Congenital Babesiosis After Maternal Infection With Borrelia burgdorferi and Babesia microti

Abstract

We describe the cases of 2 infants with congenital babesiosis born to mothers with prepartum Lyme disease and subclinical Babesia microti infection. The infants both developed anemia, neutropenia, and thrombocytopenia, and 1 infant required red blood cell transfusion. Both infants recovered with treatment. Additional studies are warranted to define the optimal management strategy for pregnant women with early Lyme disease in geographic areas in which B microti infection is endemic.

Babesiosis is caused by the parasite Babesia microti and transmitted in parts of North America by the Ixodes scapularis tick. Congenital transmission of babesiosis has been described in 7 previous cases [1–7]. In these reports, all the infants presented with fever, anemia, and thrombocytopenia, and they all required a blood transfusion. Here, we report 2 cases of congenital babesiosis in which a subclinical maternal B microti infection occurred concomitantly or sequentially with early Borrelia burgdorferi infection, manifested by erythema migrans. Early recognition and treatment enabled 1 of the infants to be managed without a blood transfusion. We also present the qualitative and quantitative polymerase chain reaction (PCR) data from these infants with congenital babesiosis.

CASE 1

A 4½-week-old term male infant from Westchester County, New York, presented to our emergency department after 2 days of fever and sleepiness. Review of systems revealed nothing abnormal other than the presenting symptoms. Maternal history was significant for Lyme disease at 32 weeks’ gestation that manifested as erythema migrans and was treated successfully with amoxicillin. At the time of the infant’s presentation, the mother was taking valacyclovir for herpes labialis. The infant had no known tick exposure.

On initial physical examination, the infant had normal vital signs and appeared well. He had scleral icterus and splenomegaly, but results of the remainder of his examination were normal. A complete blood count (CBC) revealed a leukocyte count of 6.5 × 10³ cells per mm³, a hemoglobin level of 8.4 g/dL, and a platelet count of 42 × 10³ cells per mm³. His absolute neutrophil count was 1040 cells per mm³. A complete metabolic panel revealed an elevated total bilirubin level of 2.8 mg/dL with a direct bilirubin level of 0.6 mg/dL. During a manual review of the blood smear, the laboratory technician observed intracellular parasites. The blood smear revealed 2% parasitemia for Babesia spp., and therapy with atovaquone and azithromycin was initiated. These agents were selected instead of clindamycin and quinine because of reports that they are tolerated better [8]. B microti DNA PCR testing of a whole-blood sample [9, 10] confirmed the diagnosis of B microti infection (Table 1).

Table 1.

Summary of Quantitative Babesia microti DNA PCR Results [10]

Case No.	Days After Initiation of Treatment	Copies/mL	Log10 Copies/mL	Ct	Qualitative Interpretation (via PCR)	Parasite Blood Smear Result (% Parasitemia)
1	0	46 880 700	7.67	19.8	Positive	2
	9	18 308	4.26	32.6	Positive	Negative
	15	6892	3.84	34.0	Positive	Negative
	20	10 115	4.00	33.5	Positive	NP
	48	ND	ND		Negative	Negative
2	−7	2 820 000	6.45	25.7	Positive	NP
	0	234 000 000	8.37	19.7	Positive	0.5
	2	54 400 000	7.74	20.8	Positive	0.7
	3	28 100 000	7.45	22.2	Positive	0.6
	4	11 400 000	7.06	23.4	Positive	0.5
	10	5650	3.75	34.2	Positive	Negative
	49	ND	ND		Negative	NP
	150	ND	ND		Negative	NP

Abbreviation: C_t, cycle threshold; ND, not detected; NP, parasite blood smear not performed; PCR, polymerase chain reaction.

The patient had fevers and periodic irritability for the first 48 hours of his hospitalization; the maximum temperature was 38.7°C, measured on the day of admission. During the initial days of his hospitalization, the infant’s CBC was monitored twice daily; his hematocrit nadir was 19.1% on day 3, his platelet nadir was 24 × 10³ cells per mm³ on day 2, and his absolute neutrophil count nadir was 100 cells per mm³ on day 3. His parasitemia level was monitored daily; the peak level (2%) was found at admission. With a low parasitemia level and no clinical signs of acute anemia, no blood transfusion was required. By day 4, the parasite blood smear results were negative and the patient’s neutrophil and platelet counts were improving. The patient was monitored in the hospital for 10 days until his anemia showed steady improvement; antimicrobial therapy was continued for 15 days. Babesia PCR results remained positive until 7 weeks after the initiation of treatment (Table 1). At the 2-month follow-up visit, the infant was clinically well, and his splenomegaly had resolved.

Additional investigation revealed that the mother had Babesia antibody testing performed 2 weeks after her diagnosis of Lyme disease, and her immunoglobulin M (IgM) titer was positive at 1:320. After the infant’s diagnosis, repeat maternal testing revealed an IgM titer of <1:10, an IgG titer of 1:320, and negative B microti PCR results. The placenta was unavailable for testing at the time of the infant’s diagnosis. The infant was seronegative for antibodies to B burgdorferi during his hospitalization.

CASE 2

An 18-day-old female infant from Putnam County, New York, was referred to the infectious diseases clinic for a maternal history of prepartum Lyme disease. The mother had fever and myalgias at 35 weeks’ gestation and erythema migrans at 37 weeks’ gestation. She received appropriate treatment with amoxicillin. Her infant was born at 38 weeks’ gestation, had no perinatal complications, and was well at the time of evaluation. Laboratory evaluation included normal CBC results and negative results for B burgdorferi antibody testing, but results of a B microti PCR assay were positive; a blood parasite smear was not performed (Table 1). The infant was asymptomatic, so testing was repeated the following week. This blood smear revealed 0.5% parasitemia, and her hematocrit level had decreased to 27.7% (from 39.2%), which prompted hospitalization for the treatment of congenital babesiosis with azithromycin and atovoquone. The infant’s hematocrit level decreased to a nadir of 20.1%, and she became neutropenic and thrombocytopenic. Because of symptomatic anemia, including malaise, tachycardia, and pallor, a blood transfusion was given to her on day 2. On day 4 of treatment, her parasite level remained constant, and her hematocrit level continued to fall, so clindamycin was added. The following day, her hematocrit level improved from 26.7% to 33.7%, and her parasitemia level decreased to 0.1%; the infant was discharged on hospital day 5. She completed 14 days of therapy with azithromycin, atovaquone, and clindamycin.

Results of the mother’s laboratory testing at the time of her presentation with erythema migrans were negative for B microti IgM and IgG. At the time of the infant’s presentation to the pediatric infectious diseases clinic, the mother’s PCR testing revealed the presence of Babesia, but results of a blood smear were negative; her antibody titers to B microti were positive for IgM and IgG (1:160 and 1:64, respectively). Results of repeat B microti PCR testing the following week were negative. The mother did not receive antibabesiosis treatment.

DISCUSSION

Congenital babesiosis remains a rare disease. Our 2 patients represent the eighth and ninth cases reported in the literature, all diagnosed in the northeast United States, where babesiosis is endemic [1–7]. To our knowledge, ours are the first cases of congenital babesiosis in infants whose mothers were diagnosed before delivery with Lyme disease and presumably had subclinical B microti infection. Our cases provide additional compelling evidence for vertical transmission of babesiosis [5].

Depending on the region in which it was contracted, 2% to 40% of patients with early Lyme disease are coinfected with babesiosis [11]. Most studies performed to determine coinfections in humans have been based on serologic testing and might represent sequential rather than concurrent infections [12–15]. No recent prospective studies to determine the rates of coinfection using PCR to better differentiate the true risk of acute coinfection have been performed. Studies that have evaluated tick populations found significant variability in the frequency of I scapularis ticks coinfected with B burgdorferi and B microti [16, 17]. A 2010 study that evaluated ticks from 2 locations within Westchester County, New York, where our hospital is located, found that at these locations, 3.6% and 22.4% of ticks were coinfected with B burgdorferi and B microti [16]. Substantial variability in the rates of coinfected ticks can exist in areas within close proximity, which makes it difficult to determine which patients with tick exposure are at higher risk for acquiring coinfection. In 1 study, patients with Lyme disease who were coinfected with B microti had more symptoms and a longer duration of illness than the patients who had only B burgdorferi infection, but in our study, the patients were treated only for Lyme disease and received no treatment for babesiosis [14]. Neither of the mothers in our cases reported severe or prolonged symptoms. The mother in case 1 had positive Babesia antibody testing results 2 weeks after her Lyme disease diagnosis. For case 2, Babesia antibody testing performed at the time of the mother’s Lyme disease diagnosis was negative.

Although the disease is rare, 6 of the 9 reported congenital babesiosis cases occurred in the past decade. On the basis of CDC surveillance, reported rates of Lyme disease have risen by more than 50% during this time; the number of cases of babesiosis, a reportable disease since 2011, has risen from 1124 in 2011 to 1759 cases in 2014 [18, 19]. Whether this increase is a result of heightened awareness and increased reporting or truly an increase in the number of cases is not known. Geographic expansion of both Lyme disease and babesiosis, however, has been demonstrated in recent years [20–23]. Future research should address the most appropriate management approach for pregnant women with early Lyme disease, with regard to obtaining a better understanding of whether Babesia testing should be performed and, if performed, which test modality should be used at which time(s). For those with positive test results, the optimal management approach still needs to be determined.

The clinical presentation of congenital babesiosis is similar across all previous reported cases. Each infant developed symptoms between 19 and 41 days of age and, at the time of presentation to medical attention, had fever, pallor, hemolytic anemia, and thrombocytopenia (Table 2). Neutropenia was present also in the majority of cases, including both cases presented here [1, 3, 5–7]. Our asymptomatic 18-day-old patient in case 2 was tested on the basis of clinical suspicion; 1 week later, she developed neutropenia and anemia. Although data are limited, neutropenia seems to be 1 of the hematologic findings associated with babesiosis [24]. The diagnosis in all cases was established by the presence of intraerythrocytic parasites on a blood smear; our cases were confirmed also by a B microti–specific real-time PCR assay. In the previously reported cases, parasite levels varied between 2% and 40% at presentation, and the majority of cases has levels between 2% and 5%. Our 2 patients had low-level parasitemia, and 1 had symptomatic anemia. Management of the patient in our first case differed from that in previous case reports in that blood product transfusions were not required for our patient. No current evidence for congenital B burgdorferi infection exists, which is consistent with the findings in our 2 cases.

Table 2.

Summary of Congenital Babesiosis Cases Reported in the Literature

	Case Reference Number
Clinical and Laboratory Data	1	2	3	4	5	6	7	8 (Case 1)	9 (Case 2)
Age at symptom onset (days)	30	32	19	27	41	34	26	39	18b
Presenting signs and symptoms	Fever, irritability, pallor, HSM	Fever, lethargy, poor feeding, pallor, scleral icterus, HSM	Fever, irritability, poor feeding, pallor, scleral icterus, HSM	Fever, pallor	Fever, irritability, poor feeding, pallor, scleral icterus, HSM	Fever, fussiness, vomiting, pallor, mottled skin	Fever	Fever, lethargy, pallor, scleral icterus, HSM	Well appearing
Parasitemia (%)	5	4.4	15	2	4	35–40	NA	2	0.5
Laboratory findings (initial, nadir)
WBC count (cells per mm3)	6500	NA	9000	NA	19,700	8000, 6500	6300	6500, 5300	9700, 6200
Neutrophils (%)	10	NA	18	NA	4	6, 9		16, 1.8	20.9, 10
Bands (%)	8	NA	3	NA	NA	11, 2		0, NA	0, NA
ANC (cells per mm3)	1170	NA	1890	NA	788	1360, 715	NA, 330a	1040, 100	2000, 1200
Hgb/HCT (g/ dL/%)	9.3/NA, NA/18	10.8/NA, 7.3/NA	8.8/NA, 7.0/NA	NA/24.3, NA/17.3	7.1/NA, 5.2/NA	6.1/16.9	NA, 6.3/18	8.4/24.9, 6.5/19.1	13.2/39.2, 7.0/20.1
PLT (×103 cells per mm3)	38	87	34, 23	101	100	23	NA, 52	42, 24	458, 79
TBili (mg/dL)	4.2	NA	5.9	NA	2	1.3	2.3	2.8	2.8
LDH (U/L)	894	NA	1912	NA	NA	2254	NA	577	NA
Infant Babesia testing results	IgM-/IgG-positive, PCR NP	IgM-/IgG-positive, PCR NP	IgM-/IgG-positive, PCR NP	NA	IgM-/IgG-positive, PCR-positive	IgM-/IgG-positive	IgM-negative/IgG-positive, PCR NP	IgM/IgG NP, PCR-positive	IgM/IgG, equivocal PCR-positive
Maternal Babesia testing	30 days postpartum, IgM-/IgG-positive, peripheral smear- negative, PCR NP	7 wk prepartum, IgM-/IgG- negative, illness onset, IgM-/IgG-positive, peripheral smear-negative	4 wk postpartum, IgM-/IgG-positive, PCR NP, peripheral smear-negative	Illness onset, IgM/ IgG NP, PCR-positive, peripheral smear NP	Birth, placenta PCR- positive; 6 wk postpartum, total AB-positive, PCR-negative, peripheral smear-negative	Postpartum IgM-/ IgG-positive, PCR-negative	4 wk postpartum, IgM/IgG and peripheral smear reported to confirm active infection	8 wk prepartum, IgM- positive; postpartum, IgM-negative/ IgG-positive	1 wk prepartum, IgM-/IgG- negative; 4 wk postpartum, IgM-/IgG-positive, peripheral smear-negative, PCR-positive
Transfusion	Yes	Yes	Yes	Yes	Yes	Yes	Yes	No	Yes
Treatment	Clindamycin, quinine	Clindamycin, quinine, azithromycin	Atovaquone, azithromycin	Atovaquone, azithromycin	Atovaquone, azithromycin	Quinine, atovaquone, azithromycin	Atovaquone, azithromycin	Atovaquone 40 mg/kg/ day (divided q12h), azithromycin 10 mg/ kg day 1 then 5 mg/ kg/day	Atovaquone 40 mg/kg/day (divided q12h), azithromycin 10 mg/kg day 1 then 5 mg/kg/day, clindamycin 30 mg/kg/day (divided q8h)
Treatment duration (days)	10	12	10	NR	9	NR	NR	15	14

Abbreviations: AB, antibody; ANC, absolute neutrophil count; HCT, hematocrit; Hgb, hemoglobin; HSM, hepatosplenomegaly; LDH, lactate dehydrogenase; NA, not available; NP, not performed; NR, not reported; PLT, platelet; qnh, every n hours; TBili, total bilirubin; WBC, white blood cell.

^aValue from personal communication with Nick Surra and John Jesus.

^bInfant’s age at time of presentation to the infectious diseases clinic, infant did not present with symptoms.

Throughout the hospitalizations, CBCs were monitored closely. For patient 1, the platelet count reached a nadir on day 2 of treatment, the same day as the last fever, whereas neutrophils reached a nadir the following day. Rising cell counts were interpreted as a favorable response to treatment. Although data are limited, platelet and neutrophil count recovery might be the first sign of improvement in patients with babesiosis and could be used as a marker of treatment response. For patient 2, the nadir platelet count was on day 2 of hospitalization and the nadir neutrophil count was on day 3. This patient did not have any recorded fevers. Patient 2’s neutropenia and thrombocytopenia improved after the addition of clindamycin. No comparative antibiotic regimen data for children exist; however, Krause et al [8] reported adverse events in 72% of adults treated with clindamycin and quinine but only 15% in those treated with azithromycin and atovoquone. Our empiric antibiotic selection for both infants was based on these adult data. Clindamycin was added to the regimen for patient 2 as a result of persistent parasitemia and decreasing hematocrit levels; however, her neutrophil and platelet counts had started to increase the day on which clindamycin was added. Because the infant’s symptoms resolved after a transfusion and her neutrophil and platelet counts were beginning to rise, clindamycin might not have been necessary. Evidence that clindamycin and atovoquone are an effective treatment combination also exists [10, 25, 26]. With so few reported cases, the optimal regimen for neonates might be difficult to determine.

Qualitative B microti PCR results are not generally useful in determining treatment response or duration of therapy, because positive results can represent detection of DNA from dead parasites [10]. Babesia PCR assays can be 20- to 100-fold more sensitive than peripheral smear examinations, and results often remain positive after the blood smear has become negative [9, 10]. The quantitative results for our infants (Table 1) reveal a nearly 4-log₁₀ reduction in B microti DNA copies/mL over the 10- to 15-day treatment courses. No clinical evidence of disease relapse in our patients was found after therapy. Reports for duration of therapy in infants with babesiosis have been variable (9–15 days in congenitally acquired [1–6] and 7–28 days in transfusion-related [27] cases). Both of our infants were treated longer than the recommended 7 to 10 days [8] because of concerns about possible impaired parasite clearance in neonates. However, had quantitative PCR results been available during the hospitalizations that revealed the significant 3- to 4-log₁₀ reduction, the clinicians might not have extended therapy.

In conclusion, congenital babesiosis is an emerging infectious disease that should be considered in the differential diagnosis of febrile neonates with anemia and thrombocytopenia, with or without neutropenia, who are born in areas of endemicity or whose mothers traveled to such areas during pregnancy. In case 1 and others [4, 5], careful evaluation of the peripheral blood smear by laboratory technicians resulted in detection of parasitemia. We presume that early recognition and treatment helped limit the parasite burden for our patients and likely contributed to the avoidance of blood transfusion for patient 1. These cases highlight the need for more research regarding the management of pregnant women with early Lyme disease in areas in which B microti infection is endemic.

Notes

Acknowledgments. We thank Yanira C. Andrade in the hematology laboratory at Westchester Medical Center for the identification of Babesia parasites during blood smear review.

Financial support. No funding was secured for this study.

Potential conflicts of interest. Dr Wormser reports receiving research grants from Immunetics, Inc, Rarecyte, Inc, Institute for Systems Biology, and Quidel Corporation; he owns equity in Abbott, has been an expert witness in malpractice cases involving Lyme disease and babesiosis, and is an unpaid board member of the American Lyme Disease Foundation. Dr Wang reports receiving research grants from Immunetics, Inc. The remaining authors have no financial relationships relevant to this article to disclose. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.