Brucellosis in pregnancy: a case report

Introduction

Brucellosis is one of the most prevalent zoonotic illnesses worldwide (1,2). Most cases occur in developing countries; human brucellosis is rare in the United States with approximately 124 cases recorded in 2023 by the Centers for Disease Control and Prevention (CDC) (3). The causative pathogens, Brucella spp., are small, Gram-negative coccobacilli. Of the 13 species, B. abortus, B. melitensis, B. suis, and B. canis cause human infection (4,5). B. melitensis is the most common cause of human brucellosis worldwide (2).

Most cases of human brucellosis occur through consumption of unpasteurized dairy products or contact with infected animals, their tissues, or body fluids (6,7). Other forms of transmission include inhalation of aerosols, sexual transmission, and direct contact through wounds, skin, or mucous membranes. Although extremely rare, human-to-human transmission may occur, including vertical transmission during pregnancy or through breastmilk (2,8).

Clinical manifestations of brucellosis are variable, nonspecific, and can range from asymptomatic to severe disease. Common symptoms include fever, sweats, fatigue, myalgia, arthralgia, and headache (9). Incubation period can range from 5 days up to 6 months but is often 2–4 weeks (10,11). The infection can lead to osteomyelitis, endocarditis, meningitis (5,10), and in pregnancy brucellosis, is associated with adverse obstetrical outcomes (12). We present a case of human brucellosis due to B. canis in a pregnant female acquired through transmission from a domestic dog, and the subsequent treatment course. We present this article in accordance with the CARE reporting checklist (available at https://acr.amegroups.com/article/view/10.21037/acr-24-110/rc).

Case presentation

A 17-year-old gravida 2, parity 1 (G2P1) at 35 weeks and 2 days (35w2d) gestation presented to the hospital with 10 days of lower back pain, nausea, vomiting, and costovertebral tenderness. She had suspected pyelonephritis. Blood and urine cultures were drawn prior to the initiation of empiric intravenous (IV) antibiotics. While admitted, the patient remained afebrile and normotensive. Blood cultures showed no growth at 48 hours; urine cultures grew urogenital flora. The patient reported resolution of symptoms and was discharged two days later on a 14-day course of cephalexin.

Three days after discharge, our microbiology laboratory identified Brucella spp. by matrix-assisted laser desorption/ionization-time of flight (MALDI-TOF) from the patient’s blood cultures at 96 hours. The patient was contacted and instructed to return to our facility for readmission. Blood cultures were sent to the Mississippi State Department of Health and subsequently the CDC for confirmation. Upon return, the patient continued to deny any systemic or focal symptoms, and her physical exam was unremarkable. The patient was started on ceftriaxone 2 g IV every 12 hours and rifampin 600 mg by mouth (PO) every 24 hours. Gentamicin 5 mg/kg IV was started a day later and these three antimicrobials were continued throughout her admission. During this time, she remained afebrile and hemodynamically stable. A transthoracic echocardiogram was negative for endocarditis. Further imaging studies for evaluation of metastatic sites of infection were deferred until after the patient delivered. Testing done by the CDC confirmed the identification of B. canis by polymerase chain reaction (PCR). Notably, Brucella immunoglobulin (Ig) IgM and IgG serologies were negative by enzyme-linked immunoassay. Upon questioning, the patient did not have any significant travel history. She denied any sick household contacts. She reported that her only non-human exposure was to her pet dog. She did report that she had assisted with her dog’s delivery of a litter of stillborn puppies about 6 weeks prior to the onset of symptoms.

After 8 days, the patient was discharged on rifampin and ceftriaxone with plans to later transition to rifampin and doxycycline after she delivered. Gentamicin was given while inpatient and stopped after 7 days upon her discharge. Around 2 weeks later, the patient was readmitted for delivery. Liver function tests were noted to be elevated upon readmission with alanine aminotransaminase noted at 287 units per liter (U/L) and aspartate aminotransaminase noted at 141 U/L, so rifampin was discontinued. These labs had been normal during her previous admission. The patient delivered at 39w1d via vaginal delivery with no complications. Ceftriaxone was continued, and doxycycline 100 mg by mouth (PO) twice daily was initiated after delivery.

Additional studies, done postpartum, including computed tomography (CT) scan of the chest, abdomen, and pelvis; magnetic resonance imaging (MRI) of the spine, and transesophageal echocardiogram (TEE), revealed no metastatic foci of infection. Surgical pathology of the placenta including membrane rolls and umbilical cord with full-thickness sections observed under the microscope did not show evidence of brucellosis. Trimmed, the mature placenta weighed 560 grams. There was mild maternal decidual arteriopathy noted, but no acute chorioamnionitis was identified. Blood cultures taken from the newborn on the day of delivery showed no growth after 5 days. The patient was discharged on PO doxycycline and IV ceftriaxone, and she completed a total of 6-week-course from her first negative blood cultures. The patient was instructed not to breastfeed during antibiotic treatment.

The patient and her family initially declined to euthanize the dog when it was recommended; however, the dog later confirmed positive for B. canis on serological testing done by its veterinarian and was eventually euthanized. At the time of follow-up near the completion of antibiotic therapy, the patient reported that she was feeling well and that her baby was healthy. Liver function tests had normalized upon repeat testing.

All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee(s) and with the Helsinki Declaration (as revised in 2013). Written informed consent for publication of this case report was not obtained from the patient or the relatives after all possible attempts were made.

Discussion

The first case of human abortion due to brucellosis was reported in 1905 by Thierry followed by the second case in 1906 by Devoir (12,13). While the association of brucellosis with adverse pregnancy outcomes first dates to the early 1900s, there has historically been some controversy regarding whether brucellosis is associated with an increased risk of adverse obstetric outcomes in humans (2,12-15). However, several more recent studies have found brucellosis to be associated with adverse pregnancy outcomes in humans, including spontaneous abortion, preterm delivery, intrauterine fetal demise, low birth weight, neonatal death, and congenital brucellosis (1,7,12,13,16,17). The incidence of abortion associated with brucellosis in humans does appear to be lower than in non-human animal species (13), partly due to the lack of erythritol in the human placenta (14). Erythritol, a 4-carbon sugar present in the placenta of some non-human animal species, is a known growth factor for Brucella spp. (2,13,16) and can promote expression of Brucella virulence factors (13,15,18). Furthermore, research suggests there is anti-brucellosis activity present in human amniotic fluid (2,13,16), making treatment of brucellosis in pregnancy of particular concern (13). In addition to obstetric complications, there have also been reports of transmission of the bacterium from the infected mothers to the obstetrics team during delivery as well as transmission to the infant through an infected mother’s breast milk (2,13,19). While there is not an estimated time frame for the transmission period via breastmilk, reports of infection occurring several months after delivery assumed by breastfeeding have been documented (2,6,8,19-23). Additionally, there is uncertainty as to when a mother may resume breastfeeding after treatment initiation. Some research recommends stopping until the infection is eradicated while others state breastfeeding may resume 48–96 hours after treatment begins (13,21-23).

Of note, our patient was found to have B. canis, which is a particularly rare cause of human brucellosis. There are less than 60 human cases of B. canis infection reported internationally as of a 2022 report but human exposure is likely underrecognized due to lack of B. canis serologic tests for humans (5,10,24). B. canis is endemic in Asia, Africa, and the Americas (13). The incidence and prevalence of brucellosis among pregnant women are unknown even in endemic regions. A large multicenter study reported 242 (2.1%) pregnant women among 11,602 adult brucellosis patients (13). Although predominantly in dogs, there is documentation of positive antibody titers for B. canis in foxes and coyotes and reports of B. canis in cattle and cats (4,25). Transmission to humans occurs mainly through exposure to infected dogs and their fluids, particularly maternal-fetal tissue present during delivery of puppies (5). Current seroprevalence in dogs in the United States is unknown. Previous studies done in the 1970s found that seroprevalence rates in the United States range from 0–10.1% among various shelter, stray, or domestic dog populations (4). A 2018 cross-sectional study of 571 shelter dogs in Mississippi by Hubbard et al. estimated a mean true prevalence of B. canis of 7.4% (26). Infected dogs may display nonspecific symptoms, including fatigue and weight loss. Manifestations may include spondylodiscitis, epididymitis, orchitis, and prostatitis (4,10). The cure is often difficult to achieve in dogs, and persistent infection or relapse are common; euthanasia is generally recommended (10). The CDC recommends post-exposure prophylaxis mainly to workers with high-risk exposure although considerations may be made on a case-by-case basis (27).

Although serologic testing is commonly used for diagnosis of infection with the Brucella genus, PCR and culture were the only options for diagnosing B. canis in our patient (10,24,27). This is due to the aforementioned limits on serologic testing in humans. Brucella spp. cell wall morphology is classified as either smooth or rough based on the structure of the O-polysaccharide subunit of the lipopolysaccharide (10). Commercially available serologic assays detect antibodies against smooth Brucella species only (B. abortus, melitensis, and suis) and will therefore not detect antibodies against B. canis, a smooth lipopolysaccharide, which explains our patient’s negative Brucella serologies despite confirmation of positive cultures (4,10,26,28).

Treatment of brucellosis in humans, regardless of species, typically involves combination antibiotic therapy, monotherapy is not recommended and is associated with higher rates of failure and relapse (10,29,30). The Sixth Report of the Joint Food and Agriculture Organization and World Health Organization (WHO) Expert Committee on Brucellosis from 1986 reports that rifampin 600–900 mg daily in combination with doxycycline 200 mg daily for at least 6 weeks as the treatment of choice, with doxycycline for 6 weeks in combination with streptomycin for 3 weeks as an alternate regimen (9,10,27,31). The more recent Ioannina recommendations, created from the First International Meeting on the Treatment of Human Brucellosis, published in 2007 also recommend either doxycycline-streptomycin or doxycycline-rifampin combination therapy for 6 weeks as the treatment of choice for uncomplicated brucellosis; yet, gentamicin may be substituted for streptomycin (31). Aminoglycosides are often used for shorter durations (i.e., 5–7 days) in comparison to other medications in the regimen (31). A number of other treatment regimens have been reported such as trimethoprim-sulfamethoxazole (TMP-SMX) as part of combination therapy, and ceftriaxone and fluoroquinolone-containing regimens (8,31).

Due to the risk of adverse outcomes as well as concern for the possibility of transmission to the fetus, treatment of pregnant women is of particular importance (13). However, treatment of brucellosis in pregnancy also poses some difficulty due to the teratogenicity of commonly used medications like tetracyclines, and no randomized trials exist for the treatment of brucellosis in pregnancy (9). The WHO guidelines state that rifampin is the treatment of choice in pregnancy and note that TMP-SMX and tetracycline may be considered if rifampin is unavailable, but they do not provide specific recommendations for combination therapy in pregnancy (9,12,13,17,27). The Ioannina recommendations state that data support TMP-SMX alone or combination therapy with rifampin during pregnancy.

A combination of rifampin and TMP-SMX for 6–8 weeks has commonly been used in pregnancy, although several other regimens have been reported in the literature (2,13,27,31). In a review of a retrospective cross-sectional study of 242 pregnant women by Inan et al., 11 different regimens were reported, of which ceftriaxone plus rifampin was the most common regimen, followed by TMP-SMX plus rifampin, and TMP-SMX plus ceftriaxone plus rifampin (17). There was no association between these 3 most commonly used regimens and obstetric complications. In another review of 101 cases of pregnant women with brucellosis, Vilchez et al. described an aminoglycoside plus rifampin as the most commonly used regimen during pregnancy followed by rifampin plus TMP-SMX (12). The authors recommended the use of aminoglycoside for 1 week plus rifampin and TMP-SMX for 6 weeks (12). Successful use of rifampin monotherapy for the treatment of brucellosis in pregnancy has also been reported but should be avoided due to the theoretical risk of relapse while on monotherapy (2,31-33).

As our patient presented during the 3^rd trimester, TMP-SMX was not used given its contraindication for use during the 3^rd trimester due to the risk of kernicterus (2,12,13,17). Based on a review of treatment regimens reported in the literature, we elected to initiate treatment with ceftriaxone, rifampin, and gentamicin, with plans to transition to rifampin and doxycycline after delivery (30,34). Elevated liver tests later prompted the discontinuation of rifampin, and the patient was transitioned to doxycycline and ceftriaxone after delivery. She completed the remainder of her treatment course without any adverse effects noted. Gentamicin was administered for only 7 days while admitted to the hospital. The only IV medication given outpatient was ceftriaxone, which allowed for a relatively convenient outpatient regimen without the need for frequent monitoring of antibiotic levels.

Conclusions

In conclusion, the ambiguous presentation of the disease prompts a thorough social history work up especially in pregnant patients as the potential risk of a missed diagnosis is potentially detrimental to both the mother and newborn. Given the lack of substantial updated evidence on treatment options for brucellosis in pregnancy, we believe our treatment regimen represents a potentially useful strategy in pregnancy, particularly during the third trimester when TMP-SMX cannot be used.

Acknowledgments

We would like to thank Dr. Edith N. Oliver for providing her veterinary medicine expertise for the drafting and revising of this case report.

Funding: This work was funded by the Department of OBGYN and Infectious Disease at UMMC.

Footnote

Reporting Checklist: The authors have completed the CARE reporting checklist. Available at https://acr.amegroups.com/article/view/10.21037/acr-24-110/rc

Peer Review File: Available at https://acr.amegroups.com/article/view/10.21037/acr-24-110/prf

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://acr.amegroups.com/article/view/10.21037/acr-24-110/coif). S.A. reports that this manuscript was funded by the Department of OBGYN and Infectious Disease at UMMC. The other authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee(s) and with the Helsinki Declaration (as revised in 2013). Written informed consent for publication of this case report was not obtained from the patient or the relatives after all possible attempts were made.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

References

1. Arenas-Gamboa AM, Rossetti CA, Chaki SP, et al. Human Brucellosis and Adverse Pregnancy Outcomes. Curr Trop Med Rep 2016;3:164-72. [Crossref] [PubMed]
2. Karcaaltincaba D, Sencan I, Kandemir O, et al. Does brucellosis in human pregnancy increase abortion risk? Presentation of two cases and review of literature. J Obstet Gynaecol Res 2010;36:418-23. [Crossref] [PubMed]
3. Weekly cases* of notifiable diseases, United States, U.S. Territories, and Non-U.S. Residents week ending December 23, 2023 (Week 51). Centers for Disease Control and Prevention. Accessed July 3, 2024. Available online: https://wonder.cdc.gov//nndss/static/2023/51/2023-51-table340.html
4. Hensel ME, Negron M, Arenas-Gamboa AM. Brucellosis in Dogs and Public Health Risk. Emerg Infect Dis 2018;24:1401-6. [Crossref] [PubMed]
5. Kolwijck E, Lutgens SPM, Visser VXN, et al. First Case of Human Brucella canis Infection in the Netherlands. Clin Infect Dis 2022;75:2250-2. [Crossref] [PubMed]
6. Celebi G, Külah C, Kiliç S, et al. Asymptomatic Brucella bacteraemia and isolation of Brucella melitensis biovar 3 from human breast milk. Scand J Infect Dis 2007;39:205-8. [Crossref] [PubMed]
7. Ali S, Akhter S, Neubauer H, et al. Brucellosis in pregnant women from Pakistan: an observational study. BMC Infect Dis 2016;16:468. [Crossref] [PubMed]
8. Palanduz A, Palanduz S, Güler K, et al. Brucellosis in a mother and her young infant: probable transmission by breast milk. Int J Infect Dis 2000;4:55-6. [Crossref] [PubMed]
9. Joint FAO/WHO expert committee on brucellosis. World Health Organ Tech Rep Ser 1986;740:1-132. [PubMed]
10. Pinn-Woodcock T, Frye E, Guarino C, et al. A one-health review on brucellosis in the United States. J Am Vet Med Assoc 2023;261:451-62. [Crossref] [PubMed]
11. Brucellosis. World Health Organization. Published July 29, 2020. Accessed July 3, 2024. Available online: https://www.who.int/news-room/fact-sheets/detail/brucellosis
12. Vilchez G, Espinoza M, D’Onadio G, et al. Brucellosis in pregnancy: clinical aspects and obstetric outcomes. Int J Infect Dis 2015;38:95-100. [Crossref] [PubMed]
13. Bosilkovski M, Arapović J, Keramat F. Human brucellosis in pregnancy - an overview. Bosn J Basic Med Sci 2020;20:415-22. [PubMed]
14. Mesner O, Riesenberg K, Biliar N, et al. The many faces of human-to-human transmission of brucellosis: congenital infection and outbreak of nosocomial disease related to an unrecognized clinical case. Clin Infect Dis 2007;45:e135-40. [Crossref] [PubMed]
15. Khan MY, Mah MW, Memish ZA. Brucellosis in pregnant women. Clin Infect Dis 2001;32:1172-7. [Crossref] [PubMed]
16. Alsaif M, Dabelah K, Featherstone R, et al. Consequences of brucellosis infection during pregnancy: A systematic review of the literature. Int J Infect Dis 2018;73:18-26. [Crossref] [PubMed]
17. Inan A, Erdem H, Elaldi N, et al. Brucellosis in pregnancy: results of multicenter ID-IRI study. Eur J Clin Microbiol Infect Dis 2019;38:1261-8. [Crossref] [PubMed]
18. Petersen E, Rajashekara G, Sanakkayala N, et al. Erythritol triggers expression of virulence traits in Brucella melitensis. Microbes Infect 2013;15:440-9. [Crossref] [PubMed]
19. Lubani M, Sharda D, Helin I. Probable transmission of brucellosis from breast milk to a newborn. Trop Geogr Med 1988;40:151-2. [PubMed]
20. Tuon FF, Gondolfo RB, Cerchiari N. Human-to-human transmission of Brucella - a systematic review. Trop Med Int Health 2017;22:539-46. [Crossref] [PubMed]
21. Lawrence RM. Transmission of Infectious Diseases Through Breast Milk and Breastfeeding. In: Breastfeeding. Elsevier; 2011:406-73.
22. Arroyo Carrera I, López Rodríguez MJ, Sapiña AM, et al. Probable transmission of brucellosis by breast milk. J Trop Pediatr 2006;52:380-1. [Crossref] [PubMed]
23. Tikare NV, Mantur BG, Bidari LH. Brucellar meningitis in an infant--evidence for human breast milk transmission. J Trop Pediatr 2008;54:272-4. [Crossref] [PubMed]
24. Dentinger CM, Jacob K, Lee LV, et al. Human Brucella canis Infection and Subsequent Laboratory Exposures Associated with a Puppy, New York City, 2012. Zoonoses Public Health 2015;62:407-14. [Crossref] [PubMed]
25. Cosford KL. Brucella canis: An update on research and clinical management. Can Vet J 2018;59:74-81. [PubMed]
26. Hubbard K, Wang M, Smith DR. Seroprevalence of brucellosis in Mississippi shelter dogs. Prev Vet Med 2018;159:82-6. [Crossref] [PubMed]
27. Brucellosis Reference Guide: Exposures, Testing and Prevention. Centers for Disease Control and Prevention. Published February 2017. Accessed July 3, 2024. Available online: https://stacks.cdc.gov/view/cdc/46133
28. Krueger WS, Lucero NE, Brower A, et al. Evidence for unapparent Brucella canis infections among adults with occupational exposure to dogs. Zoonoses Public Health 2014;61:509-18. [Crossref] [PubMed]
29. Alavi SM, Alavi L. Treatment of brucellosis: a systematic review of studies in recent twenty years. Caspian J Intern Med 2013;4:636-41. [PubMed]
30. Fatani DF, Alsanoosi WA, Badawi MA, et al. Ceftriaxone use in brucellosis: A case series. IDCases 2019;18:e00633. [Crossref] [PubMed]
31. Ariza J, Bosilkovski M, Cascio A, et al. Perspectives for the treatment of brucellosis in the 21st century: the Ioannina recommendations. PLoS Med 2007;4:e317. [Crossref] [PubMed]
32. Figueroa Damian R, Rojas Rodríguez L, Marcano Tochon ES. Brucellosis in pregnancy: course and perinatal results. Ginecol Obstet Mex 1995;63:190-5. [PubMed]
33. Ozbay K, Inanmis RA. Successful treatment of brucellosis in a twin pregnancy. Clin Exp Obstet Gynecol 2006;33:61-2. [PubMed]
34. Varon E, Cohen R, Bouhanna CA, et al. Brucellosis in a 3 month-old infant. Arch Fr Pediatr 1990;47:587-90. [PubMed]