi.

2. Early disseminated disease. Dissemination of the disease is diagnosed clinically as described earlier. If rash is not present, serologic studies should be obtained.

   1. Enzyme immunoassay (EIA).

   2. Immunofluorescent-antibody assay (IFA).

   3. If both tests are negative, no further testing is needed, and clinical reevaluation for other conditions is indicated. Screening tests are known to have high false-positive rates.

   4. If either is positive, it should be followed by:

      1. Western immunoblot standardized for antibodies to B. burgdorferi. Subsequently, positive Western blot assays should include specific immunoglobulin G (IgG) and immunoglobulin M. If the Western blot assays are negative, the false-positive EIA or IFA testing suggests other spirochetal diseases, that is, syphilis, leptospirosis, an intercurrent viral disease (eg, Epstein–Barr), or an autoimmune condition such as lupus erythematosus.

3. Late disease. If late disease is suspected, only a positive IgG immunoblot is needed.

1. Maternal

   1. Early localized disease. Note: Doxycycline is the drug of choice for Lyme disease, except in pregnancy or in children <8 years of age.

      1. Amoxicillin

      2. Cefuroxime axetil (alternative)

   2. Early disseminated or late disease

      1. Oral antibiotic therapy is considered adequate.

      2. Parenteral antibiotics for a maximum of 4 weeks are only indicated in patients with symptoms of increased intracranial pressure and pleocytosis in cerebral spinal fluid. Routine lumbar puncture is not recommended.

2. Newborn

   1. Treat if infant is thought to be symptomatic at birth especially if mother is confirmed with Lyme disease but has not been adequately or appropriately treated. Consider ceftriaxone, cefotaxime, or penicillin. Obtain infectious disease consultation before starting treatment.

   2. If the infant is asymptomatic at birth given low risk for active disease, current recommendations do not call for empirical treatment, especially if the mother was appropriately treated during pregnancy. Placental pathology may offer information helpful in the decision to treat or not; consultation with an infectious disease specialist is recommended.

   3. Lyme disease is not a contraindication for breast-feeding. No evidence is known for the passage of B. burgdorferi to the infant through breast-feeding.

Prompt diagnosis and antibiotic therapy are essential. One report has revealed that 25% of infants had adverse outcomes, 15% were sick or had an abnormality, 8% resulted in fetal death, and 2% resulted in neonatal death. Antibiotic therapy resulted in only 15% with adverse outcomes. Long-term follow-up is important for recurrence of the disease.