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Consequences of brucellosis infection during pregnancy: A systematic review of the literature

Open AccessPublished:June 06, 2018DOI:https://doi.org/10.1016/j.ijid.2018.05.023

      Highlights

      • 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.

      Keywords

      Introduction

      Brucellosis is a zoonosis that can be acquired in most countries (
      • Pappas G.
      • Papadimitriou P.
      • Akritidis N.
      • Christou L.
      • Tsianos E.V.
      The new global map of human brucellosis.
      ). 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 (
      • Tuon F.F.
      • Gondolfo R.B.
      • Cerchiari N.
      Human-to-human transmission of Brucella — a systematic review.
      ).
      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) (
      • De Carles D.W.
      Premature labour in the case of undulant fever.
      ;
      • Carpenter C.M.
      • Boak R.
      Isolation of Brucella abortus from a human fetus.
      ;
      • Janbon M.
      • De Kerleau J.C.
      Brucellose humaine et avertement.
      ;
      • Hagebusch O.E.
      Undulant fever in children.
      ;
      • Williamson A.
      Abortion in Brucella abortus fever.
      ;
      • Williams E.
      Brucellosis.
      ;
      • Poole P.M.
      • Whitehouse D.B.
      • Gilchrist M.M.
      A case of abortion consequent upon infection with Brucella abortus biotype 2.
      ;
      • Porreco R.P.
      • Haverkamp A.D.
      Brucellosis in pregnancy.
      ;
      • Hassid M.
      Brossesse et Brucellose.
      ;
      • Eckman M.R.
      Brucellosis linked to Mexican cheese.
      ;
      • Schreyer P.
      • Caspi E.
      • Leiba Y.
      • Eshchar Y.
      • Sompolinsky D.
      Brucella septicemia in pregnancy.
      ;
      • Smith C.C.
      • Porter I.A.
      • Swapp G.H.
      Mid-trimester abortion due to infection with Brucella abortus.
      ;
      • Naveau S.
      • Poitrine A.
      • Delfraissy J.F.
      • Brivet F.
      • Dormont J.
      Brucellosis hepatic abscesses and pregnancy.
      ;
      • Abu Sinna N.M.
      • Al-Shab T.
      • Al-Refe’ai A.A.
      • et al.
      Neonatal brucellosis.
      ;
      • Seoud M.
      • Saade G.
      • Awar G.
      • Uwaydah M.
      Brucellosis in pregnancy.
      ;
      • Donfrancesco E.D.M.L.
      • Scribano G.E.
      • Gallo I.
      Su di un caso di brucellosi all’VIII mese di gravidanza.
      ;
      • Gloeb D.J.
      • Lupi C.
      • O’Sullivan M.J.
      Neurobrucellosis complicating pregnancy: a case report.
      ;
      • Carbajo-Ferreira A.J.
      • Ochoa-Sangrador C.
      • Canut-Blasco A.
      • Castano-Garcia M.T.
      Neonatal brucellosis.
      ;
      • Figueroa Damian R.
      • Rojas Rodriguez L.
      • Marcano Tochon E.S.
      Brucellosis in pregnancy: course and perinatal results.
      ;
      • Shamo’on H.
      • Izzat M.
      Congenital brucellosis.
      ;
      • Malone F.D.
      • Athanassiou A.
      • Nores L.A.
      • Dalton M.E.
      Poor perinatal outcome associated with maternal Brucella abortus infection.
      ;
      • Oscherwitz S.L.
      Brucellar bacteremia in pregnancy.
      ;
      • Hackmon R.
      • Bar-David J.
      • Bashiri A.
      • Mazor M.
      Brucellosis in pregnancy.
      ;
      • Giannacopoulos I.
      • Eliopoulou M.I.
      • Ziambaras T.
      • Papanastasiou D.A.
      Transplacentally transmitted congenital brucellosis due to Brucella abortus.
      ;
      • Sayilir K.
      • Kutlu S.S.
      • Baykam N.
      • Eren S.
      • Kocagul Celikbas A.
      • Dokuzoguz B.
      Spontaneous abortion due to brucellosis: report of two cases.
      ;
      • Ozbay K.
      • Inanmis R.A.
      Successful treatment of brucellosis in a twin pregnancy.
      ;
      • Imani R.
      • Shamsipoor E.
      • Khadivi R.
      Congenital brucellosis in an infant.
      ;
      • Cebesoy F.B.
      • Balat O.
      • Mete A.
      An extraordinary cause of vertebral fracture in pregnant woman: brucellosis.
      ;
      • Karcaaltincaba D.
      • Sencan I.
      • Kandemir O.
      • Guvendag-Guven E.S.
      • Yalvac S.
      Does brucellosis in human pregnancy increase abortion risk? Presentation of two cases and review of literature.
      ;
      • Elkiran O.
      • Kocak G.
      • Karakurt C.
      • Kuzucu C.
      Brucella myocarditis in a 3-month-old: probable transplacental transmission.
      ;
      • Peker N.
      • Turan V.
      • Ergenoglu M.
      • Yeniel O.
      Brucellosis in adolescent pregnancy–case report and review of literature.
      ;
      • Nuri P.
      • Volkan T.
      • Mete E.
      • Ozgur Y.
      Brucellosis in adolescent pregnancy - case report and review of literature.
      ;
      • Ceylan A.
      • Kostu M.
      • Tuncer O.
      • Peker E.
      • Kirimi E.
      Neonatal brucellosis and breast milk.
      ;
      • Dilli D.
      • Okumuş N.
      • Zenciroğlu A.
      • et al.
      Prematurity due to maternal brucella infection and review of the literature.
      ;
      • Schlembach D.
      • Jackowski-Dohrmann S.
      • Loenning-Baucke V.
      • et al.
      Brucellosis in a refugee who migrated from Syria to Germany and lessons learnt, 2016.
      ;
      • Agah J.
      • Jafarzadeh Esfehani R.
      • Kamalimanesh B.
      Different manifestation of Brucellosis in pregnancy: case reports.
      ;
      • Fatnassi R.
      • Marwen N.
      • Benltaifa A.
      • Barhoumi T.
      Specificity of Brucellosis in pregnancy: presentation of two cases and review of literature.
      ). Eleven of 43 live born infants (26%) had congenital brucellosis (5 preterm and 6 term).
      Table 1Outcome of case reports and small case series (<10 women) of women with brucellosis detected during pregnancy by year of publication.
      First author and yearCountryTotal pregnanciesSpontaneous abortionsTherapeutic abortionIUFDPreterm infantTerm infantRemarks
      deCarles (
      • De Carles D.W.
      Premature labour in the case of undulant fever.
      )

      1931
      United States11Infant died shortly after birth
      Carpenter (
      • Carpenter C.M.
      • Boak R.
      Isolation of Brucella abortus from a human fetus.
      )

      1931
      United States11B. abortus detected in fetal tissue
      Janbon (
      • Janbon M.
      • De Kerleau J.C.
      Brucellose humaine et avertement.
      )

      1939
      France11B. melitensis detected in fetal tissue
      Hagebusch (
      • Hagebusch O.E.
      Undulant fever in children.
      )

      1941
      United States7311 (with congenital brucellosis2
      Williamson (
      • Williamson A.
      Abortion in Brucella abortus fever.
      )

      1944
      United Kingdom11
      Williams (
      • Williams E.
      Brucellosis.
      )

      1973
      United Kingdom11
      Poole (
      • Poole P.M.
      • Whitehouse D.B.
      • Gilchrist M.M.
      A case of abortion consequent upon infection with Brucella abortus biotype 2.
      )

      1972
      United Kingdom11
      Porreco (
      • Porreco R.P.
      • Haverkamp A.D.
      Brucellosis in pregnancy.
      ) 1974
      United States11
      Hassid (
      • Hassid M.
      Brossesse et Brucellose.
      )

      1974
      France11
      Eckman (
      • Eckman M.R.
      Brucellosis linked to Mexican cheese.
      ) 1975
      United States
      Case epidemiologically linked to cheese purchased in Mexico
      11
      Schreyer (
      • Schreyer P.
      • Caspi E.
      • Leiba Y.
      • Eshchar Y.
      • Sompolinsky D.
      Brucella septicemia in pregnancy.
      )

      1980
      Israel11Second trimester abortion
      Smith (
      • Smith C.C.
      • Porter I.A.
      • Swapp G.H.
      Mid-trimester abortion due to infection with Brucella abortus.
      )

      1982
      Scotland11Second trimester abortion
      Naveau (
      • Naveau S.
      • Poitrine A.
      • Delfraissy J.F.
      • Brivet F.
      • Dormont J.
      Brucellosis hepatic abscesses and pregnancy.
      )

      1983
      France11Well term infant despite maternal treatment for Brucella liver abscess in second trimester
      Abu Sinna (
      • Abu Sinna N.M.
      • Al-Shab T.
      • Al-Refe’ai A.A.
      • et al.
      Neonatal brucellosis.
      )

      1988
      Kuwait21 (with congenital brucellosis1 (with congenital brucellosisThird case excluded as maternal brucellosis diagnosed post-partum.
      Seoud (
      • Seoud M.
      • Saade G.
      • Awar G.
      • Uwaydah M.
      Brucellosis in pregnancy.
      )

      1991
      Lebanon6114
      Donfrancesco (
      • Donfrancesco E.D.M.L.
      • Scribano G.E.
      • Gallo I.
      Su di un caso di brucellosi all’VIII mese di gravidanza.
      )

      1994
      Italy11
      Gloeb (
      • Gloeb D.J.
      • Lupi C.
      • O’Sullivan M.J.
      Neurobrucellosis complicating pregnancy: a case report.
      )

      1994
      United States11Preterm delivery of well infant 27 days after maternal admission with neurobrucellosis at 30 weeks gestation
      Carbajo-Ferreira (
      • Carbajo-Ferreira A.J.
      • Ochoa-Sangrador C.
      • Canut-Blasco A.
      • Castano-Garcia M.T.
      Neonatal brucellosis.
      )

      1995
      Spain11 (with congenital brucellosis)
      Figueroa- Damian (
      • Figueroa Damian R.
      • Rojas Rodriguez L.
      • Marcano Tochon E.S.
      Brucellosis in pregnancy: course and perinatal results.
      )

      1995
      Mexico44
      Shamo’on (
      • Shamo’on H.
      • Izzat M.
      Congenital brucellosis.
      )

      1999
      Jordan11 (with congenital brucellosis)
      Malone (
      • Malone F.D.
      • Athanassiou A.
      • Nores L.A.
      • Dalton M.E.
      Poor perinatal outcome associated with maternal Brucella abortus infection.
      ) 1997
      United States (immigrant from Columbia)11
      Oscherwitz (
      • Oscherwitz S.L.
      Brucellar bacteremia in pregnancy.
      )

      1997
      United States11Healthy infant despite postpartum maternal bacteremia
      Hackmon (
      • Hackmon R.
      • Bar-David J.
      • Bashiri A.
      • Mazor M.
      Brucellosis in pregnancy.
      )

      1998
      Israel7124
      Giannacopoulos (
      • Giannacopoulos I.
      • Eliopoulou M.I.
      • Ziambaras T.
      • Papanastasiou D.A.
      Transplacentally transmitted congenital brucellosis due to Brucella abortus.
      )

      2002
      Greece11 (with congenital brucellosis)
      Sayilir (
      • Sayilir K.
      • Kutlu S.S.
      • Baykam N.
      • Eren S.
      • Kocagul Celikbas A.
      • Dokuzoguz B.
      Spontaneous abortion due to brucellosis: report of two cases.
      )

      2003
      Turkey22
      Ozbay (
      • Ozbay K.
      • Inanmis R.A.
      Successful treatment of brucellosis in a twin pregnancy.
      )

      2006
      Turkey1 (twin)1 (twin)
      Imani (
      • Imani R.
      • Shamsipoor E.
      • Khadivi R.
      Congenital brucellosis in an infant.
      )

      2007
      Iran11 (with congenital brucellosis)
      Cebesoy (
      • Cebesoy F.B.
      • Balat O.
      • Mete A.
      An extraordinary cause of vertebral fracture in pregnant woman: brucellosis.
      )

      2009
      Turkey11Treatment started for maternal vertebral osteomyelitis at 13 weeks GA
      Karcaaltincaba (
      • Karcaaltincaba D.
      • Sencan I.
      • Kandemir O.
      • Guvendag-Guven E.S.
      • Yalvac S.
      Does brucellosis in human pregnancy increase abortion risk? Presentation of two cases and review of literature.
      )

      2010
      Turkey211
      Elkiran (
      • Elkiran O.
      • Kocak G.
      • Karakurt C.
      • Kuzucu C.
      Brucella myocarditis in a 3-month-old: probable transplacental transmission.
      )

      2010
      Turkey11 (with congenital brucellosis)
      Peker (
      • Peker N.
      • Turan V.
      • Ergenoglu M.
      • Yeniel O.
      Brucellosis in adolescent pregnancy–case report and review of literature.
      ) 2011
      Turkey11
      Nuri (
      • Nuri P.
      • Volkan T.
      • Mete E.
      • Ozgur Y.
      Brucellosis in adolescent pregnancy - case report and review of literature.
      )

      2011
      Turkey11
      Ceylan (
      • Ceylan A.
      • Kostu M.
      • Tuncer O.
      • Peker E.
      • Kirimi E.
      Neonatal brucellosis and breast milk.
      )

      2012
      Turkey11 (with congenital brucellosis)
      Dilli (
      • Dilli D.
      • Okumuş N.
      • Zenciroğlu A.
      • et al.
      Prematurity due to maternal brucella infection and review of the literature.
      ) 2013
      Turkey11 (with congenital brucellosis)
      Schlembach (
      • Schlembach D.
      • Jackowski-Dohrmann S.
      • Loenning-Baucke V.
      • et al.
      Brucellosis in a refugee who migrated from Syria to Germany and lessons learnt, 2016.
      )

      2016
      Germany (acquired in Syria)11
      Agah (
      • Agah J.
      • Jafarzadeh Esfehani R.
      • Kamalimanesh B.
      Different manifestation of Brucellosis in pregnancy: case reports.
      ) 2016
      Iran532
      Fatnassi (
      • Fatnassi R.
      • Marwen N.
      • Benltaifa A.
      • Barhoumi T.
      Specificity of Brucellosis in pregnancy: presentation of two cases and review of literature.
      ) 2016
      Tunisia211
      Legend: GA — gestational age; IUFD — intrauterine fetal death (≥20 weeks gestational age).
      a Case epidemiologically linked to cheese purchased in Mexico
      There were 14 case series with ≥ 10 women with brucellosis during pregnancy including 735 pregnancies (Table 2) (
      • Criscuolo E.
      • Di Carlo F.C.
      Abortion and other gynecological and obstetrical disorders in brucellosis.
      ,
      • Madkour M.
      Brucellosis in Saudi Arabia.
      ,
      • Lulu A.R.
      • Araj G.F.
      • Khateeb M.I.
      • Mustafa M.Y.
      • Yusuf A.R.
      • Fenech F.F.
      Human brucellosis in Kuwait: a prospective study of 400 cases.
      ,
      • Madkour M.M.
      Pregnancy and Brucellosis.
      ,
      • Sharif A.
      • Reyes Z.
      • Thomassen P.
      Screening for brucellosis in pregnant women.
      ,
      • AlAmoudi S.M.
      Brucellosis in pregnancy in Bisha, Saudi Arabia.
      ,
      • Garriguet J.
      • El Azzi J.
      • Sancho V.
      • Barrios F.
      Brucelosis and pregnancy.
      ,
      • Khan M.Y.
      • Mah M.W.
      • Memish Z.A.
      Brucellosis in pregnant women.
      ,
      • Elshamy M.
      • Ahmed A.I.
      The effects of maternal brucellosis on pregnancy outcome.
      ,
      • Karahocagil M.K.
      • Kolusari A.
      • Yildizhan R.
      • et al.
      Brucellosis in pregnancy: a 6-year clinical analysis.
      ,
      • Roushan M.R.
      • Baiani M.
      • Asnafi N.
      • Saedi F.
      Outcomes of 19 pregnant women with brucellosis in Babol, northern Iran.
      ,
      • Gulsun S.
      • Aslan S.
      • Satici O.
      • Gul T.
      Brucellosis in pregnancy.
      ,
      • Gulsun S.
      • Dorman V.
      • Aslan S.
      • Gul T.
      Pregnancy associated with brucellosis and acute viral hepatitis: course and outcome (co-infections in pregnancy).
      ,
      • Vilchez G.
      • Espinoza M.
      • D’Onadio G.
      • Saona P.
      • Gotuzzo E.
      Brucellosis in pregnancy: clinical aspects and obstetric outcomes.
      ). Diagnostic criteria typically included positive serology or a positive blood culture with only one study specifying that women had to be symptomatic (
      • Lulu A.R.
      • Araj G.F.
      • Khateeb M.I.
      • Mustafa M.Y.
      • Yusuf A.R.
      • Fenech F.F.
      Human brucellosis in Kuwait: a prospective study of 400 cases.
      ). 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 G.
      • Espinoza M.
      • D’Onadio G.
      • Saona P.
      • Gotuzzo E.
      Brucellosis in pregnancy: clinical aspects and obstetric outcomes.
      ). Six infants had congenital brucellosis (
      • Madkour M.M.
      Pregnancy and Brucellosis.
      ,
      • AlAmoudi S.M.
      Brucellosis in pregnancy in Bisha, Saudi Arabia.
      ,
      • Vilchez G.
      • Espinoza M.
      • D’Onadio G.
      • Saona P.
      • Gotuzzo E.
      Brucellosis in pregnancy: clinical aspects and obstetric outcomes.
      ). Two studies reported a correlation between brucellosis antibody titers as measured by serum agglutination and SA (
      • Sharif A.
      • Reyes Z.
      • Thomassen P.
      Screening for brucellosis in pregnant women.
      ,
      • Elshamy M.
      • Ahmed A.I.
      The effects of maternal brucellosis on pregnancy outcome.
      ) while three others reported no correlation (
      • Khan M.Y.
      • Mah M.W.
      • Memish Z.A.
      Brucellosis in pregnant women.
      ,
      • Karahocagil M.K.
      • Kolusari A.
      • Yildizhan R.
      • et al.
      Brucellosis in pregnancy: a 6-year clinical analysis.
      ,
      • Roushan M.R.
      • Baiani M.
      • Asnafi N.
      • Saedi F.
      Outcomes of 19 pregnant women with brucellosis in Babol, northern Iran.
      ). Two studies compared outcomes with and without documented maternal bacteremia; the first reported no increase in the incidence of SA with bacteremia (
      • Khan M.Y.
      • Mah M.W.
      • Memish Z.A.
      Brucellosis in pregnant women.
      ) while the second reported SA in 2 of 3 bacteremic women versus 0 of 13 without bacteremia (p < 0.05) (
      • Garriguet J.
      • El Azzi J.
      • Sancho V.
      • Barrios F.
      Brucelosis and pregnancy.
      ).
      Table 2Outcome of case series of women with brucellosis detected during pregnancy by year of publication.
      First author and yearCountryTotal pregnancies with brucellosisDiagnostic criteria for brucellosis during pregnancySpontaneous abortions (SA)IUFDPreterm infantTerm infant
      Criscuolo

      (
      • Criscuolo E.
      • Di Carlo F.C.
      Abortion and other gynecological and obstetrical disorders in brucellosis.
      ) 1954
      Argentina200Positive serology52 (26%)NRNRNR
      Madkour (
      • Madkour M.
      Brucellosis in Saudi Arabia.
      )

      1985
      Saudi Arabia11Compatible symptoms and positive serology5 (45%)1 (9%)1 (9%)4 (36%)
      Lulu (
      • Lulu A.R.
      • Araj G.F.
      • Khateeb M.I.
      • Mustafa M.Y.
      • Yusuf A.R.
      • Fenech F.F.
      Human brucellosis in Kuwait: a prospective study of 400 cases.
      )

      1988
      Kuwait35Compatible symptoms and positive serology with cut-off titers varying with duration of symptoms11 (31%)
      All were first trimester abortions.
      NRNRNR
      Madkour (
      • Madkour M.M.
      Pregnancy and Brucellosis.
      )

      1989
      Saudi Arabia2916 were bacteremic — others diagnosed by serology12 (41%)1 (3%)1 (3%) — had congenital brucellosis15 (52%)
      Sharif (
      • Sharif A.
      • Reyes Z.
      • Thomassen P.
      Screening for brucellosis in pregnant women.
      )

      1990
      Saudi Arabia42
      24 were symptomatic and the other 18 were detected by routine screening so may or may not have been symptomatic.
      Positive serology recognized in symptomatic women (N = 24) plus women identified by routine screening (N = 18)6 (18%)NRNRNR
      Al-Amoudi (
      • AlAmoudi S.M.
      Brucellosis in pregnancy in Bisha, Saudi Arabia.
      ) 1995
      Saudi Arabia26
      26 others had titres <1:160
      Titer ≥ 1:1604 (15%)0NR22 (85%) (1 had congenital brucellosis)
      Garriguet (
      • Garriguet J.
      • El Azzi J.
      • Sancho V.
      • Barrios F.
      Brucelosis and pregnancy.
      ) 2000
      Spain163 were bacteremic — others diagnosed by serology2 (11%)0014 (88%)
      Khan (
      • Khan M.Y.
      • Mah M.W.
      • Memish Z.A.
      Brucellosis in pregnant women.
      )

      2001
      Saudi Arabia92Positive blood culture or serology40 (43%)2 (2%)NRNR
      Elshamy (
      • Elshamy M.
      • Ahmed A.I.
      The effects of maternal brucellosis on pregnancy outcome.
      )

      2008
      Saudi Arabia55
      Only 35 were symptomatic so the other 20 may have had resolved infection.
      Positive serology15 (27%)7 (13%)6 (11%)27 (49%)
      Karahocagil (
      • Karahocagil M.K.
      • Kolusari A.
      • Yildizhan R.
      • et al.
      Brucellosis in pregnancy: a 6-year clinical analysis.
      )

      2010
      Turkey29Positive blood culture (N = 2) or serology (N = 29)7 (24%)1 (3%)2 (7%)19 (66%)
      Roushan (
      • Roushan M.R.
      • Baiani M.
      • Asnafi N.
      • Saedi F.
      Outcomes of 19 pregnant women with brucellosis in Babol, northern Iran.
      )

      2011
      Iran19Positive blood culture (N = 4) or serology (N = 19) — all had compatible symptoms during pregnancy10 (53%)009 (47%)
      Gulsun (
      • Gulsun S.
      • Aslan S.
      • Satici O.
      • Gul T.
      Brucellosis in pregnancy.
      )

      2011
      Turkey39
      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.
      Positive blood culture or serology1 (3%)07 (18%)21(54%)
      Gulsun (
      • Gulsun S.
      • Dorman V.
      • Aslan S.
      • Gul T.
      Pregnancy associated with brucellosis and acute viral hepatitis: course and outcome (co-infections in pregnancy).
      ) 2011
      Turkey56
      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)
      4 (7%)015 (27%)37 (66%)
      Vilchez (
      • Vilchez G.
      • Espinoza M.
      • D’Onadio G.
      • Saona P.
      • Gotuzzo E.
      Brucellosis in pregnancy: clinical aspects and obstetric outcomes.
      )

      2015
      Peru86
      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 pregnancy16 (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.
      Five of the 14 case series included a control group (Table 3) (
      • Sharif A.
      • Reyes Z.
      • Thomassen P.
      Screening for brucellosis in pregnant women.
      ,
      • Khan M.Y.
      • Mah M.W.
      • Memish Z.A.
      Brucellosis in pregnant women.
      ,
      • Elshamy M.
      • Ahmed A.I.
      The effects of maternal brucellosis on pregnancy outcome.
      ,
      • Karahocagil M.K.
      • Kolusari A.
      • Yildizhan R.
      • et al.
      Brucellosis in pregnancy: a 6-year clinical analysis.
      ,
      • Gulsun S.
      • Aslan S.
      • Satici O.
      • Gul T.
      Brucellosis in pregnancy.
      ) 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 M.
      • Ahmed A.I.
      The effects of maternal brucellosis on pregnancy outcome.
      ,
      • Gulsun S.
      • Aslan S.
      • Satici O.
      • Gul T.
      Brucellosis in pregnancy.
      ). Two compared cases to all pregnant women (
      • Khan M.Y.
      • Mah M.W.
      • Memish Z.A.
      Brucellosis in pregnant women.
      ,
      • Karahocagil M.K.
      • Kolusari A.
      • Yildizhan R.
      • et al.
      Brucellosis in pregnancy: a 6-year clinical analysis.
      ) 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 A.
      • Reyes Z.
      • Thomassen P.
      Screening for brucellosis in pregnant women.
      ). “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.
      Sharif (
      • Sharif A.
      • Reyes Z.
      • Thomassen P.
      Screening for brucellosis in pregnant women.
      )

      1990
      Khan (
      • Khan M.Y.
      • Mah M.W.
      • Memish Z.A.
      Brucellosis in pregnant women.
      )

      2001
      Elshamy (
      • Elshamy M.
      • Ahmed A.I.
      The effects of maternal brucellosis on pregnancy outcome.
      )

      2008
      Karahocagil (
      • Karahocagil M.K.
      • Kolusari A.
      • Yildizhan R.
      • et al.
      Brucellosis in pregnancy: a 6-year clinical analysis.
      )

      2010
      Gulsun (
      • Gulsun S.
      • Aslan S.
      • Satici O.
      • Gul T.
      Brucellosis in pregnancy.
      )

      2011
      Total
      SA in cases versus controls6/42 (14%) versus 39/495 (8%); p = 0.1540/92 (43%) versus 710/25540 (3%); p < 0.00115/55 (27%) versus 60/395 (15%); p = 0.027/29 (24%) versus 2577/33936 (8%); p < 0.001Data not presented; p > 0.0568/218 (31%) versus 3386/60366 (5%); p < 0.001
      IUFD in cases versus controlsNR2/92 (2%) versus 66/25540 (0.3%); p < 0.0017/55 (13%) versus 15/395 (4%); p = 0.0041/29 (3%) versus 76/33936 (0.2%); p < 0.001NR10/176 (6%) versus 157/59871 (0.3%); p < 0.001
      Preterm delivery in cases versus controls — all pregnanciesNRNR6/55 (11%) versus 35/395 (9%); p = 0.622/29 (7%) versus 643/33936 (2%); p = 0.057/39 (18%) versus 1/40 (2.5%); p = 0.02315/123 (12%) versus 679/34371 (2%); p < 0.001
      Preterm delivery in cases versus controls — live born infants onlyNRNR6/33 (18%) versus 35/320 (11%); p = 0.222/21 (10%) versus 643/31283 (2%); p = 0.016
      The authors concluded p>0.05, combining live births with IUFDs. It seems that they excluded SAs for controls but not cases.
      NR8/54 (15%) versus 678/31603 (2%); p < 0.001
      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.
      Nine studies described the brucellosis seroprevalence in women with adverse pregnancy outcomes in endemic countries (Table 4) with up to 46% being seropositive (
      • Sarram M.
      • Feiz J.
      • Foruzandeh M.
      • Gazanfarpour P.
      Intrauterine fetal infection with Brucella melitensis as a possible cause of second-trimester abortion.
      ,
      • Fernihough T.J.
      • Munoz W.P.
      • Mahadeyo I.
      The role of Brucella abortus in spontaneous abortion among the black population.
      ,
      • Makhseed M.
      • Harouny A.
      • Araj G.
      • Moussa M.A.
      • Sharma P.
      Obstetric and gynecologic implication of brucellosis in Kuwait.
      ,
      • Nassaji M.
      • Rahbar N.
      • Ghorbani R.
      • Lavaf S.
      The role of brucella infection among women with spontaneous abortion in an endemic region.
      ,
      • Massiha A.
      • Khoshkholgh Pahlaviani M.R.M.
      • Sedighi Kasmaie P.
      • Vand Yousefi J.
      Study of the reasons of infectious abortions in the subjects who approached Kamali Hospital, Karaj in Iran.
      ,
      • Abo-shehada M.N.
      • Abu-Halaweh M.
      Seroprevalence of Brucella species among women with miscarriage in Jordan.
      ,
      • Mohammad K.I.
      • El Ghazaly M.M.
      • Zaalouk T.K.
      • Morsy A.T.
      Maternal brucellosis and human pregnancy.
      ,
      • Rujeni N.
      • Mbanzamihigo L.
      Prevalence of Brucellosis among women presenting with abortion/stillbirth in Huye, Rwanda.
      ,
      • Puri M.
      • Patel N.
      • Gaikwad V.
      • Despande H.
      • Pandey P.
      A study of prevalence of brucellosis in cases of spontaneous abortions.
      ). The two studies with a control group reported no difference in seroprevalence between cases and controls (
      • Nassaji M.
      • Rahbar N.
      • Ghorbani R.
      • Lavaf S.
      The role of brucella infection among women with spontaneous abortion in an endemic region.
      ,
      • Abo-shehada M.N.
      • Abu-Halaweh M.
      Seroprevalence of Brucella species among women with miscarriage in Jordan.
      ). 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 M.
      • Rahbar N.
      • Ghorbani R.
      • Lavaf S.
      The role of brucella infection among women with spontaneous abortion in an endemic region.
      ) while the other attained a perfect score (
      • Abo-shehada M.N.
      • Abu-Halaweh M.
      Seroprevalence of Brucella species among women with miscarriage in Jordan.
      ). Both studies attained full marks for documenting “Selection” and “Exposure”.
      Table 4Evidence for brucellosis in case series of pregnancies with adverse outcome from endemic countries.
      Author and yearCountryIncidence of brucellosis
      Sarram (
      • Sarram M.
      • Feiz J.
      • Foruzandeh M.
      • Gazanfarpour P.
      Intrauterine fetal infection with Brucella melitensis as a possible cause of second-trimester abortion.
      )

      1974
      IranOf 51 second-trimester abortions, B. melitensis was isolated from fetal tissue and/or from maternal urine, blood, or uterine tissue in 6 cases (12%).
      Fernihough (
      • Fernihough T.J.
      • Munoz W.P.
      • Mahadeyo I.
      The role of Brucella abortus in spontaneous abortion among the black population.
      ) 1985
      South AfricaOf 125 women with SAs, none had evidence of acute brucellosis but 4 had evidence of chronic brucellosis.
      Makhsheed (
      • Makhseed M.
      • Harouny A.
      • Araj G.
      • Moussa M.A.
      • Sharma P.
      Obstetric and gynecologic implication of brucellosis in Kuwait.
      )

      1998
      KuwaitThe incidence of maternal acute or chronic Brucella infection was 2/29 (7%) with SA, 5/51 with IUFD (10%) and 18/227 (8%) with preterm delivery
      Nassaji (
      • Nassaji M.
      • Rahbar N.
      • Ghorbani R.
      • Lavaf S.
      The role of brucella infection among women with spontaneous abortion in an endemic region.
      )

      2008
      IranSeroprevalence following spontaneous abortion (6%; n = 81) was not higher than seroprevalence with normal pregnancy (14%; n = 105) with none having IgM.
      Massiha (
      • Massiha A.
      • Khoshkholgh Pahlaviani M.R.M.
      • Sedighi Kasmaie P.
      • Vand Yousefi J.
      Study of the reasons of infectious abortions in the subjects who approached Kamali Hospital, Karaj in Iran.
      )
      Iran8 of 84 women with SA (10%) had serologic evidence of brucellosis
      Abo-Shehada (
      • Abo-shehada M.N.
      • Abu-Halaweh M.
      Seroprevalence of Brucella species among women with miscarriage in Jordan.
      )

      2011
      JordanSeroprevalance did not differ in 445 women with and 445 women without SA (1.8% (95% CI: 0.6-3.0), versus 1.0% (95% CI: 0.08-1.9).
      Mohammad (
      • Mohammad K.I.
      • El Ghazaly M.M.
      • Zaalouk T.K.
      • Morsy A.T.
      Maternal brucellosis and human pregnancy.
      )

      2011
      Egypt59 of 129 women with recent or remote SA had positive serology for Brucella (46%)
      Rujeni (
      • Rujeni N.
      • Mbanzamihigo L.
      Prevalence of Brucellosis among women presenting with abortion/stillbirth in Huye, Rwanda.
      )

      2014
      Rwanda15 of 60 women with SA (N = 11) OR IUFD (n = 4) had positive serology for Brucella (25%)
      Puri (
      • Puri M.
      • Patel N.
      • Gaikwad V.
      • Despande H.
      • Pandey P.
      A study of prevalence of brucellosis in cases of spontaneous abortions.
      )

      2015
      IndiaSeroprevalence was 9% with SA.
      Legend: IUFD — intrauterine fetal death; SA — spontaneous abortion.

      Discussion

      Traditional thinking was that adverse pregnancy should be uncommon with brucellosis due to the absence of erythritol in the human placenta (
      • Al-Tawfiq J.A.
      • Memish Z.A.
      Pregnancy associated brucellosis.
      ). 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 K.
      • Al-Jasser A.
      Brucellosis: a global re-emerging zoonosis history, epidemiology, microbiology, immunology and genetics.
      ). However, Brucella has been detected from aborted fetuses (
      • Carpenter C.M.
      • Boak R.
      Isolation of Brucella abortus from a human 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 (
      • Muanda F.T.
      • Sheehy O.
      • Berard A.
      Use of antibiotics during pregnancy and risk of spontaneous abortions.
      ). 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 G.
      • Espinoza M.
      • D’Onadio G.
      • Saona P.
      • Gotuzzo E.
      Brucellosis in pregnancy: clinical aspects and obstetric outcomes.
      ,
      • Scherag A.
      • Kesselmeir M.
      • Melzer F.
      • et al.
      Brucellosis in pregnant women from Pakistan: an observational study.
      ). 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 (
      • Al-Anazi K.
      • Al-Jasser A.
      Brucellosis: a global re-emerging zoonosis history, epidemiology, microbiology, immunology and genetics.
      ).
      Maternal bacteremia, fever and disseminated intravascular coagulation have been hypothesized to result in SA and IUFD (
      • Karahocagil M.K.
      • Kolusari A.
      • Yildizhan R.
      • et al.
      Brucellosis in pregnancy: a 6-year clinical analysis.
      ). 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 M.
      • Cetin O.
      • Kurdoglu Z.
      • Akdeniz H.
      The effect of brucellosis on women’s health and reproduction.
      ). 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 A.
      • Gerart S.
      • Gorvel V.A.
      • et al.
      Pathogenic brucellae replicate in human 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) (
      • Kurdoglu M.
      • Kurdoglu Z.
      What is the role of laminin receptor 1 in human reproduction?.
      ). Brucella has not yet been detected in human trophoblasts (
      • O’Callaghan D.
      Novel replication profiles of Brucella in human trophoblasts give insights into the pathogenesis of infectious abortion.
      ) 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 G.
      • Espinoza M.
      • D’Onadio G.
      • Saona P.
      • Gotuzzo E.
      Brucellosis in pregnancy: clinical aspects and obstetric outcomes.
      ,
      • Kurdoglu M.
      • Cetin O.
      • Kurdoglu Z.
      • Akdeniz H.
      The effect of brucellosis on women’s health and reproduction.
      ).
      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 (
      • Al-Anazi K.
      • Al-Jasser A.
      Brucellosis: a global re-emerging zoonosis history, epidemiology, microbiology, immunology and genetics.
      ). 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 (
      • Bechara Z.
      Human brucellosis and abortion.
      ).
      A strength of the current study is that other recent reviews of brucellosis in pregnancy included only case series (
      • Arenas-Gamboa
      • Rossetti C.A.
      • Chaki S.P.
      • Garcia-Gonzalez D.G.
      • Adams L.G.
      • Ficht T.A.
      Human brucellosis and adverse pregnancy outcomes.
      ) or studied all modes of human-to-human transmission (
      • Tuon F.F.
      • Gondolfo R.B.
      • Cerchiari A.N.
      Human-to-human transmission of Brucella — a systematic review.
      ) 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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