MAJOR ARTICLE

Brucellosis in Pregnant Women

M. Yousuf Khan,1a Manuel W. Mah,1,2b and Ziad A. Memish1,2
1
Department of Medicine and the 2Department of Infection Prevention & Control, King Fahad National Guard Hospital, Riyadh,
Kingdom of Saudi Arabia

Brucella species occasionally cause spontaneous human abortion, but theories regarding whether they do so
more frequently than do other infectious pathogens remain controversial. We reviewed 92 pregnant women
who presented with acute brucellosis at a Saudi Arabian hospital. From 1983 through 1995, the cumulative
incidence of pregnancy and brucellosis was 1.3 cases per 1000 delivered obstetrical discharges. The incidence
of spontaneous abortion in the first and second trimesters was 43%, and the incidence of intrauterine fetal
death in the third trimester was 2%. Antepartum antimicrobial therapy with cotrimoxazole or cotrimoxazole/
rifampin was protective against spontaneous abortion (relative risk, 0.14; 95% confidence interval, 0.060.37;
P ! .0001). The beneficial effect of treatment occurred in women with febrile illness; vaginal bleeding at
presentation usually led to spontaneous abortion. This study demonstrated that the incidence of spontaneous
abortion among pregnant women with brucellosis is high and that these women should receive prompt therapy
with antimicrobial agents when they present for medical care.
Brucellosis, a zoonotic disease of global importance [1],
is endemic in Saudi Arabia (national seroprevalence,
15%) [2]. Endemicity in this region results from the
persistence of domestic animal reservoirs for Brucella
species and the human consumption of unpasteurized
dairy products [3, 4].
Various Brucella species are well-known causes of contagious abortion in cattle, sheep, goats, swine, and dogs
[5]. There is also evidence that brucellosis can produce
spontaneous abortion in humans, which has been demonstrated by rare cases in which Brucella species were
isolated from fetal or placental tissues, but it has not
been demonstrated that brucellosis causes abortions
more frequently than do other bacterial infections [6].

It is believed that brucellosis causes fewer spontaneous

abortions in humans than it does in animals because of
the absence of erythritol in the human placenta and fetus
[7]. Erythritol is a constituent of normal ungulate fetal
and placental tissue and, in cases of bovine abortion,
promotes overwhelming infection of the placenta and
fetus. An additional reason for the lesser role of Brucella
infection in human abortion is the presence of antiBrucella activity in human amniotic fluid [8].
In the present study, we reviewed the experience with
brucellosis in pregnant women at a tertiary-care hospital
in Saudi Arabia during a 13-year period. We sought to
characterize clinical presentations, the incidence of abortion, and the effect of treatment with antimicrobial agents
on the occurrence of spontaneous abortion.

Received 10 July 2000; revised 8 September 2000; electronically published 2

April 2001.

PATIENTS AND METHODS

a
Current affiliation: Department of Medicine, Maricopa Medical Center,
Phoenix, Arizona.

The King Fahad National Guard Hospital (Riyadh,

Saudi Arabia) has served the secondary- and tertiarylevel medical needs of Saudi National Guard soldiers and
their extended families since 1983. Guardsmen come
from bedouin tribes that have retained a nomadic pastoral lifestyle that includes the consumption of unpasteurized milk from goats, camels, and sheep; many of

Current affiliation: Department of Medicine, University of Calgary, Canada.

Reprints or correspondence: Dr. Ziad Memish, Infection Prevention & Control,

Dept. 2134, King Fahad National Guard Hospital, P.O. Box 22490, Riyadh 11426,
Kingdom of Saudi Arabia (memish@ngha.med.sa).
Clinical Infectious Diseases 2001; 32:11727
 2001 by the Infectious Diseases Society of America. All rights reserved.
1058-4838/2001/3208-0007$03.00

1172 CID 2001:32 (15 April) Khan et al.

these animals are known to be infected with Brucella species.

Because of their nomadic lifestyles, not all pregnant women receive prenatal care, some are lost to follow-up, and some are
treated for brucellosis at our hospital but subsequently deliver
elsewhere.
The medical record database at the hospital was reviewed,
and all patients who had a discharge diagnosis of brucellosis
and pregnancy from 1983 through 1995 were identified. The
diagnosis of acute brucellosis was based on compatible clinical
features and a serum agglutinin titer of 1:320 or a positive
blood culture result. Patient records were reviewed, and the
following information was extracted: patient age, obstetrical
history, gestational age at the time of infection, symptoms,
results of serological testing and blood cultures for Brucella,
antimicrobial therapy, delivery outcome, results of placental
cultures and histological findings, neonatal status, and neonatal
results of serological testing and cultures for Brucella. The first
trimester of pregnancy was defined as a gestational age of 12
weeks; the second trimester of pregnancy, 112 to 24 weeks;
and the third trimester of pregnancy, 124 weeks. Patients with
brucellosis were considered to have been treated if they received
therapy with cotrimoxazole, rifampin, or a tetracycline for at
least 4 weeks. Fetal deaths that occurred at 24 weeks gestation
were designated spontaneous abortions, while deaths that
occurred at 124 weeks gestation were designated intrauterine
fetal deaths.
A variety of microbiological methods were used at our hospital during the 13-year period to isolate Brucella species, determine antimicrobial susceptibility, and detect agglutinating
antibodies; these methods have been described in detail elsewhere [911]. In brief, samples of blood and body fluids were
cultured by use of the automated BACTEC System (Becton
Dickinson). Before 1987, identification of Brucella organisms
to the species level was not done because of technical limitations
in the microbiology laboratory. In subsequent years, Brucella
isolates were identified to the species level by use of standard
biochemical methods. Antimicrobial susceptibility tests were
performed according to a standard disk diffusion method. Agglutination tests for antibody to Brucella were performed by
means of a microtiter serial dilution technique.
Epidemiological associations were expressed as relative risk
with 95% CIs, and statistical significance was assessed by use
of the x2 test or 2-tailed Fishers exact test where appropriate.
All statistical measures were generated by use of Epi-Info, version 6 (Centers for Disease Control and Prevention).

(cumulative incidence, 1.3 cases of brucellosis in pregnant

women per 1000 delivered obstetrical discharges [0.3 cases of
brucellosis in pregnant women per 1000 hospital admissions]).
The characteristics of the 92 pregnant women with acute brucellosis are shown in table 1. The mean age of the women was
26.9 years. Seventy-one (81%) of 88 women had 3 or more
pregnancies prior to the study period, 62 (72%) of 86 had
never spontaneously aborted before, and 44 (48%) of 92 presented during the second trimester of pregnancy.
Overall, 40 (43%) of 92 pregnant women with acute brucellosis had spontaneous abortions during the first or second
trimester, and 2 (2%) had intrauterine fetal deaths in the third
trimester (table 2). The incidence of abortion was significantly
higher during the first and second trimesters than it was during
the third trimester. To put these rates in context, we calculated
the incidence of spontaneous abortion or intrauterine fetal
death for all women for the period from July 1999 through
June 2000. During this 1-year interval, the total rate of spontaneous and missed abortions (i.e., early fetal death before completion of 24 weeks of gestation with retention of dead fetus
or retained products of conception, not following spontaneous
Table 1.
Characteristics of 92 pregnant women
with acute brucellosis in Saudi Arabia.

Characteristic

No. (%)
of patients

Age range, y (n p 92)

1620

14 (15)

2125

32 (35)

2630

19 (21)

3135

15 (16)

3642

10 (11)

4347

2 (2)

No. of pregnancies prior to the study

period (n p 88)
0

4 (4)

6 (7)

7 (8)

71 (81)

No. of spontaneous abortions prior

to the study period (n p 86)a
0

62 (72)

16 (18)

4 (5)

4 (5)

Trimester of pregnancy (n p 92)

RESULTS
From 1983 through 1995, there were 545 cases of brucellosis
at the hospital, of which 92 (17%) occurred in pregnant women

23 (25)

44 (48)

25 (27)

Includes patients who had intrauterine deaths.

Brucellosis in Pregnant Women CID 2001:32 (15 April) 1173

Table 2. Occurrence of spontaneous abortion

and intrauterine death, according to trimester of
pregnancy, in 92 women with acute brucellosis
in Saudi Arabia.

No. of
patients

No. (%) of
spontaneous
abortions

First

23

12 (52)

Second

44

28 (64)

Third

25

2 (8)

92

42 (46)

Trimester of pregnancy

Total

a
a

NOTE. Difference in the incidence of abortion was

significant for first vs. third trimester (P ! .001) and second
vs. third trimester (P ! .0001), but not for first vs. second
trimester (P p .4).
a

These were or included intrauterine fetal deaths.

abortion, induced abortion, or delivery) during the first and

second trimesters combined was 2.8% (589 spontaneous abortions and 121 missed abortions among the 25,540 women who
received antenatal care), and the rate of intrauterine fetal death
during the third trimester was 0.3% (66 intrauterine fetal deaths
among the remaining 24,830 pregnant women who did not
abort during the first or second trimesters).
Of the 92 pregnant women with brucellosis, 91 had positive
serum agglutinin titers that ranged from 1:320 to 1:20,480;
the geometric mean titer was 1:2560. Serological testing was
not performed for 1 patient; brucellosis in this patient was
diagnosed by a blood culture result that was positive for Brucella
species. There was no apparent relationship between the magnitude of the titer and the occurrence of bacteremia. Serum
agglutinin titers 1:2560, compared with those !1:2560, were
not significantly associated with the occurrence of spontaneous
abortion (P p .5).
Fifty-two of the 92 women had blood cultures performed.
Twenty-two (42%) of these cultures had positive results: 16
yielded Brucella melitensis, 1 yielded Brucella abortus, and 5
yielded Brucella species that were not identified to the species
level. Antimicrobial susceptibility testing for these 22 isolates
revealed that 18 were susceptible to cotrimoxazole and 4 were
resistant. Eight (36%) of 22 women with brucella bacteremia
aborted, and 16 (53%) of the 30 women for whom blood
cultures were negative aborted; this difference in the incidence
of abortion was not statistically significant (P p .2).
The incidence of abortion according to pregnancy trimester,
clinical presentation, and treatment is shown in table 3. Overall,
of the 92 pregnant women with brucellosis, 41 (45%) received
treatment. With all pregnancy trimesters represented, 100% of
38 women who presented with preterm febrile illness received
antimicrobial therapy, and there was 1 intrauterine fetal death
(3%). Of the women in the first and second trimesters who
presented with vaginal bleeding and either with or without
1174 CID 2001:32 (15 April) Khan et al.

fever, 3 (8%) of 40 were treated with antimicrobial agents, and

all aborted. None of 14 women with febrile illness at term or
postpartum were treated, and there was 1 fetal death. Overall,
60 (65%) of the 92 women with brucellosis were febrile.
The details of antepartum antimicrobial treatment are presented in table 4. Cotrimoxazole was administered as 1 doublestrength tablet (800 mg or sulfamethoxazole and 160 mg of
trimethoprim), given orally b.i.d., and rifampin was administered as 600900 mg, given orally q.d. Antepartum treatment
with antimicrobial agents was significantly more protective
against the occurrence of abortion than was inadequate treatment or no treatment (RR, 0.14; 95% CI, 0.060.37; P !
.0001). However, the incidence of abortion among 22 patients
who received treatment with cotrimoxazole was not significantly different from that of 17 patients who received treatment
with a combination of cotrimoxazole and rifampin (P p .6).
Follow-up data were available for 36 infants of the 41 women
who were treated: 33 (92%) were normal and well at followup, and 3 (8%) delivered prematurely (2 of the premature
infants died).
Serum agglutinin titers were measured for 7 of the infants
born to women with brucellosis, and 4 of them had titers 1:
320. Cultures of blood specimens from 6 newborns (1 week
of age) were performed, but only 1 had a result that was positive
for Brucella species; culture of blood from the mother of this
infant with bacteremia was not done. The mothers of 4 of the
6 newborns for whom cultures were performed had brucella
bacteremia, and all presented during the second trimester.
Placentas and fetuses were not systematically studied in this
case series. Cultures of 11 placental specimens and 1 fetal specimen did not yield Brucella species. Histological examination
of 28 placental samples revealed nonspecific inflammatory
changes in 22 of them.

DISCUSSION
We found that the incidence of spontaneous abortion and
intrauterine death among a retrospective cohort of 92 pregnant
women with acute brucellosis due primarily to B. melitensis
was 46%. As shown in the Results section, the rates of spontaneous abortion and intrauterine death among women with
active brucellosis substantially exceeded the rates of spontaneous abortion and intrauterine death among the general population of pregnant women at our institution during the corresponding trimesters. The frequency of fetal loss among
patients with brucellosis was comparable in the first and second
trimesters, but intrauterine fetal death during the third trimester was uncommon. Most of these women were older than
20 years of age, were not primigravid, and most had not had
a spontaneous abortion prior to the study period. Our rate of
incidence exceeds the 10% rate reported by Criscuolo and di

Table 3. Incidence of spontaneous abortion and intrauterine death, according to

pregnancy trimester and clinical presentation, among 92 pregnant women with acute
brucellosis in Saudi Arabia.
No. of patients
Trimester of pregnancy, presentation

Treated

Had spontaneous
abortion

12

11

Total

First
Vaginal bleeding with or without febrile illness
Predominantly febrile illness

12

11

Second
Vaginal bleeding with or without febrile illness

28c

28

Predominantly febrile illness

16d

16

14e

1f

11

11

92

41

42

Third
Febrile illness at term or postpartum
Preterm febrile illness
Total
a
b
c
d
e
f
g

Brucella bacteremia in 1 patient.

Brucella bacteremia in 2 patients, 9 normal deliveries, and 2 premature newborns.
Brucella bacteremia in 7 patients.
Brucella bacteremia in 6 patients, 15 normal deliveries, and 1 premature newborn.
Brucella bacteremia in 6 patients and 1 fetal death. All patients were treated postpartum.
Intrauterine death.
No patients had bacteremia, and all were treated before delivery.

Carlo [12] in 200 cases of B. melitensis infection in pregnant

women; however, it is similar to the rate of abortion of 31%
among 35 women who were in the first trimester of pregnancy
and who had brucellosis, which was reported by Lulu et al.
[13], and a 40% rate among 30 pregnant women with brucellosis, which was reported by Madkour [14]. Conversely, Sarram et al. [15] observed that, among 51 women who had spontaneous abortions during their second trimester, 11.6% had B.
melitensis infection, while Makhseed et al. [16] diagnosed acute
or chronic brucellosis in 7% of 29 women who had spontaneous
abortions and 10% of 51 women who had intrauterine fetal
deaths.
In his classic monograph, Spink [17] stated that . . . the
passage of time has produced no definitive evidence that the
Brucellae produce abortions any more frequently than do other
species of bacteria. This statement is difficult to verify because
data on the incidence of abortion caused by other microorganisms are lacking or are not directly comparable. For example, Campylobacter species, like Brucella species, are welldescribed causes of abortion in animals; however, in a series
of 10 pregnant women with Campylobacter jejuni infection who
were at a single hospital, only 1 (10%) had premature labor at
28 weeks gestation that resulted in a neonatal death [18]. Other
reports of Campylobacter infection in pregnant women include
a report of a series of cases that were selected on the basis of
the occurrence of abortion [19] and single case reports of fetal
loss in association with septic shock, bacteremia, and diarrheal
illness [2022].

A MEDLINE search of the literature published from 1966

through 2000 that used the terms E. coli and abortion did
not yield any reports of studies of patients with Escherichia coli
bacteremia or sepsis who experienced spontaneous abortion.
A similar search for an association between Salmonella species
and spontaneous abortion yielded 1 report of a study of 30
pregnancies that were complicated by typhoid fever and that
resulted in 3 spontaneous abortions (10%) [23].
Although comparative data are limited, an incidence of abortion from 10% to 42% in patients with active brucellosis exceeds that observed in patients infected with other organisms,
such as Campylobacter species and Salmonella species, and suggests that Brucella species may indeed produce human aborTable 4.
Antepartum antimicrobial treatment and
pregnancy outcomes for pregnant women with acute
brucellosis in Saudi Arabia.
No. of patients

Treatment

Treated

Had normal
deliveries

Had spontaneous
abortion or
fetal death
3

CMZ

23

19

CMZ Rif

17

16

41

36

Rif
Total

NOTE. Standard antimicrobial therapy was given to 51 patients

after abortion or delivery. CMZ, cotrimoxazole; Rif, rifampin.
a

Three deliveries were premature.

Brucellosis in Pregnant Women CID 2001:32 (15 April) 1175

tions more frequently than do other bacterial pathogens.

Clearly, there is a need for better evidence to verify this suggestion, which would come from case-control studies; however,
the selection of an appropriate control group is problematic,
because our understanding of the pathogenesis of spontaneous
abortion in women with brucellosis is poor.
Bacteremia is mentioned as a risk factor for spontaneous
abortion in the literature, but our study found no association
between maternal bacteremic status and spontaneous abortion.
Furthermore, although it was not systematically studied, 22 of
28 placental samples that we examined had only nonspecific
inflammation. The lack of evidence of uteroplacental involvement in some cases of abortion has been noted by other investigators [7, 14]. Collectively, these data reveal that women
with active brucellosis may abort despite the absence of erythritol in the human placenta and fetus, the absence of bacteremia, and the absence of specific histological abnormalities
in the placenta. Endotoxin has been implicated in the pathogenesis of brucellosis [24], and it is possible that its promotility
effect on uterine smooth muscle plays a role in abortion [25].
An important observation from the present study is that the
natural history of brucellosis in pregnant women may be altered
by early institution of antimicrobial therapy. When pregnant
women with febrile brucellosis are treated with antimicrobial
agents before vaginal bleeding occurs, most deliver normally.
However, vaginal bleeding at presentation is an ominous sign: it
rarely happens in women who receive treatment with antimicrobial agents, and it is associated with a high rate of spontaneous
abortion. Whether the low rate of treatment in cases of vaginal
bleeding is a marker for failure to diagnose brucellosis and
whether it plays a permissive role in subsequent abortion or
intrauterine fetal death is difficult to determine from our data.
The most important reservation against treating brucellosis
in pregnant women is the possibility that the patient would
experience adverse effects of the antimicrobial agents [26]. Although the number of patients in this study was not large, we
were still able to extract from our findings that cotrimoxazole
and rifampin appear to be safe agents for treating brucellosis
in pregnant women, because there were no specific drug-related
adverse effects in the 36 newborns for whom there were followup data. Other researchers have argued that the potential adverse effects of cotrimoxazole in pregnant women may be overstated [27], and that the duration of treatment with rifampin
is longer for pregnant women with tuberculosis than it is for
pregnant women with brucellosis [28, 29].
In conclusion, this study demonstrated a remarkably high
incidence of first and second trimester spontaneous abortions
among pregnant women with active brucellosis. Occurrence of
abortion was not associated with either the magnitude of the
serum agglutinin titer or the presence of brucella bacteremia.

1176 CID 2001:32 (15 April) Khan et al.

However, antimicrobial therapy with either cotrimoxazole or

cotrimoxazole plus rifampin had a strong protective effect
against abortion. Future controlled studies are required before
one can establish the pathogenetic role of brucellosis in causing
human spontaneous abortion and whether Brucella species are
more likely to cause abortion than are other infectious pathogens. However, even in the absence of such studies, the necessity of treating pregnant patients who have brucellosis immediately is clear, because brucellosis can cause fetal death at
any stage of pregnancy, whether maternal infection is mild or
severe. Therefore, treatment must not be withheld [30].

Acknowledgments

We thank Dr. Frank Kiel for his valued collaboration in the

brucellosis research conducted at King Fahad National Guard
Hospital (Riyadh, Saudi Arabia).

References
1. Matyas Z, Fujikura T. Brucellosis as a world problem. Dev Biol Stand
1984; 56:320.
2. Al Sekait MA. Seroepidemiological survey of brucellosis antibodies in
Saudi Arabia. Annals of Saudi Medicine 1999; 19:21922.
3. Kiel FW, Khan MY. Brucellosis in Saudi Arabia. Soc Sci Med 1989;
29:9991001.
4. Cooper CW. Risk factors in transmission of brucellosis from animals
to humans in Saudi Arabia. Trans R Soc Trop Med Hyg 1992; 86:2069.
5. Young EJ. Brucella species. In: Mandell GL, Bennett JE, Dolin R, eds.
Mandell, Douglas and Bennetts principles and practice of infectious
diseases. 4th ed. New York: Churchill Livingstone, 1995:205360.
6. Young EJ. Human brucellosis. Rev Infect Dis 1983; 5:82142.
7. Poole PM, Whitehouse DB, Gilchrist MM. A case of abortion consequent upon infection with Brucella abortus biotype 2. J Clin Pathol
1972; 25:8824.
8. Seoud M, Saade G, Awar G, Uwaydah M. Brucellosis in pregnancy. J
Reprod Med 1991; 36:4415.
9. Memish Z, Mah MW, Al Mahmoud S, Al Shaalan M, Khan MY. Brucella
bacteremia: clinical and laboratory observations in 160 patients. J Infect
2000; 40:5963.
10. Kiel FW, Khan MY. Analysis of 506 consecutive positive serologic tests
for brucellosis in Saudi Arabia. J Clin Microbiol 1987; 25:13847.
11. Bannatyne RM, Jackson MC, Memish Z. Rapid diagnosis of Brucella
bacteremia by using the BACTEC 9240 system. J Clin Microbiol
1997; 35:26734.
12. Criscuolo E, di Carlo FC. El aborto y ostras manifestaciones ginecobstetricas en el curso de la brucelosis humana. Rev Fac Cien Med Univ
Nac Cordoba 1954; 12:32130.
13. Lulu AR, Araj GF, Khateeb MI, Mustafa MY, Yusuf AR, Fenech FF.
Human brucellosis in Kuwait: a prospective study of 400 cases. Q J
Med 1988; 66:3954.
14. Madkour MM. Pregnancy and brucellosis. In: Madkour MM, ed. Brucellosis. London: Butterworth, 1989:197204.
15. Sarram M, Feiz J, Foruzandeh M, Gazanfarpour P. Intrauterine fetal
infection with Brucella melitensis as a possible cause of second-trimester
abortion. Am J Obstet Gynecol 1974; 119:65760.
16. Makhseed M, Harouny A, Araj G, Moussa MA, Sharma P. Obstetric
and gynecologic implication of brucellosis in Kuwait. J Perinatol
1998; 18:1969.

17. Spink WW. The nature of brucellosis. Minneapolis: The University of

Minnesota Press, 1956:14590.
18. Simor AE, Ferro S. Campylobacter jejuni infection occurring during
pregnancy. Eur J Clin Microbiol Infect Dis 1990; 9:1424.
19. Simor AE, Karmali MA, Jadavji T, Roscoe M. Abortion and perinatal
sepsis associated with campylobacter infection. Rev Infect Dis 1986; 8:
397402.
20. Sauerwein RW, Bisseling J, Horrevorts AM. Septic abortion associated
with Campylobacter fetus subspecies fetus infection: case report and
review of the literature. Infection 1993; 21:3313.
21. Farrell DJ, Harris MT. A case of intrauterine fetal death associated with
maternal Campylobacter coli bacteraemia. Aust N Z J Obstet Gynaecol
1992; 32:1724.
22. Denton KJ, Clarke T. Role of Campylobacter jejuni as a placental pathogen. J Clin Pathol 1992; 45:1712.
23. Buongiorno R, Schiraldi O. Treatment of typhoid fever in pregnancy.
Chemioterapia 1984; 3:1369.

24. Ganado W, Bannister W. Bacteraemia in human brucellosis. BMJ

1960; 1:6013.
25. Urbascheck B. Motility-promoting effect of the Brucella abortus and
Brucella melitensis endotoxin on the smooth uterine muscle. Nature
1964; 202:883.
26. Hall WH. Modern chemotherapy for brucellosis in humans. Rev Infect
Dis 1990; 12:106099.
27. Williams E. Letter to the editor. The Practitioner 1983; 227:339.
28. Centers for Disease Control and Prevention. Initial therapy for tuberculosis in the era of multidrug resistance: recommendations of the
Advisory Council for the Elimination of Tuberculosis. MMWR Morb
Mortal Wkly Rep 1993; 42(RR-7):18.
29. Davidson PT. Managing tuberculosis during pregnancy. Lancet 1995;
346:199200.
30. Joint Food and Agriculture Organization/World Health Organization
Expert Committee on Brucellosis. 6th report (WHO technical report
series 740). Geneva: World Health Organization, 1986.

Brucellosis in Pregnant Women CID 2001:32 (15 April) 1177