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Alberta Research Centre for Health Evidence, Department of Pediatrics, University of Alberta, Alberta SPOR SUPPORT Unit Knowledge Translation Platform, Edmonton, Alberta, Canada
Brucellosis in pregnancy almost certainly leads to spontaneous abortion.
•
Brucellosis in pregnancy probably increases the risk of intra-uterine fetal death and prematurity.
•
About 2% of infants exposed in-utero develop congenital brucellosis.
Abstract
Background
The aim was to establish the incidence of adverse outcomes with brucellosis infection during pregnancy.
Methods
Ovid Medline (1946-), Ovid Embase (1974-), and Web of Science (Clarivate Analytics) (1900-), the World Health Organization website and Google were searched September 27, 2017 for (i) outcomes 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 (<10 women), there were 20 spontaneous abortions (SAs) (31%), 2 intra-uterine fetal deaths (IUFDs) (3%) and 11 cases of congenital brucellosis (17%). In 14 larger case series there were 181 SAs in 679 pregnancies (27%), 19 IUFDs in 458 pregnancies (4%), and 44 preterm infants (12%) plus 6 infants with congenital brucellosis (2%) in 362 pregnancies. SA, IUFD and preterm delivery incidence were increased with meta-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.
). Human infection stems from direct contact with infected animals, inhalation of contaminated animal feces or consumption of infected animal products. Human-to-human transmission via blood transfusion, bone marrow transplantation, sex, transplacental or perinatal exposure, and breast milk have been documented (
Brucellosis in pregnancy is of special interest as it remains controversial whether it is a precipitant of poor outcomes beyond congenital brucellosis. This is the first systematic review with meta-analysis analyzing whether brucellosis increases the incidence of other adverse pregnancy outcomes.
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 populations) 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 seroprevalence 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-statement.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) (
). Diagnostic criteria typically included positive serology or a positive blood culture with only one study specifying that women had to be symptomatic (
). 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 (
). Two studies compared outcomes with and without documented maternal bacteremia; the first reported no increase in the incidence of SA with bacteremia (
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.
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.
Positive blood culture (N = 33) or serology (N = 101) — all had compatible symptoms during pregnancy
16 (19%)
7 (8%)
12 (14%)
51 (58%)
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.
) 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 (
) 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 (
). “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).
Table 3Studies with a control group reporting adverse outcome from brucellosis infection in pregnancy.
Nine studies described the brucellosis seroprevalence in women with adverse pregnancy outcomes in endemic countries (Table 4) with up to 46% being seropositive (
). 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 (
Seroprevalence following spontaneous abortion (6%; n = 81) was not higher than seroprevalence with normal pregnancy (14%; n = 105) with none having IgM.
). 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 (
). Furthermore, fetal infection is not a 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% (Table 1, Table 2) which is clearly increased from the 5% incidence of spontaneous abortion in a recent large population-based study (
). 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 (
). 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 hepatosplenomegaly are the most commonly encountered presentations (
). 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 (
). 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 (
) 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) (
) 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 (
Pregnant women with untreated brucellosis have also been reported to be at high risk for premature rupture of membrane (PROM), chorioamnionitis, postpartum endometritis, and intrauterine growth retardation but there are no studies with a control group (
). There is no evidence that brucellosis leads to infertility. In a study from Columbia, 24 women with repeat spontaneous abortions were found to have evidence of brucellosis (6 had active infection) and all had subsequent successful pregnancies (
) 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)
16
(ante-natal* or antenatal* or ante-partum* or antepartum* or pre-natal* or prenatal*).tw,kf. (125254)
17
((birth* or deliver*) adj2 (pre-mature* or premature* or pre-term* or preterm*)).tw,kf. (32498)
18
((dead* or death* or loss* or mortalit*) adj2 (endouterine* or fetal* or fetus* or foetal* or foetus* or intrauterine*)).tw,kf. (17713)
19
(expect* adj1 (female? or mother? or wom#n)).tw,kf. (1985)
20
miscarr*.tw,kf. (12222)
21
pregnan*.tw,kf. (478075)
22
(still-birth* or stillbirth*).tw,kf. (11181)
23
or/7-22 [Combined MeSH & text words for pregnancy & pregnancy complications] (1010466)
24
and/6,23 [Combined concepts of brucellosis & pregnancy] (1234)
25
exp animals/not humans/(4588723)
26
24 not 25 [Excluded animal studies] (409)
27
(bovine or cattle or herd* or mice or rat or rats).ti. (1216881)
28
26 not 27 [Additional animal studies filter] (344)
29
remove duplicates from 28 (331)
Database: Ovid Embase 1974 to 2017 September 26
Date conducted: 27 September 2017
1
Brucella/(4449)
2
Brucella melitensis/(2418)
3
brucellosis/(11230)
4
brucell*.tw,kw. (16045)
5
((Cyprus or Gibraltar or Malta or undulant) adj1 fever*).tw,kw. (301)
6
or/1-5 [Combined Emtree & text words for brucellosis] (18344)
7
exp fetus death/(36766)
8
intrauterine infection/(5454)
9
exp labor complication/(170468)
10
exp pregnancy/(679494)
11
pregnancy complication/(72177)
12
pregnant woman/(58106)
13
exp prenatal care/(135692)
14
spontaneous abortion/(36736)
15
abortion*.tw,kw. (64438)
16
(ante-natal* or antenatal* or ante-partum* or antepartum* or pre-natal* or prenatal*).tw,kw. (157757)
17
((birth* or deliver*) adj2 (pre-mature* or premature* or pre-term* or preterm*)).tw,kw. (45193)
18
((dead* or death* or loss* or mortalit*) adj2 (endouterine* or fetal* or fetus* or foetal* or foetus* or intrauterine*)).tw,kw. (21369)
19
(expect* adj1 (female? or mother? or wom#n)).tw,kw. (2356)
20
miscarr*.tw,kw. (19747)
21
pregnan*.tw,kw. (570547)
22
(still-birth* or stillbirth*).tw,kw. (14498)
23
or/7-22 [Combined Emtree & text words for pregnancy & pregnancy complications] (1087768)
24
and/6,23 [Combined concepts of brucellosis & pregnancy] (1133)
25
exp animal/not human/(4874029)
26
24 not 25 [Excluded animal studies] (438)
27
(bovine or cattle or herd* or mice or rat or rats).ti. (1347825)
28
26 not 27 [Additional animal studies filter] (364)
29
remove duplicates from 28 (349)
Database: Web of Science Core Collection via Clarivate Analytics
Date conducted: 27 September 2017
#1 TS = (brucell* OR “Cyprus fever” OR “Gibraltar fever” OR “Malta fever” OR “undulant fever”) OR TI = (brucell* OR “Cyprus fever” OR “Gibraltar fever” OR “Malta fever” OR “undulant fever”) Indexes = SCI-EXPANDED, SSCI, A&HCI, CPCI-S, CPCI-SSH, BKCI-S, BKCI-SSH, ESCI, CCR-EXPANDED, IC Timespan = All years (15,160)
#2 TS = (abortion* OR miscarr* OR pregnan* OR “premature birth” OR “preterm birth” OR “still birth*" OR stillbirth*) OR TI = (abortion* OR miscarr* OR pregnan* OR ‘premature birth’ OR “preterm birth” OR “still birth*" OR stillbirth*) Indexes = SCI-EXPANDED, SSCI, A&HCI, CPCI-S, CPCI-SSH, BKCI-S, BKCI-SSH, ESCI, CCR-EXPANDED, IC Timespan = All years (477,903)
#3 #2 AND #1 (836)
#4 TS = (animal or animal-model* or animals or bovine or canine* or cat or cats or cattle or dog or dogs or dolphin* or feline or felines or hamster or hamsters or herd* or mice or monkey or monkeys or mouse or pig or piglet or piglets or pigs or porcine or primate* or rabbit or rabbits or rat or rats or rodent or rodents or sheep or swine or swines) OR TI = (animal or animal-model* or animals or bovine or canine* or cat or cats or cattle or dog or dogs or dolphin* or feline or felines or hamster or hamsters or herd* or mice or monkey or monkeys or mouse or pig or piglet or piglets or pigs or porcine or primate* or rabbit or rabbits or rat or rats or rodent or rodents or sheep or swine or swines) Indexes = SCI-EXPANDED, SSCI, A&HCI, CPCI-S, CPCI-SSH, BKCI-S, BKCI-SSH, ESCI, CCR-EXPANDED, IC Timespan = All years (4,969,143)
#5 #3 NOT #4 (126)
27 (bovine or cattle or herd* or mice or rat or rats).ti. (1216881)
28 26 not 27 [Additional animal studies filter] (344)
29 remove duplicates from 28 (331)
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