International Journal of Infectious Diseases 73 (2018) 18–26

Contents lists available at ScienceDirect

International Journal of Infectious Diseases

journal homepage: www.elsevier.com/locate/ijid

Review

Consequences of brucellosis infection during pregnancy:

A systematic review of the literature
Manal Alsaifa , Kamal Dabelaha , Robin Featherstoneb , Joan L. Robinsonc,*
a
Department of Pediatrics, King Abdulaziz Hospital, Ministry of National Guard Hospital, Al-Ahsa, Saudi Arabia
b
Alberta Research Centre for Health Evidence, Department of Pediatrics, University of Alberta, Alberta SPOR SUPPORT Unit Knowledge Translation Platform,
Edmonton, Alberta, Canada
c
Stollery Children’s Hospital and University of Alberta, Edmonton, Alberta, Canada

A R T I C L E I N F O A B S T R A C T

Article history: Background: The aim was to establish the incidence of adverse outcomes with brucellosis infection during
Received 20 February 2018 pregnancy.
Received in revised form 14 May 2018 Methods: Ovid Medline (1946-), Ovid Embase (1974-), and Web of Science (Clarivate Analytics) (1900-),
Accepted 30 May 2018
the World Health Organization website and Google were searched September 27, 2017 for (i) outcomes
Corresponding Editor: Eskild Petersen, Aar-
hus, Denmark
with brucellosis diagnosed during pregnancy and (ii) studies with retrospective diagnosis of maternal
brucellosis following adverse pregnancy outcomes.
Results: Sixty studies met inclusion criteria. In 65 pregnancies from 28 case reports and 9 small case series
Keywords:
Brucellosis
(<10 women), there were 20 spontaneous abortions (SAs) (31%), 2 intra-uterine fetal deaths (IUFDs) (3%)
Pregnancy and 11 cases of congenital brucellosis (17%). In 14 larger case series there were 181 SAs in 679 pregnancies
Congenital infection (27%), 19 IUFDs in 458 pregnancies (4%), and 44 preterm infants (12%) plus 6 infants with congenital
Spontaneous abortion brucellosis (2%) in 362 pregnancies. SA, IUFD and preterm delivery incidence were increased with meta-
Intrauterine fetal death analysis of the 5 case series with controls. Nine studies described brucellosis seroprevalence with adverse
pregnancy outcomes with no increased seroprevalence in the two studies with controls.
Conclusions: Brucellosis almost certainly causes SA with increasing evidence that it also leads to IUFD and
prematurity. Congenital brucellosis occurs in approximately 2% of infants exposed in-utero.
© 2018 The Author(s). Published by Elsevier Ltd on behalf of International Society for Infectious Diseases.
This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-
nc-nd/4.0/).

Contents

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18
Search strategy, selection criteria and data collection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19
Results . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19
Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23
Conflict of interest statement . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24
Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25

Introduction contaminated animal feces or consumption of infected animal

products. Human-to-human transmission via blood transfusion,
Brucellosis is a zoonosis that can be acquired in most bone marrow transplantation, sex, transplacental or perinatal
countries (Pappas et al., 2006). Human infection stems exposure, and breast milk have been documented (Tuon et al.,
from direct contact with infected animals, inhalation of 2017a).
Brucellosis in pregnancy is of special interest as it remains
controversial whether it is a precipitant of poor outcomes beyond
* Corresponding author at: 3-556 ECHA 11405-87 Ave, Edmonton, AB T6G 1C9,
congenital brucellosis. This is the first systematic review with
Canada. meta-analysis analyzing whether brucellosis increases the inci-
E-mail address: jr3@ualberta.ca (J.L. Robinson). dence of other adverse pregnancy outcomes.

https://doi.org/10.1016/j.ijid.2018.05.023
1201-9712/© 2018 The Author(s). Published by Elsevier Ltd on behalf of International Society for Infectious Diseases. This is an open access article under the CC BY-NC-ND
license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

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 M. Alsaif et al. / International Journal of Infectious Diseases 73 (2018) 18–26 19

Search strategy, selection criteria and data collection
For this systematic review with meta-analysis, the databases
Ovid Medline (1946-), Ovid Embase (1974-), and Web of Science
(Clarivate Analytics) (1900-) were searched for concepts related to
brucellosis and pregnancy (excluding studies in animal popula-
tions) on September 27, 2017 (Appendix A). The World Health
Organization website and Google were searched for relevant
reports. No language or date range restrictions were applied and all
study designs were considered. Results were exported into
EndNote X7 and duplicates removed. Reference lists of previous
reviews were hand-searched. Cases or case series were included if
one or more women had brucellosis detected during pregnancy
and the incidence of at least one of the following outcomes was
reported for all cases in the series: spontaneous abortion (SA),
intra-uterine fetal death (IUFD), preterm or term live born infant,
and/or congenital brucellosis. Cases were excluded if maternal
brucellosis was recognized only after an infant was diagnosed with
congenital brucellosis. Case series from endemic countries
retrospectively seeking evidence of brucellosis in women with
adverse pregnancy outcomes were also included if they described
testing for minimum ten women.
Data recorded for the case reports and case series included
country and outcome(s). The assumption was made that the terms
“normal delivery” or “uncomplicated delivery” implied that the
infant was term. Case series with  10 women were reported
separately as larger series would be less subject to reporting bias;
the diagnostic criteria for brucellosis and any outcome data from a
control group were also recorded for these studies. Meta-analysis
was limited to case series with women with brucellosis and their
controls; results of all applicable studies were combined and
incidence rates compared in cases and controls with a Chi-squared
test. A p value of 0.05 was considered to be significant.
For case series looking for evidence of brucellosis with adverse
pregnancy outcomes, the population studied and the seropreva-
lence of brucellosis were recorded.
To assess the risk of bias, the Newcastle-Ottawa Quality
Assessment Scale was applied to studies that included a control
group (http://ohri.ca/programs/clinical_epidemiology/nosgen.
pdf). The Preferred Reporting Items for Systematic Reviews and
Meta-Analyses (PRISMA) guidelines (http://www.prisma-state-
ment.org/Default.aspx) were followed for reporting the results.
This systematic review was registered with PROSPERO
(CRD42017072061). Support for this study was provided by the
Alberta SPOR SUPPORT Unit Knowledge Translation Platform.
Results
The search yielded 544 records of which 60 met the inclusion
criteria (Figure 1). Other titles were excluded after full text review
as maternal brucellosis was diagnosed after congenital brucellosis
(n = 14), the article was not relevant (n = 7), they were review
articles or a book chapter (n = 6), there was no pregnancy outcome
data (n = 4), this was a conference abstract for a subsequently
published study (n = 2), the article could not be translated (n = 1),
remote and recent pregnancy outcomes were combined (n = 1) or
the diagnosis of maternal brucellosis was presumptive (n = 1).
There were 28 case reports and nine small case series (<10
women) (Table 1) with outcomes reported for 65 pregnancies
complicated by brucellosis leading to 20 SAs (31%), one therapeutic
abortion (2%), 2 IUFDs (3%), 11 preterm infants (17%), and 31 term
deliveries (48% – includes one set of twins) (De Carles, 1931;

Records idenƟfied through database Records idenƟfied through reference

searching lists of review arƟcles (n=9)
IdenƟficaƟon

(n=810)

Records aŌer duplicates removed

(n=544)
Screening

Records screened Records excluded

(n=544) (n=449)

Full-text arƟcles excluded:

Maternal infecƟon diagnosed aŌer
Full-text arƟcles assessed infant found to have congenital
for eligibility brucellosis (n=13)
Eligibility

(n=95) Not relevant (n=7)

Review arƟcle or book chapter
(n=6)
No pregnancy outcome data (n=4)
Duplicate data (n=2)
Could not translate (n=1)
Current and remote pregnancy
outcomes combined (n=1)
Maternal diagnosis unproven (n=1)
Included

Studies included
(n=60)

Figure 1. Flow diagram for systematic review.

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Table 1
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Outcome of case reports and small case series (<10 women) of women with brucellosis detected during pregnancy by year of publication.
First author and year
deCarles (De Carles, 1931)
1931
Carpenter (Carpenter and Boak,
1931)
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1931
Janbon (Janbon and De Kerleau,
1939)
1939
Hagebusch (Hagebusch, 1941)
1941
Williamson (Williamson, 1944)
1944
Williams (Williams, 1973)
1973
Poole (Poole et al., 1972)
1972
Porreco (Porreco and
Haverkamp, 1974) 1974
Hassid (Hassid, 1974)
1974
Eckman (Eckman, 1975) 1975
Schreyer (Schreyer et al., 1980)
1980
Smith (Smith et al., 1982)
1982
Naveau (Naveau et al., 1983)
1983
Abu Sinna (Abu Sinna et al.,
1988)
1988
Seoud (Seoud et al., 1991)
1991
Donfrancesco (Donfrancesco
et al., 1994)
1994
Gloeb (Gloeb et al., 1994)
1994
Carbajo-Ferreira (Carbajo-
Ferreira et al., 1995)
1995
Figueroa- Damian (Figueroa
Damian et al., 1995)
1995
Shamo’on (Shamo’on and Izzat,
1999)
1999
Malone (Malone et al., 1997)
1997
Oscherwitz (Oscherwitz, 1995)
1997
20
Country Total pregnancies Spontaneous abortions Therapeutic abortion IUFD Preterm infant Term infant Remarks
United States 1 1 Infant died shortly after birth
United States 1 1 B. abortus detected in fetal
tissue
France 1 1 B. melitensis detected in fetal
tissue
United States 7 3 1 1 (with congenital 2
brucellosis
United Kingdom 1 1
United Kingdom 1 1
M. Alsaif et al. / International Journal of Infectious Diseases 73 (2018) 18–26
United Kingdom 1 1
United States 1 1
France 1 1
a
United States 1 1
Israel 1 1 Second trimester abortion
Scotland 1 1 Second trimester abortion
France 1 1 Well term infant despite
maternal treatment for Brucella
liver abscess in second
trimester
Kuwait 2 1 (with congenital 1 (with congenital Third case excluded as
brucellosis brucellosis maternal brucellosis diagnosed
post-partum.
Lebanon 6 1 1 4
Italy 1 1
United States 1 1 Preterm delivery of well infant
27 days after maternal
admission with
neurobrucellosis at 30 weeks
gestation
Spain 1 1 (with congenital
brucellosis)
Mexico 4 4
Jordan 1 1 (with congenital
brucellosis)
United States (immigrant 1 1
from Columbia)
United States 1 1 Healthy infant despite
postpartum maternal
bacteremia
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Hackmon (Hackmon et al., Israel 7 1 2 4

1998)
1998
Giannacopoulos Greece 1 1 (with congenital
(Giannacopoulos et al., 2002) brucellosis)
2002
Sayilir (Sayilir et al., 2003) Turkey 2 2
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2003
Ozbay (Ozbay and Inanmis, Turkey 1 (twin) 1 (twin)
2006)
2006
Imani (Imani et al., 2007) Iran 1 1 (with congenital
2007 brucellosis)
Cebesoy (Cebesoy et al., 2009) Turkey 1 1 Treatment started for maternal
2009 vertebral osteomyelitis at 13
weeks GA
Karcaaltincaba (Karcaaltincaba Turkey 2 1 1

M. Alsaif et al. / International Journal of Infectious Diseases 73 (2018) 18–26

et al., 2010)
2010
Elkiran (Elkiran et al., 2010) Turkey 1 1 (with congenital
2010 brucellosis)
Peker (Peker et al., 2011) 2011 Turkey 1 1
Nuri (Nuri et al., 2011) Turkey 1 1
2011
Ceylan (Ceylan et al., 2012) Turkey 1 1 (with congenital
2012 brucellosis)
Dilli (Dilli et al., 2013) 2013 Turkey 1 1 (with congenital
brucellosis)
Schlembach (Schlembach et al., Germany (acquired in Syria) 1 1
2016)
2016
Agah (Agah et al., 2016) 2016 Iran 5 3 2
Fatnassi (Fatnassi et al., 2016) Tunisia 2 1 1
2016

Legend: GA — gestational age; IUFD — intrauterine fetal death (20 weeks gestational age).
a
Case epidemiologically linked to cheese purchased in Mexico

21
22 M. Alsaif et al. / International Journal of Infectious Diseases 73 (2018) 18–26

Carpenter and Boak, 1931; Janbon and De Kerleau, 1939;
Hagebusch, 1941; Williamson, 1944; Williams, 1973; Poole et al.,
1972; Porreco and Haverkamp, 1974; Hassid, 1974; Eckman, 1975;
Schreyer et al., 1980; Smith et al., 1982; Naveau et al., 1983; Abu
Sinna et al., 1988; Seoud et al., 1991; Donfrancesco et al., 1994;
Gloeb et al., 1994; Carbajo-Ferreira et al., 1995; Figueroa Damian
et al., 1995; Shamo’on and Izzat, 1999; Malone et al., 1997;
Oscherwitz, 1995; Hackmon et al., 1998; Giannacopoulos et al.,
2002; Sayilir et al., 2003; Ozbay and Inanmis, 2006; Imani et al.,
2007; Cebesoy et al., 2009; Karcaaltincaba et al., 2010; Elkiran
et al., 2010; Peker et al., 2011; Nuri et al., 2011; Ceylan et al., 2012;
Dilli et al., 2013; Schlembach et al., 2016; Agah et al., 2016; Fatnassi
et al., 2016). Eleven of 43 live born infants (26%) had congenital
brucellosis (5 preterm and 6 term).
There were 14 case series with  10 women with brucellosis
during pregnancy including 735 pregnancies (Table 2) (Criscuolo
and Di Carlo, 1954; Madkour, 1985; Lulu et al., 1988; Madkour,
1989; Sharif et al., 1990; AlAmoudi, 1995; Garriguet et al., 2000;
Khan et al., 2001; Elshamy and Ahmed, 2008; Karahocagil et al.,
2010; Roushan et al., 2011; Gulsun et al., 2011a,b; Vilchez et al.,
2015). Diagnostic criteria typically included positive serology or a
positive blood culture with only one study specifying that women
had to be symptomatic (Lulu et al., 1988). Reported obstetric
outcomes included 185 SAs in 679 pregnancies (27%) and 19 IUFDs
in 458 pregnancies (4%). Gestational age was reported for all live
born infants in 10 studies with 44 of 362 being preterm (12%). One
maternal death was attributed to brucellosis (Vilchez et al., 2015).
Six infants had congenital brucellosis (Madkour, 1989; AlAmoudi,
1995; Vilchez et al., 2015). Two studies reported a correlation
between brucellosis antibody titers as measured by serum
agglutination and SA (Sharif et al., 1990; Elshamy and Ahmed,
2008) while three others reported no correlation (Khan et al., 2001;
Karahocagil et al., 2010; Roushan et al., 2011). Two studies
compared outcomes with and without documented maternal

Table 2
Outcome of case series of women with brucellosis detected during pregnancy by year of publication.

First author and year Country Total Diagnostic criteria for brucellosis during Spontaneous IUFD Preterm infant Term infant
pregnancies pregnancy abortions
with (SA)
brucellosis
Criscuolo Argentina 200 Positive serology 52 (26%) NR NR NR
(Criscuolo and Di
Carlo, 1954) 1954
Madkour (Madkour, Saudi Arabia 11 Compatible symptoms and positive serology 5 (45%) 1 1 (9%) 4 (36%)
1985) (9%)
1985
Lulu (Lulu et al., 1988) Kuwait 35 Compatible symptoms and positive serology 11 (31%)a NR NR NR
1988 with cut-off titers varying with duration of
symptoms
Madkour (Madkour, Saudi Arabia 29 16 were bacteremic — others diagnosed by 12 (41%) 1 1 (3%) — had 15 (52%)
1989) serology (3%) congenital
1989 brucellosis
Sharif (Sharif et al., Saudi Arabia 42b Positive serology recognized in symptomatic 6 (18%) NR NR NR
1990) women (N = 24) plus women identified by
1990 routine screening (N = 18)
Al-Amoudi (AlAmoudi, Saudi Arabia 26c Titer  1:160 4 (15%) 0 NR 22 (85%) (1 had
1995) 1995 congenital
brucellosis)
Garriguet (Garriguet Spain 16 3 were bacteremic — others diagnosed by 2 (11%) 0 0 14 (88%)
et al., 2000) 2000 serology
Khan (Khan et al., 2001) Saudi Arabia 92 Positive blood culture or serology 40 (43%) 2 NR NR
2001 (2%)
d
Elshamy (Elshamy and Saudi Arabia 55 Positive serology 15 (27%) 7 6 (11%) 27 (49%)
Ahmed, 2008) (13%)
2008
Karahocagil Turkey 29 Positive blood culture (N = 2) or serology (N = 29) 7 (24%) 1 2 (7%) 19 (66%)
(Karahocagil et al., (3%)
2010)
2010
Roushan (Roushan Iran 19 Positive blood culture (N = 4) or serology (N = 19) 10 (53%) 0 0 9 (47%)
et al., 2011) — all had compatible symptoms during
2011 pregnancy
Gulsun (Gulsun et al., Turkey 39e Positive blood culture or serology 1 (3%) 0 7 (18%) 21(54%)
2011a)
2011
Gulsun (Gulsun et al., Turkey 56f 4 (7%) 0 15 (27%) 37 (66%)
2011b) 2011
g
Vilchez (Vilchez et al., Peru 86 Positive blood culture (N = 33) or serology 16 (19%) 7 12 (14%) 51 (58%)
2015) (N = 101) — all had compatible symptoms during (8%)
2015 pregnancy

Legend: IUFD — intrauterine fetal death; SA — spontaneous abortion; SAT — serum agglutination titer.
a
All were first trimester abortions.
b
24 were symptomatic and the other 18 were detected by routine screening so may or may not have been symptomatic.
c
26 others had titres < 1:160
d
Only 35 were symptomatic so the other 20 may have had resolved infection.
e
30 had acute, 2 had sub-acute, 3 had chronic and 4 had relapsed brucellosis. It is possible that some or all cases overlap with those included in the second Gulsun study in
the table.
f
24 of the 56 women had acute viral hepatitis in addition to acute brucellosis: hepatitis B (n = 12); hepatitis C (n = 7); hepatitis A (n = 5)
g
One maternal death at 31 weeks gestational age related to disseminated intravascular coagulation while bacteremic with Brucella — One congenital malformation not
further described (made the assumption that the infant was term) — Four infants of unknown gestation had congenital brucellosis.

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 M. Alsaif et al. / International Journal of Infectious Diseases 73 (2018) 18–26 23

Table 3
Studies with a control group reporting adverse outcome from brucellosis infection in pregnancy.

Sharif (Sharif et al., Khan (Khan et al., Elshamy (Elshamy Karahocagil Gulsun (Gulsun Total
1990) 2001) and Ahmed, 2008) (Karahocagil et al., et al., 2011a)
1990 2001 2008 2010) 2011
2010
SA in cases versus controls 6/42 (14%) versus 40/92 (43%) versus 15/55 (27%) versus 7/29 (24%) versus Data not 68/218 (31%) versus
39/495 (8%); 710/25540 (3%); 60/395 (15%); 2577/33936 (8%); presented; 3386/60366 (5%);
p = 0.15 p < 0.001 p = 0.02 p < 0.001 p > 0.05 p < 0.001
IUFD in cases versus controls NR 2/92 (2%) versus 66/ 7/55 (13%) versus 1/29 (3%) versus 76/ NR 10/176 (6%) versus 157/
25540 (0.3%); 15/395 (4%); 33936 (0.2%); 59871 (0.3%); p < 0.001
p < 0.001 p = 0.004 p < 0.001
Preterm delivery in cases NR NR 6/55 (11%) versus 2/29 (7%) versus 643/ 7/39 (18%) versus 15/123 (12%) versus
versus controls — all 35/395 (9%); 33936 (2%); p = 0.05 1/40 (2.5%); 679/34371 (2%);
pregnancies p = 0.62 p = 0.023 p < 0.001
Preterm delivery in cases NR NR 6/33 (18%) versus 2/21 (10%) versus NR 8/54 (15%) versus 678/
versus controls — live born 35/320 (11%); 643/31283 (2%); 31603 (2%); p < 0.001
infants only p = 0.22 p = 0.016a

Legend: IUFD — intrauterine fetal death; NR — nor reported; SA — spontaneous abortion.

a
The authors concluded p > 0.05, combining live births with IUFDs. It seems that they excluded SAs for controls but not cases.

bacteremia; the first reported no increase in the incidence of SA
with bacteremia (Khan et al., 2001) while the second reported SA
in 2 of 3 bacteremic women versus 0 of 13 without bacteremia
(p < 0.05) (Garriguet et al., 2000).
Five of the 14 case series included a control group (Table 3)
(Sharif et al., 1990; Khan et al., 2001; Elshamy and Ahmed, 2008;
Karahocagil et al., 2010; Gulsun et al., 2011a) so the Newcastle-
Ottawa Quality Assessment Scale for Cohort Studies was applied.
Two scored very low for “Selection” and “Comparability” as they
provided no details on how controls were selected (Elshamy and
Ahmed, 2008; Gulsun et al., 2011a). Two compared cases to all
pregnant women (Khan et al., 2001; Karahocagil et al., 2010) so
scored high on “Selection” and “Comparability”, being marked
down only because it was not practical to exclude brucellosis in all
controls. The fifth study had a perfect score on “Selection” and
“Comparability” as they compared women from rural Saudi Arabia
with and without positive serology (Sharif et al., 1990). “Outcomes”
appeared equally likely to be captured in cases and controls in all
five studies. It was therefore concluded that the strength of
evidence was moderate. With meta-analysis, the incidence of all
three adverse outcomes were increased (Table 3).
Nine studies described the brucellosis seroprevalence in
women with adverse pregnancy outcomes in endemic countries
(Table 4) with up to 46% being seropositive (Sarram et al., 1974;
Fernihough et al., 1985; Makhseed et al., 1998; Nassaji et al., 2008;
Massiha et al., 2010; Abo-shehada and Abu-Halaweh, 2011;
Mohammad et al., 2011; Rujeni and Mbanzamihigo, 2014; Puri
et al., 2015). The two studies with a control group reported no
difference in seroprevalence between cases and controls (Nassaji
et al., 2008; Abo-shehada and Abu-Halaweh, 2011). The Newcastle-
Ottawa Quality Assessment Scale for Case Control Studies was
applied to these two studies. One was marked down on
“Comparability” as there was no matching for age, rural versus
urban residence or socioeconomic status (Nassaji et al., 2008)
while the other attained a perfect score (Abo-shehada and Abu-
Halaweh, 2011). Both studies attained full marks for documenting “
Selection” and “Exposure”.
Discussion
Traditional thinking was that adverse pregnancy should be
uncommon with brucellosis due to the absence of erythritol in the
human placenta (Al-Tawfiq and Memish, 2013). This sugar is
present in animal placentas and promotes Brucella growth.
Another theory was that anti-Brucella activity in amniotic fluid
would prevent infection of the fetus (Al-Anazi and Al-Jasser, 2013).
However, Brucella has been detected from aborted fetuses
(Carpenter and Boak, 1931). Furthermore, fetal infection is not a

Table 4
Evidence for brucellosis in case series of pregnancies with adverse outcome from endemic countries.

Author and year Country Incidence of brucellosis

Sarram (Sarram et al., 1974) Iran Of 51 second-trimester abortions, B. melitensis was isolated from fetal tissue and/or from maternal urine,
1974 blood, or uterine tissue in 6 cases (12%).
Fernihough (Fernihough et al., 1985) South Africa Of 125 women with SAs, none had evidence of acute brucellosis but 4 had evidence of chronic brucellosis.
1985
Makhsheed (Makhseed et al., 1998) Kuwait The incidence of maternal acute or chronic Brucella infection was 2/29 (7%) with SA, 5/51 with IUFD (10%) and
1998 18/227 (8%) with preterm delivery
Nassaji (Nassaji et al., 2008) Iran Seroprevalence following spontaneous abortion (6%; n = 81) was not higher than seroprevalence with normal
2008 pregnancy (14%; n = 105) with none having IgM.
Massiha (Massiha et al., 2010) Iran 8 of 84 women with SA (10%) had serologic evidence of brucellosis
Abo-Shehada (Abo-shehada and Jordan Seroprevalance did not differ in 445 women with and 445 women without SA (1.8% (95% CI: 0.6-3.0), versus
Abu-Halaweh, 2011) 1.0% (95% CI: 0.08-1.9).
2011
Mohammad (Mohammad et al., Egypt 59 of 129 women with recent or remote SA had positive serology for Brucella (46%)
2011)
2011
Rujeni (Rujeni and Mbanzamihigo, Rwanda 15 of 60 women with SA (N = 11) OR IUFD (n = 4) had positive serology for Brucella (25%)
2014)
2014
Puri (Puri et al., 2015) India Seroprevalence was 9% with SA.
2015

Legend: IUFD — intrauterine fetal death; SA — spontaneous abortion.

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24 M. Alsaif et al. / International Journal of Infectious Diseases 73 (2018) 18–26
prerequisite for an adverse outcome as it seems likely that
maternal brucellosis can precipitate abortion of a healthy fetus.
Therefore, not surprisingly, the incidence of SA in women with
brucellosis was about 25% (Tables 1 and 2) which is clearly
increased from the 5% incidence of spontaneous abortion in a
recent large population-based study (Muanda et al., 2017). The
incidence of SA was above 20% in 8 of 14 case series that included a
minimum of 10 women. Three of five studies that compared the
rate of SA to controls found a statistically significant higher rate
despite having relatively small sample sizes (92, 55, and 29
women) (Table 3). The incidence of IUFD ranged up to 13% (4% with
all studies combined) while the incidence of preterm delivery
ranged from 0% to 27% (13% with all studies combined); meta-
analysis of the studies with controls suggested that both adverse
outcomes are more common than expected for the population
(Table 3). The two studies that compared the incidence of a
retrospective diagnosis of maternal brucellosis in women from
endemic areas with and without adverse pregnancy outcomes
found no differences but the sample sizes were relatively small
(445 and 81 cases). The incidence of congenital brucellosis is best
estimated from the larger case series (2%) as many of the case
reports were written to highlight this diagnosis.
Human brucellosis has an incubation period ranging from
weeks to months, and has protean clinical manifestations that
can wax and wane and mimic infectious and non-infectious
diseases. Sustaining a high index of suspicion for infection is
essential, particularly in high risk individuals living in endemic
areas. Pregnancy is considered to be a high risk condition due to
impaired immunological status. The incidence of brucellosis
during pregnancy is not known in endemic countries as there is
not routine testing. The majority of seropositive pregnant
women report a history of unpasteurized milk consumption
or contact with animals (Vilchez et al., 2015; Scherag et al.,
2016). Thus, potential occupational exposure and family history
of brucellosis should be obtained during prenatal care in
endemic areas. The clinical manifestations of brucellosis in
pregnancy are non-specific and similar to those in non-pregnant
women; fever, chills, sweating, arthralgia, and hepatospleno-
megaly are the most commonly encountered presentations (Al-
Anazi and Al-Jasser, 2013).
Maternal bacteremia, fever and disseminated intravascular
coagulation have been hypothesized to result in SA and IUFD (
Karahocagil et al., 2010). However, adverse outcomes occur in the
absence of maternal bacteremia and some postulate that an
allergic mechanism contributes to recurrent SAs with chronic
maternal brucellosis (Kurdoglu et al., 2015). There are recent
studies of the pathophysiological mechanism of adverse outcomes.
Trophoblasts are cells that nourish the embryo and eventually
develop into part of the placenta. Brucella has been proven to be
capable of replication in trophoblasts (Ben Amara et al., 2013)
which could interfere with their invasive capacity, potentially
related to their effect on laminin-receptor-1 (laminin are
extracellular proteins that are an integral part of the structure
of all tissues) (Kurdoglu and Kurdoglu, 2015). Brucella has not yet
been detected in human trophoblasts (O’Callaghan, 2013) but such
studies are difficult to perform as brucellosis is rarely diagnosed
prior to abortion. Appropriate antibiotics during pregnancy appear
to improve the prognosis; a 6 week course of two antibiotics is
commonly prescribed but there is no consensus on the optimal
choice of antibiotics (Vilchez et al., 2015; Kurdoglu et al., 2015).
Pregnant women with untreated brucellosis have also been
reported to be at high risk for premature rupture of membrane
(PROM), chorioamnionitis, postpartum endometritis, and intra-
uterine growth retardation but there are no studies with a control
group (Al-Anazi and Al-Jasser, 2013). There is no evidence that
brucellosis leads to infertility. In a study from Columbia, 24 women
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with repeat spontaneous abortions were found to have evidence of
brucellosis (6 had active infection) and all had subsequent
successful pregnancies (Bechara, 1978).
A strength of the current study is that other recent reviews of
brucellosis in pregnancy included only case series (Arenas-
Gamboa et al., 2016) or studied all modes of human-to-human
transmission (Tuon et al., 2017b) with no analysis of composite
outcomes or meta-analysis of studies with controls. A limitation of
the current study is that the majority of women were diagnosed on
the basis of serology alone. High titers are usually but not always
indicative of active infection. The case reports and small case series
are likely to be biased towards cases with adverse outcomes. There
is a small possibility that a confounding factor that increases the
risk of brucellosis during pregnancy also increases the risk of SA,
IUFD or prematurity such that the link is not causal.
In conclusion, this review affirms that brucellosis is a particular
problem for pregnant women as it almost certainly increases the
risk of SA. Evidence is also accumulating that brucellosis increases
the incidence of IUFD and preterm delivery. Further data are
required to determine the true magnitude of these effects.
Physicians dealing with pregnant women living in endemic areas
should consider the diagnosis of brucellosis when they present
with fever, especially for those with social and occupational risk as
early diagnosis and prompt therapy almost certainly improve
neonatal outcome. Education on avoidance of exposure to
potentially infected animals and consumption of their milk by
pregnant women living in endemic areas is key.
Conflict of interest statement
None of the authors has a conflict of interest related to this
manuscript.
Acknowledgements
The authors would like to thank Bonita E. Lee who performed
the statistics for the paper.
Funding
This work was supported by the Alberta SPOR SUPPORT Unit
Knowledge Translation Platform.
Appendix A
Database: Ovid MEDLINE(R) Epub Ahead of Print, In-Process &
Other Non-Indexed Citations, Ovid MEDLINE(R) Daily and Ovid
MEDLINE(R) 1946 to Present
Date conducted: 27 September 2017
1 Brucella/(3916)
2 Brucella melitensis/(1307)
3 Brucellosis/(10839)
4 brucell*.tw,kf. (16873)
5 ((Cyprus or Gibraltar or Malta or undulant) adj1 fever*).tw,kf.
(673)
6 or/1-5 [Combined MeSH & text words for brucellosis] (18102)
7 Abortion, Spontaneous/(19157)
8 exp Fetal Death/(29076)
9 exp Pregnancy/(854893)
10 Pregnancy Complications/(86982)
11 exp Pregnancy Complications, Infectious/(42920)
12 Pregnant Women/(6511)
13 Premature Birth/(10867)
14 Prenatal Care/(24624)
15 abortion*.tw,kf. (59566)
 M. Alsaif et al. / International Journal of Infectious Diseases 73 (2018) 18–26 25

16 (ante-natal* or antenatal* or ante-partum* or antepartum* or Indexes = SCI-EXPANDED, SSCI, A&HCI, CPCI-S, CPCI-SSH, BKCI-S,
pre-natal* or prenatal*).tw,kf. (125254) BKCI-SSH, ESCI, CCR-EXPANDED, IC Timespan = All years (15,160)
17 ((birth* or deliver*) adj2 (pre-mature* or premature* or pre- #2 TS = (abortion* OR miscarr* OR pregnan* OR “premature
term* or preterm*)).tw,kf. (32498) birth” OR “preterm birth” OR “still birth*" OR stillbirth*) OR
18 ((dead* or death* or loss* or mortalit*) adj2 (endouterine* or TI = (abortion* OR miscarr* OR pregnan* OR ‘premature birth’ OR
fetal* or fetus* or foetal* or foetus* or intrauterine*)).tw,kf. “preterm birth” OR “still birth*" OR stillbirth*) Indexes = SCI-
(17713) EXPANDED, SSCI, A&HCI, CPCI-S, CPCI-SSH, BKCI-S, BKCI-SSH, ESCI,
19 (expect* adj1 (female? or mother? or wom#n)).tw,kf. (1985) CCR-EXPANDED, IC Timespan = All years (477,903)
20 miscarr*.tw,kf. (12222) #3 #2 AND #1 (836)
21 pregnan*.tw,kf. (478075) #4 TS = (animal or animal-model* or animals or bovine or
22 (still-birth* or stillbirth*).tw,kf. (11181) canine* or cat or cats or cattle or dog or dogs or dolphin* or feline or
23 or/7-22 [Combined MeSH & text words for pregnancy & felines or hamster or hamsters or herd* or mice or monkey or
pregnancy complications] (1010466) monkeys or mouse or pig or piglet or piglets or pigs or porcine or
24 and/6,23 [Combined concepts of brucellosis & pregnancy] primate* or rabbit or rabbits or rat or rats or rodent or rodents or
(1234) sheep or swine or swines) OR TI = (animal or animal-model* or
25 exp animals/not humans/(4588723) animals or bovine or canine* or cat or cats or cattle or dog or dogs or
26 24 not 25 [Excluded animal studies] (409) dolphin* or feline or felines or hamster or hamsters or herd* or
27 (bovine or cattle or herd* or mice or rat or rats).ti. (1216881) mice or monkey or monkeys or mouse or pig or piglet or piglets or
28 26 not 27 [Additional animal studies filter] (344) pigs or porcine or primate* or rabbit or rabbits or rat or rats or
29 remove duplicates from 28 (331) rodent or rodents or sheep or swine or swines) Indexes = SCI-
EXPANDED, SSCI, A&HCI, CPCI-S, CPCI-SSH, BKCI-S, BKCI-SSH, ESCI,
Database: Ovid Embase 1974 to 2017 September 26 CCR-EXPANDED, IC Timespan = All years (4,969,143)
Date conducted: 27 September 2017 #5 #3 NOT #4 (126)
27 (bovine or cattle or herd* or mice or rat or rats).ti. (1216881)
1 Brucella/(4449) 28 26 not 27 [Additional animal studies filter] (344)
2 Brucella melitensis/(2418) 29 remove duplicates from 28 (331)
3 brucellosis/(11230)
4 brucell*.tw,kw. (16045) References
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