Lyme Disease in Pregnancy: Case Report and Review of the Literature

Abstract

Unlabelled:
Lyme disease is the most common vector-borne disease in the United States. A number of other spirochetal diseases, if contracted in pregnancy, have been shown to cause fetal harm and there is concern over a similar effect with gestational borreliosis. Previously published individual case reports have suggested a possible association between gestational borreliosis and adverse pregnancy outcome; however, no specific pattern of teratogenicity has been shown, and a causal relationship has never been proven. In addition, larger epidemiological and serological series have consistently failed to demonstrate an increased risk to pregnant women who develop Lyme disease if they receive appropriate antimicrobial therapy. We describe a favorable outcome in a 42-year-old woman who developed Lyme disease in the third trimester and was treated with a full course of oral amoxicillin. In addition, we offer a review of the relevant literature regarding Lyme disease and pregnancy. The appropriate investigation and management of a woman with gestational borreliosis are discussed.

Target audience:
Obstetricians & Gynecologists, Family Physicians.

Learning objectives:
After completion of this article, the reader should be able to recall that Lyme disease is not an uncommon disease during pregnancy and can occur in states outside of the Northeast, explain that the diagnosis is made clinically and may be confirmed by laboratory tests, state that treatment is recommended during pregnancy, and summarize that there is no consistent data of adverse fetal effects even though the placenta is infected.

Full text

CHIEF EDITOR’SNOTE: This article is part of a series of continuing education activities in this Journal through which a total
of 36 AMA/PRA Category 1 CreditsTM can be earned in 2007. Instructions for how CME credits can be earned appear on the
last page of the Table of Contents.
Lyme Disease in Pregnancy: Case
Report and Review of the Literature
Colin A. Walsh, MB,* Elizabeth W. Mayer, MD,† and Laxmi V. Baxi, MD‡
*Resident and ‡Professor, Department of Obstetrics and Gynecology, Columbia University Medical Center at
the New York Presbyterian Hospital, New York, New York; and †Assistant Clinical Professor, Department of
Medicine, Columbia University College of Physicians and Surgeons, New York, New York
Lyme disease is the most common vector-borne disease in the United States. A number of other
spirochetal diseases, if contracted in pregnancy, have been shown to cause fetal harm and there
is concern over a similar effect with gestational borreliosis. Previously published individual case
reports have suggested a possible association between gestational borreliosis and adverse preg-
nancy outcome; however, no specific pattern of teratogenicity has been shown, and a causal
relationship has never been proven. In addition, larger epidemiological and serological series have
consistently failed to demonstrate an increased risk to pregnant women who develop Lyme disease
if they receive appropriate antimicrobial therapy. We describe a favorable outcome in a 42-year-old
woman who developed Lyme disease in the third trimester and was treated with a full course of oral
amoxicillin. In addition, we offer a review of the relevant literature regarding Lyme disease and
pregnancy. The appropriate investigation and management of a woman with gestational borreliosis
are discussed.
Target Audience: Obstetricians & Gynecologists, Family Physicians
Learning Objectives: After completion of this article, the reader should be able to recall that Lyme
disease is not an uncommon disease during pregnancy and can occur in states outside of the Northeast,
explain that the diagnosis is made clinically and may be confirmed by laboratory tests, state that treatment
is recommended during pregnancy, and summarize that there is no consistent data of adverse fetal
effects even though the placenta is infected.
Lyme disease is the most common vector-borne disease
in the United States (1). It is caused by the spirochete
Borrelia burgdorferi and transmitted by the deer tick Ix-
odes dammini. Other spirochetal infections, most notably
syphilis, are known to cross the placental barrier and cause
well-defined effects in the fetus. As such, it is hypothe-
sized that Lyme disease, contracted in pregnancy, may
give rise to its own congenital syndrome, although this
remains unproven. Here we present the case of a woman
who presented with Lyme arthritis at 34 weeks gestation
and had a favorable outcome following antimicrobial treat-
ment. In addition, we review available literature on Lyme
disease in pregnancy, as well as the appropriate manage-
ment of a woman presenting in pregnancy with evidence
of gestational borreliosis.
CASE REPORTS
A 42-year-old woman, gravida 4 para 2, presented
at 34 weeks gestation complaining of new onset left
knee pain for one week. Her antepartum course had
The authors have disclosed that they have no financial relation-
ships with or interests in any commercial companies pertaining to
this educational activity.
Lippincott Continuing Medical Education Institute, Inc. has
identified and resolved all faculty conflicts of interest regarding
this educational activity.
Reprints will not be available.
Address correspondence to: Dr. Laxmi Baxi, Professor of Clin-
ical Obstetrics and Gynecology, Columbia University Medical
Center, New York, NY 10032. E-mail: lvb1@columbia.edu.
CME REVIEWARTICLE
Volume 62, Number 1
OBSTETRICAL AND GYNECOLOGICAL SURVEY
Copyright © 2006
by Lippincott Williams & Wilkins
1
41

been uncomplicated, including a nonreactive Rapid
Plasma Reagin for syphilis. On physical examina-
tion, the left knee joint was swollen and tender to
palpation. Examination of the musculoskeletal sys-
tem was otherwise unremarkable. There was no ob-
vious rash. She lived in New York City and denied
recent sick contacts. Of note, the previous summer
she had begun spending time in the Hamptons on
Long Island. Her past medical history was unremark-
able, although of note, she was investigated for knee
and hip pain at age 32. At this time, antinuclear
antibody, rheumatoid factor, and Lyme testing by
Western blot were negative, and the arthralgia was
attributed to exercise-related trauma.
The patient was referred to the orthopedic service
for further evaluation. Arthrocentesis of the left knee,
performed at 34 ⫹5 weeks, revealed a blood-stained
effusion, containing 44,000 white cells and 74,000
red cells per mm3. Aerobic and anaerobic cultures of
the fluid were negative. Serological testing of anti-
DNA, ANA, and rheumatoid factor was negative.
However, ELISA testing revealed positive Lyme an-
tibodies (ratio 4.21). This was confirmed by Western
blot analysis, which was consistent with (⫹) IgM and
(⫹) IgG antibodies. Polymerase chain reaction (PCR)
performed on the fluid aspirated during arthrocentesis
showed no evidence of B. burgdorferi. Oral amoxicillin
500 mg t.i.d. was commenced. One week later, the
patient developed significant swelling of the other knee
and 150 mL of fluid was aspirated by arthrocentesis
with symptomatic relief. On the chance that the pla-
centa was involved, weekly assessment of the fetus by
biophysical profile was performed. At 39 ⫹2 weeks
she underwent elective induction of labor, and delivered
a healthy female infant. Mother and baby were dis-
charged home on postpartum day two.
Pathological examination of the placenta, using Go-
mori methenamine and Warthin Starry silver stains, did
not identify any spirochetes. Serological testing of the
umbilical cord blood revealed (⫹) IgG antibody, likely
to have crossed from the maternal circulation, and (⫺)
IgM antibody. After delivery, her arthritis flared again.
At this time, synovial fluid drained at arthrocentesis was
positive for B. burgdorferi by PCR. She was re-treated
with a course of oral amoxicillin (500 mg t.i.d. for 14
days) and is currently doing well, five months postpar-
tum. At no stage did she manifest any neurological or
cardiac complications.
DISCUSSION
Lyme disease is a tick-borne illness, first described
in 1977, following an outbreak of oligoarticular ar-
thritis in Old Lyme, Connecticut. The spirochete
Borrelia burgdorferi, identified in 1982 by Burgdor-
fer et al (2), is the principal etiological agent, with
other members of the Borrelia species accounting for
a minority of cases. It is transmitted by the deer tick,
Ixodes dammini and, to a lesser degree, by other vec-
tors, including Ixodes pacificus (3). Lyme borreliosis
has been described in the United States, Europe, China,
Australia, and a number of other regions. Indeed, anti-
bodies to B. burgdorferi were found in 30% of blood
donors in Dar Es Salam in Africa (4). Regions where
Lyme disease is endemic mirror the geographic distri-
bution of its main vector, I. dammini.
As classically described by Steere et al (5), Lyme
disease occurs in three stages, although these stages
are broadly defined and may overlap, or occur out of
sequence. Early localized disease is characterized by
the “erythema (chronicum) migrans” (EM) rash, an
expanding red annular lesion often with a clear center
(Bull’s eye), which usually appears between four
days and three weeks after the tick bite. Although
pathognomonic, EM is not seen uniformly, and esti-
mates of its occurrence range from 50% to 80% of
cases (6,7). A significant portion of patients can de-
velop multiple, smaller secondary skin lesions, which
spare the palms and soles. The second stage of the
disease is characterized by neurological or cardiac find-
ings. The typical presentation of neurological Lyme
disease is meningitis, cranial nerve palsies (7th and, less
frequently, 3rd and 6th nerves), and peripheral radicu-
lopathies, although only a minority of patients will
exhibit this triad. Cardiac disease usually manifests as
atrioventricular (AV) block, most commonly 1st-degree
AV block. Myocardial dysfunction is much less com-
mon. Late Lyme disease is suggested by chronic
arthritis and/or neurological problems. Intermittent
inflammatory arthritis of a large joint, especially the
knee, is typical of late Lyme disease and should be
distinguished from the generalized arthralgias, which
commonly occur in the early stage. Large joint effu-
sions may occur, although B. burgdorferi is rarely
isolated from the effusion. Neurological sequelae
seen later include demyelination disorders, cognitive
impairment, and chronic fatigue.
Diagnosis of Lyme disease
Lyme disease may be diagnosed on clinical grounds
alone, if the erythema migrans rash is present. Labora-
tory studies are likely to be negative at this early stage
in the infection. Serological diagnosis is indicated when
the clinical picture is not diagnostic. Enzyme-linked
immunosorbent assay (ELISA) is the most commonly
42 Obstetrical and Gynecological Survey

used initial test. The result from an ELISA is expressed
as a ratio of the sample’s optical density to that of a set
of normal values, with ⬎1.00 considered reactive and
⬍1.00 nonreactive. ELISA is associated with sensitiv-
ities of 68%–84% and specificities of 83%–100%, de-
pending on the commercial kit used (8). Given the high
rate of false positive serology associated with ELISA
assays, positive (and equivocal) ELISA results should
be confirmed with the more specific Western Blot anal-
ysis. Western blot (immunoblot) detects antibodies to
individual components of the organism itself, such as
outer surface proteins and heat shock proteins (osp).
The Centers for Disease Control and Prevention have
proposed criteria for interpreting Western blot results,
with the detection of various proteins consistent with
IgM and/or IgG positivity (9). IgM antibodies to B.
burgdorferi appear 2–4 weeks after the EM rash and
decline to low levels after 4–6 months. IgG antibodies
appear after 6–8 weeks, peak at 4–6 months, and
remain elevated despite therapy. As such, although
positive ELISA and Western blot testing indicate
the presence of antibodies to B. burgdorferi, they
do not make the diagnosis of active Lyme disease
as the antibodies persist long after the disease was
treated. In view of this, the diagnosis of Lyme
disease should never be made on laboratory evi-
dence alone. The diagnosis should be based upon
the clinical likelihood of the disease, with serolog-
ical testing used for confirmation.
Literature Search
This review is based on a search of PubMed, re-
stricted to English-language articles published between
1977 and 2005. The following terms were used in the
literature search: Lyme disease in pregnancy, gesta-
tional borreliosis, and erythema migrans in pregnancy.
Individual case reports, retrospective and prospective
cohort studies, and review articles were included, with
further references obtained from articles identified in
the initial search.
Cases with Pathologic Correlation
In 1983, the first case of transplacental transmission
of presumed B. burgdorferi was reported by Shirts et al
(10). A 27-year-old woman presented at 30 weeks ges-
tation with fever of unknown etiology. She was treated
with cefemandole and a cesarean delivery was subse-
quently performed at 34 weeks for nonreassuring fetal
status. Initially, the infant had hyperbilirubinemia and a
petechial rash, but did well following ampicillin treat-
ment. Although no serological tests for Lyme disease
were available, a peripheral blood smear from the infant
revealed Borrelia-like spirochetes. In addition, exami-
nation of the placenta showed Borrelia within the lu-
men of the cord vessels. Although the woman lived in
an area endemic for Lyme disease, the results of testing
for syphilis were not reported and a positive diagnosis
of B. burgdorferi was not made.
Following this, Schlesinger et al (11) reported the
first well-documented case of transplacental trans-
mission of confirmed B. burgdorferi. He described a
woman who developed EM-associated Lyme disease
in the first trimester and did not receive antibiotics.
Subsequently, her infant was born at 35 weeks and died
at 39 hours of age. Postmortem examination revealed
multiple cardiac defects, and spirochetes were demon-
strated in the infant’s spleen, kidneys, bone marrow,
and later, in the myocardium. MacDonald et al (12)
described a similar case, in which a retrospective diag-
nosis of Lyme infection was made in a woman who
delivered a stillborn infant. Despite a clinical history
consistent with EM in the first trimester, antimicrobial
therapy had not been instituted. A small ventricular
septal defect was found at autopsy and spirochetes were
demonstrated in the fetal adrenal gland, myocardium,
liver, and in the placenta. In a later publication by the
same author (13), the case of a 23-year-old woman
who presented with EM and aseptic meningitis in
the second trimester of pregnancy was reported.
She was treated with penicillin, and a healthy
infant was delivered at term with no evidence of
spirochetes on placental examination.
Adverse pregnancy outcome associated with Lyme
disease, despite antibiotic therapy, was first reported
by Weber et al (14). The woman in this case received
seven days of oral penicillin, after developing EM in
the first trimester. Her infant was delivered at term by
vacuum extraction and died within day 1 of life from
acute respiratory distress. Postmortem examination
revealed small areas of hemorrhage in the tentorium
and falx cerebri, associated with microscopic cere-
bral edema and congestion. B. burgdorferi was iden-
tified in the fetal brain and liver. The diagnosis was
that of respiratory failure as a consequence of “peri-
natal brain damage.”
A 29-year-old woman who developed EM at 24
weeks was described by Mikkelsen et al (15). Sero-
logical testing demonstrated positive antibodies to B.
burgdorferi and she received penicillin. A healthy
infant was delivered at 39 weeks, and serological and
pathological examinations were negative. Schutzer et
al (6) reported the appearance of EM in a woman at
27 weeks. She was treated with ceftriaxone and de-
livered a healthy infant at term. Lavoie et al (16)
Lyme Disease in Pregnancy YCME Review Article 43

reported a neonatal death on day 8 of life secondary
to severe hypertension, metabolic acidosis, myocar-
dial dysfunction, and abdominal aortic thrombosis.
Although his mother was seronegative for Lyme
antibodies, autopsy revealed spirochetes in the brain
and heart, with B. burgdorferi cultured from the
frontal cerebral cortex. The mother gave a history of
migratory arthralgias over a number of years.
MacDonald performed a study of perinatal autop-
sies and placental pathology examinations between
1978 and 1988 in Long Island in New York, a region
endemic for Lyme disease (13). He documented 13
cases of transplacental transmission of B. burgdor-
feri, in which the organism was identified in fetal
tissues by culture (5 cases), immunohistochemistry
(2 cases) or indirect immunofluorescence (6 cases).
In only one of these cases was Lyme disease diag-
nosed during the pregnancy. A 28-year-old woman
developed EM during the 2nd trimester and was
treated with oral penicillin. Following birth, placental
cultures yielded spirochetes although the infant did
well. The remaining cases were retrospective diag-
noses made following adverse pregnancy outcomes
associated with unrecognized, and therefore un-
treated, gestational Lyme disease. They included a
term stillbirth in a mother who gave a history of
borreliosis in the first trimester, which was previ-
ously reported by the same author (13). There were 6
cases of transplacental transmission associated with
spontaneous mid-trimester abortions, 4 of which had
congenital anomalies including, atrial septal defect,
ventricular septal defect, coarctation of the aorta, and
hydrocephalus. There were 2 cases of early neonatal
deaths with evidence of spirochetes in fetal tissue
(although B. burgdorferi is not specified). Both these
cases had ventricular septal defects and in addition,
one had omphalocele and meningomyelocele and the
other had an absent left hemidiaphragm. B.burgdor-
feri was also cultured from renal tissue in a normally
formed 12 week abortus. Finally, spirochetes were
found in the placentas of two term live-born infants
who developed respiratory distress, but ultimately
did well.
Additional Reports and Series
Markowitz et al (17) reported 19 cases of gestational
borreliosis, with onset between 1976 and 1984. Seven-
teen had the EM rash, characteristic of this infection
and, of these, 13 received appropriate antibiotic therapy.
Two women presented without the EM rash—one with
facial palsy and arthritis and the other with arthritis and
positive serology. Neither received antibiotic therapy.
Normal pregnancy outcome, with term gestation and no
anatomic or developmental anomalies, occurred in 14
(74%) of women. Adverse pregnancy outcomes were
reported in the remaining 5 cases—2 cases with onset
of infection in the 1st trimester, 2 in the 2nd trimester
and one in the 3rd trimester. Adverse outcome was
reported in 77% (10/13) of those who received antimi-
crobial therapy, and 66% (4/6) of those who did not. In
no case of an adverse outcome was there evidence of B.
burgdorferi infection in the fetus or infant.
A 34-year-old presented with EM at 6 weeks, was
treated with penicillin, and had an intrauterine fetal
demise at 20 weeks. Postmortem examination and
culture and immunofluorescence of fetal tissue were
normal. A 32-year-old who developed fever and fa-
cial palsy at 10 weeks was not treated. She delivered
a healthy infant at 36 weeks. A 30-year-old woman,
who was treated with erythromycin for EM at 20
weeks, delivered an infant with syndactyly of the
2nd/3rd toes but was otherwise healthy. The fourth
adverse outcome was in a 31-year-old woman who
was treated with oral penicillin after developing EM
at 27 weeks. Her infant, born at term, was subse-
quently diagnosed with cortical blindness and devel-
opmental delay at 8 months of age. By 1 year of age,
the child had no serum antibodies to B. burgdorferi.
Work-up for other etiologies for the blindness was
negative. The final adverse outcome, a generalized
petechial rash, occurred in an infant born to a 31-
year-old woman who developed EM and meningitis
at 37 weeks. The infant was delivered 1 week later
and, following treatment with penicillin for 10 days,
the rash faded.
Following a number of individual case reports docu-
menting congenital cardiac lesions on a background of
maternal gestational Lyme disease (11,12,16,18), a ret-
rospective case control study was performed by
Strobino et al (19) to evaluate a possible causal rela-
tionship between the two. 1957 children with cardiac
anomalies were matched to 2750 control subjects. A
questionnaire was used to assess maternal history of
tick-bites and prior diagnosis of Lyme disease. They
found no association between a maternal history of
preconception or periconception Lyme disease and con-
genital heart disease.
Maraspin et al (20) reported the outcomes of 58
Slovenian women with erythema migrans in pregnancy.
In a later publication, they extended this evaluation to
105 women (21). The intent was to treat all with 14
days of antibiotics, although in 3 cases, ceftriaxone
therapy was discontinued prematurely after develop-
ment of a rash. Ninety-three women (89%) delivered a
healthy infant at term. Adverse outcomes were docu-
44 Obstetrical and Gynecological Survey

mented in the remaining 12 cases, although the authors
note that the incidence of preterm delivery, total con-
genital malformations, cardiac anomalies, and missed
abortion in their cohort was not higher than that of their
general obstetric population (Table 1).
Serological Investigations
There are a number of studies that attempt to
answer whether or not mothers who are seropositive
(positive IgG) for Lyme disease at conception are at
increased risk for adverse outcomes. Nadal et al (18)
examined cord blood samples from 1416 mothers in
a one-year period in a Swiss population. Antibodies
to B. burgdorferi (IgG ⬎1:64) were found in 15
cases. However, 3 of these women had syphilis, con-
firmed by serology, and thus, their Lyme serology was
probably falsely positive. This left 12 women (0.85%)
with true positive serology, of which one had evidence
of active Lyme disease during the 1st trimester of
pregnancy, which went undiagnosed and untreated. Her
infant was born with an isolated VSD, and had negative
serology at 10 months of age. There were 6 minor
adverse outcomes among the remaining infants, includ-
ing low birth weight (chronic placental insufficiency),
hypotonia (reported as attributable to a maternal medi-
cation), macrocephaly, supraventricular tachycardia,
and hyperbilirubinemia (2 cases). These 6 infants were
all normal at 9–17 months of age. A causal relationship
between seropositivity in the mother and congenital
anomalies was not established in this series.
A larger, prospective study was subsequently per-
formed by Strobino et al (22). They recruited 2014
pregnant women in Westchester, New York, an area
where Lyme disease is endemic. Testing for Lyme
serology was performed at the first antenatal visit and
again at delivery. Eleven women (0.7%) were seropos-
itive at the initial visit, of whom, 5 gave a history of
previous Lyme disease. Of the initially seropositive
group, 2 women subsequently delivered infants with
minor anomalies (metatarsus adductus and stomach re-
flux) and 1 woman delivered an infant with the VATER
association. One woman seroconverted during preg-
nancy, and her infant was unaffected. Significant dif-
ferences in obstetric outcomes between the seropositive
and seronegative women were not observed. Specifi-
cally, neither active disease, nor a history of disease,
was associated with fetal death, decreased birth-weight,
or preterm delivery.
In a subsequent study, the same authors compared
umbilical cord samples from 2057 children born in
an area endemic for Lyme disease, to the same num-
ber born in a nonendemic area (23). The cord blood
was positive for IgG antibodies to B. burgdorferi in
0.8% of cases in the nonendemic region, but in 8% of
cases in the endemic region. No samples in either
group demonstrated IgM antibodies. Six women in
the endemic group reported Lyme disease in the
index pregnancy, and all were treated with antibiot-
ics. Of these, hypospadias was seen in one infant,
with normal outcomes in the other five cases. A
general increase in congenital malformations was not
demonstrated in the endemic group; indeed, overall
malformations were slightly more common in the
control group (89 vs. 78 per 1000) although the
difference was not statistically significant. However,
there were more cardiac malformations in infants
born in the borreliosis-endemic area (13 vs. 5 per
1000; P⬍0.05). Interestingly, within the endemic
population, no relationship was found between the
rate of cardiac malformations and a history of clinical
or serological Lyme disease, and whether borreliosis
was responsible for the difference between the two
areas is not clear. In another serological study of 143
women, Dlesk et al (24) reported that asymptomatic
Lyme seropositivity did not increase the risk of spon-
taneous abortion.
Lyme-Associated Neurological Disease in
Pregnancy
Facial nerve palsy, the most commonly seen cra-
nial nerve palsy, complicates approximately 10% of
cases of Lyme disease (25). It is bilateral in approx-
imately 8% of cases (26). There are 2 reported cases
of gestational borreliosis presenting as isolated facial
nerve palsy. Schaumann et al (27) reported the case
of a woman who developed unilateral facial nerve
palsy in the second trimester of a dizygotic twin
pregnancy. She recalled a tick bite one month earlier
while hiking. Lyme disease was confirmed by sero-
logical testing and she was treated with intravenous
ceftriaxone for 14 days. Cord blood samples and
PCR of placental tissue were negative for B. burg-
dorferi. Grandsaerd et al (28) described the occur-
rence of borreliosis-related facial palsy in a woman at
14 weeks gestation. Maternal serology was positive,
and she was also treated with a 14-day regimen of
ceftriaxone. Both mothers delivered healthy infants
without complication.
Congenital Borreliosis Syndrome?
Although the population studies are quite large, the
total numbers of women reported in the literature with
onset of Lyme disease in pregnancy are still relatively
Lyme Disease in Pregnancy YCME Review Article 45

TABLE 1
Lyme disease in pregnancy: a review of the literature
Author Presentation Tri-mester Treatment Route Days
Gestation at
Delivery
(Weeks)
Placental
Cultures
Maternal
Serology Outcome
Shirts10 Fever 3 Cefamandole IV 10 38 (⫹) N/A Transient hyperbilirubinemia
Schlesinger11 EM, arthralgia 1 No treatment — — 35 N/A (⫹) NND from cardiac defects
MacDonald12 EM 1 No treatment — — Term (⫹)(⫹) Intrauterine death/AVSD
Weber14 EM 1 1 m units propicillin tid PO 7 Term N/A (⫺) NND/respiratory failure from
“perinatal brain damage”
Mikkelsen15 EM 2 1 m units phenoxy-
methylpenicillin t.i.d.
IV 10 39 (⫺)(⫺) Normal
MacDonald13 EM, aseptic
meningitis
2 Penicillin IV 10 38 (⫺)(⫺) Normal
Lavoie16 Arthralgia N/A No treatment — — — (⫺)(⫺) NND/myocardial dysfunction
Trevisan29 None N/A No treatment — — 39 N/A (⫹) Recurrent adenopathy
Grandsaerd28 VII nerve palsy 2 2 gm ceftriaxone daily IV 14 38 N/A (⫹) Normal
Markowitz17 EM (17) 1 (8) Penicillin (12) PO N/A 20 – 40 (⫺) (1) (⫺) (5) 14 term—normal
VII nerve palsy 2 (7) PO N/A N/A N/A (14) One 20 week intrauterine
demise
and arthritis (1) 3 (2) Erythromycin (18) One 36 week—normal
Arthritis (1) N/A and penicillin (1) One term with syndactyly
(2) — — One term with cortical
blindness
No treatment (6) One term with petechial rash
Schutzer6EM 3 2 gm ceftriaxone daily IV 21 N/A N/A (⫹) Normal
Maraspin21 EM (105) 1 (25) 2 gm ceftriaxone daily IV 14 25– 40 N/A (⫺) (95) 93 term—normal
2 (43) (100) (105) (⫹) (10) Two 25 week NND
3 (37) One 26 week with RDS
10 m units benzyl-
penicillin b.i.d. (3)
IV 14 One 33 week
hyperbilirubinemia
Two 36 week (1 AVSD, 1
normal)
Three term with urological
anomalies
1 m units phenoxy-
penicillin t.i.d. (2)
PO 14 One term with syndactyly
Two spontaneous abortions
Strobino22 Flu-like illness 2 No treatment — — N/A N/A (⫹) Normal
Nadal18 EM, arthralgia,
headache
1 No treatment — — N/A N/A (⫹) VSD
Schaumann27 VII nerve palsy 2 2 gm ceftriaxone daily IV 14 N/A N/A (⫹) Normal (twins)
Numbers in parentheses indicate number of cases. N/A, not available; PO, oral; IV, intravenous; NND, neonatal death; RDS, respiratory distress syndrome; AVSD, atrioventricular
septal defect.
46 Obstetrical and Gynecological Survey

small (Table 1). There remains concern over the poten-
tial for a “congenital borreliosis syndrome,” similar to
that seen with syphilis and, indeed, with leptospirosis
and relapsing fever. Trevisan et al (29) reported the case
of recurrent rash and lymphadenopathy in an infant,
beginning at 3 weeks of age. Punch biopsy of the skin
lesions revealed spirochetal infection, resembling B.
burgdorferi. Maternal serology showed positivity for
the IgG antibody, which implies maternal exposure
before delivery, although whether this occurred in preg-
nancy is unclear. Serological testing for borreliosis in
the infant was initially negative by Western blot, al-
though on a subsequent presentation, IgG antibody was
positive by Western blot criteria.
Gerber et al (30) surveyed 162 pediatric neurolo-
gists in Lyme endemic areas, to see whether neuro-
logical sequelae similar to those seen with congenital
syphilis were present in children with a positive
history of Lyme disease. No congenital neurological
syndrome related to borreliosis was identified, al-
though clearly this only relates to potential congen-
ital problems with a neurological component. From
the evidence available, it seems reasonable to con-
clude that no distinct pattern of teratogenicity from
Lyme infection has been described, and the existence
of a congenital Lyme syndrome analogous to con-
genital syphilis remains unproven.
Treatment of Lyme Disease in Pregnancy
In 2000, the Infectious Diseases Society of Amer-
ica published evidence-based recommendations for
treatment of Lyme disease (31). Although the opti-
mal antimicrobial therapy for pregnant women pre-
senting with Lyme disease is not clearly defined,
their recommendation was that pregnant women re-
ceive the same therapy as the nonpregnant population
according to the manifestation of their disease. How-
ever, some agents, which are commonly used outside
pregnancy–primarily doxycycline–are not suitable
for use in pregnant women. Amoxicillin and third-
generation cephalosporins are considered safe in
pregnancy and form the mainstay of treatment. First-
generation cephalosporins are ineffective, in vitro
and clinically, and should be avoided (32).
Although it is accepted that gestational borreliosis
requires prompt treatment, there is insufficient data to
support the routine use of intravenous regimens in all
cases. Early localized infection should be treated with
oral amoxicillin 500 mg three times daily for 14–21
days (31,33,34). In allergic patients, cefuroxine axetil
500 mg twice daily may be substituted. Neurological
complications require intravenous ceftriaxone (2 gm
daily) or cefotaxime (2 gm three times daily) for 14–28
days, although the oral regimen above may be consid-
ered in the event of an isolated facial nerve palsy
without evidence of neuroborreliosis. Arthritis may be
treated either with an extended (30–60 days) oral regi-
men or with intravenous agents. While oral treatment
may be suitable for 1st-degree AV block, more serious
cardiac manifestations require intravenous treatment
and possibly cardiac monitoring. Macrolide antibiotics
are not recommended as first-line agents and should be
reserved for women intolerant of amoxicillin or cefu-
roxime axetil. Based on the large serological studies
outlined above (17,22), there does not appear to be
evidence to support the routine treatment of women
who are seropositive for antibodies to B. burgdorferi at
the time of conception.
Prevention of Lyme Disease in Pregnancy
The best method currently available for prevent-
ing Lyme disease in pregnancy is avoidance of
exposure to the vector ticks. However, if exposure
cannot be avoided in nonpregnant patients, most author-
ities recommend the use of tick repellents, such as
DEET (N,N-diethyl-3-methylbenxamide) (35). Reas-
suringly, there is no evidence that the use of DEET by
pregnant women poses a threat to the developing fetus
(36,37). In addition, women in areas endemic for Lyme
disease should perform regular self-examinations for
evidence of ticks. There is some evidence that trans-
mission of B. burgdorferi is more likely with prolonged
tick attachment and so, if found, prompt removal of
ticks is prudent, and may reduce infection rates. Several
prospective, randomized, double-blinded trials involve
nonpregnant persons bitten by I. scapularis ticks who
were then treated empirically with placebo, penicillin,
tetracycline, or amoxicillin (38–40). The conclusion
from these trials is that routine antimicrobial prophy-
laxis is not recommended for all persons following a
tick bite. However, some practitioners treat pregnant
women differently, and do prescribe amoxicillin after a
tick bite, particularly in cases of prolonged (⬎48 hours)
tick attachment in highly endemic regions. Although no
study has looked specifically at the role of prophylactic
antibiotic treatment in the pregnant population after tick
exposure, data from the larger series detailed above
suggest that favorable outcomes can be expected when
gestational borreliosis is treated with standard antibiotic
regimens. If prophylactic antibiotics are not adminis-
tered, women exposed to ticks should be monitored
closely for signs of tick-borne illness.
Lyme Disease in Pregnancy YCME Review Article 47

The Effect of Pregnancy on Lyme Disease
It has been proposed that the increased progesterone
and interleukin-4 production seen in pregnant women
may affect the clinical course of Lyme disease in these
women when compared to a nonpregnant cohort. Ani-
mal studies have found an attenuation of the effects of
Lyme disease in a pregnant mouse model (41). How-
ever, there are currently no studies to substantiate this
effect in pregnant human subjects.
Questions that Arise
Can the Organism Responsible for Lyme Disease
Cross the Placenta?
The possibility of transplacental infection with
Borrelia burgdorferi has been well documented by a
number of individual reports (11,12,14,16).
Does Transplacental Transmission Increase the
Likelihood of an Adverse Pregnancy Outcome and
is There a Specific Pattern of Complications That
Can Occur?
Whether transplacental transmission of B. burgdor-
feri poses a threat to the fetus remains unclear. The
actual numbers of women with confirmed gestational
Lyme disease reported in the literature are quite small,
which limits our ability to identify specific adverse
pregnancy outcomes associated with contracting Lyme
disease while pregnant, and more importantly, to prove
a causal—and not merely a co-incidental—relationship.
A number of reports have suggested an association
between Lyme disease and various congenital anoma-
lies and pregnancy and neonatal complications. Such
associations include cardiac malformations, syndactyly,
urological anomalies, blindness, meningomyelocele,
neonatal hyperbilirubinemia, neonatal rash, and recur-
rent lymphadenopathy. However, no study has been
able to show a definitive link between gestational Lyme
disease and an increased risk of congenital anomalies.
Indeed, the wide variety of anomalies described and the
lack of a specific pattern of teratogenicity argue
against a causal link. This is further substantiated by
the consistent absence of a fetal inflammatory or
immunological response in affected cases, which
would be expected if the spirochetes were causing
active infection.
If There is Concern of Adverse Outcome, Will Anti-
microbial Therapy Ameliorate This Risk and What
is the Optimal Agent, Route of Administration and
Duration of Treatment?
Given the unproven risk to the fetus in a pregnancy
complicated by Lyme disease, it is difficult to estab-
lish with certainty the need for antimicrobial therapy
for such patients. Some reports have documented
adverse outcomes following untreated gestational
borreliosis (11,12,16,29), and the increased aware-
ness to Lyme disease recently means that our con-
clusions on untreated disease continue to be drawn
from this small number of cases. In addition, there have
been documented cases of adverse pregnancy outcome
in association with positive placental culture of B. burg-
dorferi (10,12,13). Furthermore, individual reports of
appropriately treated Lyme disease–including our
own–have shown no association with adverse fetal
outcomes (6,15,27,28). Thus, antibiotic treatment for
pregnant women with confirmed gestational borreliosis
is recommended. Suggested antibiotic regimens follow
those used in nonpregnant patients as listed above de-
termined by the initial manifestations of the infection.
Are Women With a Confirmed History Before
Pregnancy, and Thus With Positive Lyme Antibod-
ies, at Increased Risk?
A number of studies have demonstrated no increased
incidence of adverse pregnancy outcome in women who
are seropositive at conception. Neither routine serology
screening for all pregnant women nor empirical treatment
of those found to have positive Lyme serology at concep-
tion has been shown to be beneficial.
Are There Any Problems With the Literature to
Date on This Issue, as Reviewed in This Paper?
Much of the evidence on gestational Lyme disease
is derived from individual case reports. However, a
number of larger series are also included, which may
be subject to statistical bias. Many of these series use
questionnaires to assess the Lyme-related history of
women with affected infants (23) or positive serol-
ogy (19), introducing the possibility of recall bias.
Studies in areas endemic for Lyme disease, where
women are more informed on this issue and more
likely to report tick-related problems to health pro-
fessionals, may also be subject to reporting bias. The
study of pediatric neurologists to address the exis-
tence of a congenital borreliosis syndrome includes
only those cases which warrant referral to a pediatric
neurology specialist and thus contains an inherent
selection bias (30). The largest series to date on
gestational Lyme disease (21) treated every patient
with parenteral antibiotics. By the authors’ own ad-
mission, this is “rather aggressive” and is not cur-
rently recommended for otherwise uncomplicated
Lyme disease presenting with EM in pregnancy. This
limits the utility of their conclusions for incorpora-
tion into general obstetric practice.
48 Obstetrical and Gynecological Survey

CONCLUSIONS
•Lyme disease is the most common vector-borne
disease in the United States, with about 15,000
cases reported each year and rising. As such, we
can expect this disease to complicate pregnancy
with increasing frequency.
•Women suspected of contracting Lyme disease
in pregnancy should be tested for antibodies to
B. burgdorferi using ELISA techniques, fol-
lowed by Western Blot in positive or equivocal
cases, to reduce the rate of false-positive serol-
ogy. Clinical correlation is vital and the diagno-
sis of Lyme disease should never be made on the
basis of laboratory findings alone.
•Confirmed transplacental transmission of B. burg-
dorferi has been documented in several cases;
however the existence of a congenital borreliosis
syndrome, equivalent to that seen with syphilis,
remains unproven. As such, elective termination
has no role in the management of pregnancy com-
plicated by Lyme disease.
•Women with a confirmed diagnosis of Lyme dis-
ease in pregnancy should receive appropriate anti-
microbial treatment according to their disease
manifestation. Treatment regimens are essentially
the same as that of nonpregnant patients, although
doxycycline is contraindicated.
•There is no evidence for treating asymptomatic
women who are found to be seropositive for Lyme
antibodies in pregnancy.
•Routine antibiotic prophylaxis for pregnant women
following a tick-bite is not recommended.
•There is no evidence that Lyme disease can be trans-
mitted to the infant through breast-feeding (42).
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