Gestational syphilis and stillbirth in the Americas: a systematic review and meta-analysis

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1 Artículo de revisión / Review Pn Americn Journl of Pulic Helth nd stillirth in the Americs: systemtic review nd met-nlysis Luren Arnesen, 1 Suznne Serruy, 1 nd Plo Durán 1 Suggested cittion Arnesen L, Serruy S, Durán P. nd stillirth in the Americs: systemtic review nd met-nlysis. Rev Pnm Slud Pulic. 2015;37(6): strct Key words Ojective. To perform systemtic review nd met-nlysis of reported estimtes of the ssocition etween gesttionl syphilis (GS) nd stillirth in the Americs region. Methods. Cochrne Lirry, Emse, LILACS, MEDLINE/PuMed, PLOS, nd ScienceDirect were serched for originl reserch studies quntifying the reltionship etween GS nd stillirth in the region. A finl smple of eight studies ws selected. A cumultive met-nlysis plus four sugroup met-nlyses of study dt on the ssocition etween mternl syphilis during pregnncy nd stillirth were conducted. The four met-nlyses were sed on 1) definition of cses nd the control; 2) syphilis tretment (presence or sence, effective or ineffective); 3) definition of stillirth s showing no signs of life t irth ; nd 4) definition of stillirth sed on low irth weight nd gesttionl ge. Rndom-effects metnlyses were used to clculte pooled estimtes of stillirth with exposure to GS, nd ech sugroup nlysis ws tested for heterogeneity. Results. Women with GS hd incresed odds of stillirth (pooled odds rtio (OR): 6.87; 95% confidence intervl: 2.93, 16.08). There ws considerle heterogeneity cross the eight studies (percentge of vrince (I 2 ) = 95). The funnel plot ws not sttisticlly significnt, pointing to lck of puliction is. Incresed odds of stillirth mong pregnnt women with syphilis were lso seen in ll four sugroup met-nlyses. Conclusions. GS is mjor contriuting fctor for stillirths in the Americs. Interventions trgeting GS re highly cost-effective nd, long with high-qulity point-of-cre testing, should e implemented cross the region to help rech the gol of eliminting congenitl syphilis. Stillirth; syphilis; Americs; Ltin Americ; West Indies. The World Helth Orgniztion (WHO) estimtes tht million pregnncies re ffected y syphilis ech yer, mking congenitl syphilis more common thn perintl HIV infection (1 4). Among pregnncies ffected y syphilis, 50% 80% will result in dverse irth outcomes without proper tretment (1, 4 6). Prominent mong these 1 Pn Americn Helth Orgniztion, Montevideo, Uruguy. Send correspondence to: Luren Arnesen, lurenrnesen@gmil.com outcomes is stillirth, which occurs in 30% 40% of cses (4 6). Glolly, syphilis is the min cuse for more thn stillirths nnully (1, 2, 7). In res of high syphilis prevlence s mny s hlf of ll stillirths my e ttriuted to tht infection (5, 8). Glolly, the Americs region hs the highest incidence rte of syphilis nd ccounts for up to 25% of the 2 million nnul cses of gesttionl syphilis (GS) (3, 9). Prevlence of GS in the Americs (Cnd, Ltin Americ nd the Crien, nd the United Sttes) vries y country from 0.0% 7.0% (1, 2, 9 11). Ech yer, n estimted stillirths in the Americs re ttriutle to congenitl syphilis, defined s n infnt orn to mother who ws untreted or indequtely treted for syphilis during pregnncy, or n infnt with positive syphilis test (3, 10, 12). In 1995, the Pn Americn Helth Orgniztion (PAHO) pproved the Re- 422 Rev Pnm Slud Pulic 37(6), 2015

2 Arnesen et l. nd stillirth in the Americs: review nd nlysis Review gionl Pln of Action for the Elimintion of Congenitl Syphilis, defining elimintion s incidence of 0.5 cses of congenitl syphilis, including stillirths, per irths (13). In 2010, PAHO Memer Sttes pproved strtegy nd pln of ction 2 tht ffirmed these elimintion gols nd set trget dte of 2015 (3, 10, 15). Elimintion is possile with proper tretment single dose of 2.4 million units of enzthine penicillin G (BPG), in most cses, which is lmost 100% effective t preventing syphilis-ssocited dverse outcomes in pregnncy when given in timely mnner (1, 5, 7, 15, 16). Moreover, the cost-effectiveness of ntentl syphilis screening nd tretment hs een shown repetedly (5, 6, 16). The World Bnk nd WHO oth cite ntentl syphilis screening nd tretment s one of the most cost-effective interventions ville (1, 10). While stillirth nd other dverse irth outcomes due to syphilis re preventle through cost-effective interventions, syphilis-ttriutle stillirths re still occurring in the Americs. Pst reserch in the region showed n incresed risk of stillirth with exposure to GS (17 24). Overll, reserch in the region hs focused on GS prevlence, the persistence of inequlities in helth outcomes relted to GS, clls to ction (to test nd tret pregnnt women), nd smll geogrphic res within given country, nd hs not included exmintion of GS nd stillirth t the regionl level (17 25). To the est of the uthors knowledge, no previous met-nlysis hs exmined the reltionship etween GS nd stillirth in the Americs. The systemtic review nd met-nlyses reported here identified nd nlyzed reported estimtes of the ssocition etween GS nd stillirth in the region. MATERIALS AND METHODS A systemtic review nd five metnlyses (one cumultive nlysis nd four sugroup nlyses) were crried out in ccordnce with Met-nlysis Of Oservtionl Studies in Epidemiology (MOOSE) guidelines nd Preferred Reporting Items for Systemtic Reviews nd Met-Anlyses (PRISMA) requirements for systemtic reviews nd metnlyses (26, 27). 2 Strtegy nd Pln of Action for the Elimintion of Mother-to-Child Trnsmission of HIV nd Congenitl Syphilis (14). Serch strtegy nd inclusion criteri Using text serch strings, serch ws conducted for studies tht exmined the ssocition etween GS nd stillirth for ll yers covered in the following dtses up to 6 Octoer 2013: Cochrne Lirry, Emse, LILACS, MEDLINE/ PuMed, PLOS (ll journls), nd ScienceDirect (journls only). Pulictions found in the serch were included in the nlysis if they contined t lest one term from ech of the five ctegories ( syphilis, mother-to-child trnsmission, pregnncy, stillirth, nd Americs region ) shown in Tle 1. Studies in English, French, Portuguese, nd Spnish were considered. Reports pulished only s strcts were excluded if ll necessry dt were not ville in the strct. Reference lists were then mnully serched for other potentil studies of relevnce to the nlysis. The five met-nlyses covered originl oservtionl, cse-control, cohort, or rndomized tril studies conducted in the Americs tht reported 1) counts of syphilis-positive pregnnt women (ll stges of infection), 2) counts of syphilisnegtive pregnnt women, nd 3) the numer of stillirths ssocited with ech group (Figure 1). Animl reserch, systemtic reviews, nd other met-nlyses were excluded. When studies reported outcomes from more thn one yer, the most recent dt were used. For overlpping studies, the most relevnt nlysis ws considered. Becuse there is no interntionl consensus on the definition of stillirth, the criteri for use of this term vry in the literture (5, 8, 16, 17, 20). In this nlysis, the definitions used y the uthors of the originl study were used s the clssifiction criterion for two sugroup met-nlyses. Two independent reserchers extrcted dt on the numer of stillirths mong mothers with GS, nd mong mothers without GS, nd the totls in ech group, from the eight studies selected for the finl smple. The dt were then discussed to rtionlize ny differences in extrcted vlues, resulting in greed-upon vlues presented in ech study. Sttisticl nlysis The undjusted odds rtio (OR) estimtes nd corresponding 95% confidence intervls (CIs) were clculted from the dt extrcted from ech study. A cumultive met-nlysis ws used to ssess the overll reltionship etween GS nd stillirth. Rndom-effects models were used to estimte the pooled ORs nd the respective 95% CIs. The I 2 sttistic ws used to test for heterogeneity (percentge of vrince) due to differences in the studies eyond rndom chnce. Puliction is ws ddressed with visul inspection of funnel plot. TABLE 1. Serch terms used to identify reference pool of selected rticles on stillirth in syphilis-positive nd syphilis-negtive women (n = 8), Americs region, Syphilis Ctegory Mother-to-child trnsmission (MTCT) Pregnncy Stillirth Americs region Serch terms Syphilis, congenitl syphilis, gesttionl syphilis, gret pox, lues, chncre, treponeml infection, treponeml, mternl syphilis, T. plldium Mother to child trnsmitted infection, mother to child, MTCT, trnsplcentl, verticl trnsmission, verticl perintl trnsmission Pregnncy, pregnnt women, women, pregnnt, womn, pregnncies, gesttion Stillirth, stillorn, fetl deth, mortlity, deth, perintl mortlity Ltin Americ, Americ, Crien, Americs, US, USA, United Sttes, United Sttes of Americ, Anguill, Antigu nd Brud, Antigu & Brud, Antigu, Brud, Netherlnds Antilles, Argentin, Aru, Bhms, Brdos, Belize, Bermud, Bolivi, Brzil, Cnd, Chile, Colomi, Cost Ric, Cu, Dominic, Ecudor, El Slvdor, Grend, Gudeloupe, Guteml, French Guin, Guyn, Hiti, Hondurs, Cymn Islnds, Turks nd Cicos Islnds, Turks & Cicos Islnds, Turks, Cicos, British Virgin Islnds, Virgin Islnds, Jmic, Mrtinique, Mexico, Montserrt, Nicrgu, Pnm, Prguy, Peru, Puerto Rico, Venezuel, Dominicn Repulic, Sint Kitts nd Nevis, St. Kitts nd Nevis, Sint Kitts & Nevis, St. Kitts & Nevis, Sint Kitts, St. Kitts, Nevis, St. Vincent nd the Grendines, Sint Vincent & the Grendines, Sint Vincent nd the Grendines, St. Vincent & the Grendines, St. Vincent, Sint Vincent, Grendines, Sint Luci, Surinm, Trinidd nd Togo, Trinidd & Togo, Trinidd, Togo, Uruguy Rev Pnm Slud Pulic 37(6),

3 Review Arnesen et l. nd stillirth in the Americs: review nd nlysis Four sugroup met-nlyses were crried out to exmine potentil sources of heterogeneity. Two of the nlyses were sed on whether tretment ws fctor in dividing the study comprison groups. The first of those nlyses included studies tht compred untreted nd/or ineffectively treted syphilis-positive mothers with those treted effectively for syphilis nd/or syphilis-negtive mothers. The second compred syphilis-positive mothers to syphilis-negtive mothers. Two dditionl met-nlyses were crried out sed on definitions of stillirth. The first included studies tht defined stillirth s the fetus showing no signs of life t irth. The second included studies tht defined stillirth y lower ounds on irth weight nd/or gesttionl ge. The I 2 sttistic ws used to test for heterogeneity in ech sugroup fter controlling for the respective identifying covrite. All pooled nlyses were done in Review Mnger (RevMn) version 5.2 (The Nordic Cochrne Centre, The Cochrne Collortion, Copenhgn, Denmrk). RESULTS A totl of potentil references were identified for the study, of which 19 were eligile for review y two independent reserchers (Figure 1). Eleven studies were excluded ecuse they were sed on modeled estimtes, did not link gesttionl syphilis nd stillirth cses, nlyzed the sme study popultion s nother included reference, lcked non-syphilis comprison group, or did not indicte the numer of stillirths oserved in the non-syphilis group. The eight studies remining fter the two independent reserchers reviews were included in the met-nlysis (17, 20, 24, 25, 28 31). Cittions for excluded ppers re ville from the uthors. The studies tht were included were conducted from 1945 to 2015 in the Americs. The iggest proportion of selected studies were crried out in the United Sttes, followed y Argentin nd Bolivi. Studies vried in terms of focus (which included efficcy of syphilis tretment nd the effect of syphilis on stillirth) nd y whether syphilis tretment ws given to ll mothers, some mothers, or no mothers. Tle 2 shows the chrcteristics of the eight studies included in the nlysis (n = ). The selected studies used three different definitions of stillirth: 1) fetus weighing 500 g (17) t > 20 weeks gesttion (28), 2) fetus showing no signs of life t full term (31), nd 3) fetus showing no signs of life t delivery (24, 25). One study reported rnges for gesttionl ge nd irth weight (24 42 weeks nd g, respectively) (20). Two studies did not define stillirth or present rnges for gesttionl ge or irth weight (29, 30). Selected comprison groups FIGURE 1. Flow chrt of process nd criteri used in literture review selection of eight studies on stillirth in syphilis-positive nd syphilis-negtive women, Americs region, Potentilly relevnt references collected: Potentilly pplicle references selected for review: Potentil references reviewed y two independent reserchers for lignment with study definition : 19 References included in the met-nlysis: 8 Duplicte references excluded: 7 References excluded: 995 Outside the Americs: 243 Not focused on syphilis: 579 Not MTCT : 115 Stillirth not reported on: 44 Not originl reserch: 14 References excluded: 11 Modeled estimtes: 1 Syphilis nd stillirth cses not linked: 2 Used sme study popultion s nother reference: 1 No non-syphilis comprison group: 5 Stillirth count for non-syphilis group missing: 2 Mother-to-child trnsmission. Studies were included if they fulfilled the following criteri: ssessed syphilis s the min exposure; the outcome of interest ws stillirth, or stillirth ws included in the outcome (e.g., dverse irth outcomes); reported count of stillirths for oth syphilitic women nd non-syphilitic women; conducted in the Americs. One sugroup met-nlysis exmined tretment s contriutor to heterogeneity nd included studies compring untreted nd ineffectively treted GS to successfully treted cses nd those (25, 29, 30). The sugroup hd pooled OR of (95% CI: 0.99, ). While still showing some heterogeneity (I 2 = 75%), the studies included in this sugroup were more homogeneous thn the cumultive metnlysis (Tle 3). Another sugroup met-nlysis investigted specific tretment ut excluded tretment s grouping fctor, including only those studies compring syphilis cses with non-syphilitic controls, divided without regrd to tretment (17, 20, 24, 28, 31). The sugroup hd pooled OR of 6.21 (95% CI: 2.23, 17.34) nd heterogeneity similr to the cumultive met-nlysis, with I 2 = 97% (Tle 3). Selected definitions of stillirth Two met-nlyses were conducted sed on the study s definition of stillirth. One sugroup defined stillirth s fetus orn without signs of life (24, 25) nd hd pooled OR of 2.46 (95% CI: 1.36, 4.46). This sugroup ws more homogeneous thn those included in the first two met-nlyses, with n I 2 = 64% (Tle 3). The second sugroup included studies tht defined stillirth sed on 424 Rev Pnm Slud Pulic 37(6), 2015

4 Arnesen et l. nd stillirth in the Americs: review nd nlysis Review TABLE 2. Chrcteristics of eight studies included in review nd nlysis to determine the odds of stillirth in syphilis-positive nd syphilisnegtive women, Americs region, Led uthor, dte, nd reference Alexnder 1999 (30) Arnesen 2015 (24) CDC 1998 (29) Greenwood 1994 (17) Ingrhm 1950 (31) Lumignon 2002 (25) McFrlin 1994 (28) Southwick 2001 (20) Loction United Sttes (Dlls, Texs) Argentin, Bolivi, Colomi, Ecudor, El Slvdor, Guyn, Hiti, Hondurs, Nicrgu, Prguy, Uruguy, United Sttes (Bltimore, Mrylnd) Jmic United Sttes (Phildelphi, Pennsylvni) Argentin (Rosrio), Cu (Hvn), Sudi Ari (Jeddh), Thilnd (Kohn Ken Province) United Sttes (Detroit, Michign) Bolivi (Cochm, El Alto, L Pz) Study period 1 Sep Aug 1989 Jn 2009 Dec Jn Mr Sep Aug 1987 Smple size Popultion 340 Pregnnt women with untreted syphilis All live or stillorn deliveries 90 Pregnnt women with syphilis Singleton fetl deths Comprison (exposure) tretment filures versus successful tretment Untreted gesttionl syphilis or ineffectively treted versus successful tretment Pregnnt women Women with erly or lte syphilis Not stted Pregnnt women Untreted gesttionl syphilis versus successful tretment or women Sep 1991 Oct 1992 Jun Nov Pregnnt women with syphilis All live or stillorn deliveries Mother treted efore delivery Tretment given Comments Yes (ll) Penicillin All serologic testing done t the sme l. Four of six tretment filures delivered within two weeks of tretment (possile Jrisch- Herxheimer rections) Not reported No dt on postprtum syphilis test Yes (controls only) Penicillin Mternl demogrphics similr etween cses nd controls Not reported Dtes of study for cses nd controls overlpped ut were not equl periods of time (longer for cses) No Dtes of study for cses nd controls overlpped ut were not ll the sme dtes Yes (controls only) Some Decision mde t the institutionl level Penicillin or erythromycin Those negtive for syphilis nd those treted were in the control group. Adjusted for non-rndomized nture of the syphilitic sttus vrile Chrts reviewed retrospectively, so not recorded y uniformly trined stff. Eight women desensitized to penicillin llergy Some Penicillin Tretment frequently given t delivery or efore dischrge Not pplicle. U.S. Centers for Disese Control nd Prevention. lower ounds for irth weight (500 nd 400 g) nd/or gesttionl ge (20 nd 24 weeks) (17, 20, 28) nd hd pooled OR of 4.94 (95% CI: 3.77, 6.48). Sttisticlly, this ws the most homogeneous sugroup in the nlysis, with n I 2 = 14% (Tle 3). Cumultive estimtes nd heterogeneity Cumultive nlysis of the irths showed sttisticlly significnt increse in the odds of stillirth mong mothers with syphilis during pregnncy (pooled OR: 6.87; 95% CI: 2.93, 16.08; Tle 4). The rndom-effects model ws used for this nlysis ecuse the study popultions hd not een treted for syphilis homogeneously. There ws considerle heterogeneity mong the studies in the met-nlysis (I 2 = 95%). The funnel plot ws not sttisticlly significnt, pointing to lck of puliction is. DISCUSSION The nlysis shows positive reltionship etween GS nd stillirth, s other rticles from the Americs hve reported previously (3, 18, 19, 21 23, 32). Previous reserch round the world hs lso shown GS to e ssocited with reltive risk (RR) of 2 5 for stillirth, with some studies showing noticely higher risk, such s reserch conducted in Tnzni tht found syphilis-positive women hd n RR of 18 for stillirth (5, 33 35). Pst studies hve lso reported n incresed likelihood of stillirth mong syphilis-positive women; one study conducted in Mozmique reported n OR of 5.3 for stillirth mong syphilis-positive women, nd recent Rev Pnm Slud Pulic 37(6),

5 Review Arnesen et l. nd stillirth in the Americs: review nd nlysis TABLE 3. Estimted odds of stillirth in syphilis-positive nd syphilis-negtive women sed on review nd nlysis of eight selected studies, y sugroup, Americs region, Led uthor, dte, nd reference Exposed to syphilis Not exposed to syphilis Odds rtio Events Totl Events Totl Weight (%) M-H, rndom (95% CI ) M-H, rndom, 95% CI Sugroup 1: No tretment nd ineffective tretment for syphilis vs. effective tretment for syphilis nd no syphilis Alexnder 1999 (30) (15.52, ) CDC c 1998 (29) (0.23, 84.26) Lumignon 2002 (25) (1.90, 6.52) Totl (95% CI) d (0.99, ) Totl events Heterogeneity: Tu 2 = 3.86, Chi 2 = 7.98, df = 2 (P = 0.02); I 2 = 75% e Test for overll effect: Z f = 1.95 (P = 0.05) Sugroup 2: Syphilis vs. no syphilis Arnesen 2015 (24) (1.32, 2.76) Greenwood 1994 (17) (3.86, 6.20) Ingrhm 1950 (31) (23.96, 53.30) McFrlin 1994 (28) (1.84, 6.97) Southwick 2001 (20) (3.71, 16.01) Totl (95% CI) (2.23, 17.34) Totl events Heterogeneity: Tu 2 = 1.30, Chi 2 = , df = 4 (P < ); I 2 = 97% Test for overll effect: Z = 3.49 (P = ) Sugroup 3: Stillirth defined s no signs of life t delivery Arnesen 2015 (24) (1.32, 2.76) Lumignon 2002 (25) (1.90, 6.52) Totl (95% CI) (1.36, 4.46) Totl events Heterogeneity: Tu 2 = 0.12, Chi 2 = 2.81, df = 1 (P = 0.09); I 2 = 64% Test for overll effect: Z = 2.98 (P = 0.003) Sugroup 4: Stillirth defined y lower ounds on irth weight nd/or gesttionl ge Greenwood 1994 (17) (3.86, 6.20) McFrlin 1994 (28) (1.84, 6.97) Southwick 2001 (20) (3.71, 16.01) Totl (95% CI) (3.77, 6.48) Totl events Heterogeneity: Tu 2 = 0.01, Chi 2 = 2.32, df = 2 (P = 0.31); I 2 = 14% Test for overll effect: Z = (P < ) Rndom Mntel Henszel odds rtio. Confidence intervl. c U.S. Centers for Disese Control nd Prevention. d Not pplicle. e Tu 2: : tu-squred test sttistic; Chi 2 : chi-squred test sttistic; df: degrees of freedom; I 2 : % of vrince. f Z: z-test sttistic. met-nlysis shows tht fetl loss nd stillirth re 21% more frequent mong syphilis-positive women (36, 37). Overll, the cumultive met-nlysis showed tht syphilis-positive women in the Americs hve 6.87 times higher odds of stillirth compred to women tht do not hve syphilis; no evidence of puliction is ws found (Tle 4). The sugroup met-nlyses lso showed incresed odds of stillirth mong women with GS (Tle 5). All of the nlyses were presented in rndom-effects models ecuse ll ut one of the four sugroups hd high heterogeneity (i.e., they were not homogeneous popultions). These study smple chrcteristics lso llowed the uthors to generlize the results to popultions in the Americs region the focus of this nlysis. All relevnt dt tht were found were used in the cumultive met-nlysis in order to convey the most comprehensive overview of the current reltionship etween GS nd stillirth in the Americs. Studies tht either did not investigte the reltionship etween GS nd stillirth or were conducted with study popultion outside the Americs were excluded. Of the eight studies included in the cumultive met-nlysis, one included comined dt from Sudi Ari nd Thilnd s well s Argentin nd Cu (25). This study ws included in the nlysis nonetheless ecuse it stted low prevlence of syphilis for Sudi Ari nd Thilnd nd thus ppered to e minly representtive of the sitution in the Americs. Syphilis tretment is nerly 100% effective nd prevents dverse irth outcomes ttriutle to syphilis (1, 5, 7, 15, 426 Rev Pnm Slud Pulic 37(6), 2015

6 Arnesen et l. nd stillirth in the Americs: review nd nlysis Review TABLE 4. Estimted odds of stillirth in syphilis-positive nd syphilis-negtive women sed on review nd nlysis of eight selected studies, Americs region, Led uthor, dte, nd reference Exposed to syphilis Not exposed to syphilis Odds rtio Weight Events Totl Events Totl (%) M-H, rndom (95% CI ) M-H, rndom (95% CI) Alexnder 1999 (30) (15.52, ) Arnesen 2015 (24) (1.32, 2.76) CDC c 1998 (29) (0.23, 84.26) Greenwood 1994 (17) (3.86, 6.20) Ingrhm 1950 (31) (23.96, 53.30) Lumignon 2002 (25) (1.90, 6.52) McFrlin 1994 (28) (1.84, 6.97) Southwick 2001 (20) (3.71, 16.01) Totl (95% CI) d (2.93, 16.08) Totl events Heterogeneity: Tu 2 = 1.19, Chi 2 = , df = 7 (P < ); I 2 = 95% e Test for overll effect: Z f = 4.44 (P < ) Rndom Mntel Henszel odds rtio. Confidence intervl. c U.S. Centers for Disese Control nd Prevention. d Not pplicle. e Tu 2: : tu-squred test sttistic; Chi 2 : chi-squred test sttistic; df: degrees of freedom; I 2 : % of vrince. f Z: z-test sttistic. TABLE 5. Summry of met-nlyses of eight selected studies on stillirth in syphilis-positive nd syphilis-negtive women, y sugroup, Americs region, Met-nlysis Numer % of of studies Pooled OR 95% CI vrince c Cumultive met-nlysis (2.93, 16.08) 95 Sugroup 1: No tretment nd ineffective tretment for syphilis vs. effective tretment for syphilis nd no syphilis (0.99, ) 75 Sugroup 2: Syphilis vs. no syphilis (2.23, 17.34) 97 Sugroup 3: Stillirth defined s no signs of life t delivery (1.36, 4.46) 64 Sugroup 4: Stillirth defined y lower ounds on irth weight nd/or gesttionl ge (3.77, 6.48) 14 OR: odds rtio. CI: confidence intervl. c Heterogeneity (I 2 ). 16, 32). Therefore, the sugroup metnlysis of the ssocition etween GS nd stillirth only included studies tht compred no syphilis tretment or ineffective syphilis tretment with successful syphilis tretment or syphilis-negtive mothers. The ssocition etween GS nd stillirth in this met-nlysis ws stronger thn in ny other sugroup met-nlysis (pooled OR: 13.23; 95% CI: 0.99, ). Syphilis reinfection of pregnnt women treted for syphilis during pregnncy is firly common nd results in GS exposure for the neonte for the durtion of the pregnncy nd delivery (1, 2, 6, 15). Therefore, one sugroup met-nlysis compred the reltionship etween GS nd stillirth mong cses clerly identified s syphilis-positive to controls unmistkly clssified s syphilis-negtive. The pooled OR for this met-nlysis comprison ws 6.21 (95% CI: 2.23, 17.34) the closest to tht of the cumultive met-nlysis (pooled OR: 6.87; 95% CI: 2.93, 16.08) versus ll other sugroups. The results (Tle 3) clerly show tht syphilis is n importnt fctor tht needs to e further ddressed in the region in order to comt stillirth. The ility to test nd tret women the sme dy hs een cited s cost-effective, timely, nd successful wy to prevent dverse irth outcomes ssocited with untreted GS (2, 7, 16, 19, 32) nd would help increse the numer of GS cses tht get tretment, resulting in fewer cses of congenitl syphilis, including stillirth ttriutle to syphilis. In countries with higher prevlence of syphilis, the infection is responsile for greter proportion of stillirths (5, 8). Comtting stillirth nd other dverse irth outcomes ttriutle to syphilis is esier in these high-prevlence settings ecuse testing nd treting for syphilis during pregnncy cn e mde the norm. This is especilly true in settings using the new point-of-cre syphilis tests, which lso help mitigte the numer of women who test positive for syphilis ut re lost to follow-up, compred to trditionl syphilis testing tht requires return visit to the helth cre fcility for the results. Regrdless of the level of syphilis prevlence, syphilis testing nd tretment progrms re mong the most cost-effective interventions ville (1, 5, 6, 10, 16, 32) nd need to e implemented cross the Americs in order for the region to ttin the gol of eliminting congenitl syphilis. Limittions This nlysis hd some limittions. First, it included studies tht did not specify if GS cses hd een treted or not, nd some tht did not specify if successfully treted GS cses were included in the cse or control group. This could hve led to is in either direction, depending on how cses nd controls were nd if they were misclssified. Second, interntionlly, rective nontreponeml test confirmed y trepone- Rev Pnm Slud Pulic 37(6),

7 Review Arnesen et l. nd stillirth in the Americs: review nd nlysis ml test is considered confirmtory for syphilis (6, 19, 32). In this nlysis, the determintion s to whether or not mother ws GS cse or not ws left to the uthors of the originl study. This could hve led to clssifiction is, s some settings do not hve the resources to perform nontreponeml testing, nd clssifiction stndrds differ y institution. Finlly, the definition of stillirth remins miguous in the interntionl reserch community (16). As result, the definition of stillirth ws not uniform cross the eight studies nlyzed in the cumultive met-nlysis. To ddress this discrepncy, the studies were divided into two different sugroup metnlyses depending on how they defined stillirth. Two studies defined ll fetuses showing no signs of life t delivery s stillorn (pooled OR: 2.46; 95% CI: 1.36, 4.46) nd three studies used lower irth weight nd/or gesttionl ge ounds s criteri for the stillorn clssifiction (pooled OR: 4.94; 95% CI: 3.77, 6.48). Recommendtions Future reserch on the ssocition etween GS nd stillirth in the Americs should control for mternl syphilis tretment, definition of stillirth, prtner syphilis tretment, nd definition of testing considered confirmtory for syphilis. Uniform definitions nd welldocumented tretment would show the ssocition in question with the lest possile clssifiction is. Future interventions ddressing loss to followup mong women who receive pointof-cre syphilis testing nd tretment should ensure third-trimester syphilis testing nd pplicle tretment (6), using sustinle progrms, to help eliminte congenitl syphilis in the Americs region nd eyond. Conclusions These met-nlyses provide snpshot of the current sitution regrding GS nd stillirth in the Americs region. Although the studies included in the nlysis used different definitions for stillirth s well s cse nd control selection, they ll showed consistent reltionship etween GS nd stillirth. One strength of the nlysis ws the fct tht ll included studies exmined dverse irth outcomes specificlly, stillirth in pregnncies with GS exposure compred to those without GS exposure, nd thus llowed for ssessment of the incresed odds of stillirth in the presence of untreted GS during pregnncy. Bsed on the results of oth the cumultive nd sugroup met-nlyses, GS is mjor contriuting fctor for stillirths in the Americs. Interventions trgeting GS re highly cost-effective nd, long with high-qulity point-of-cre testing, should e implemented cross the region to help rech the gol of eliminting congenitl syphilis. Conflicts of interest. None. REFERENCES 1. Wlker DG, Wlker GJ. 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8 Arnesen et l. nd stillirth in the Americs: review nd nlysis Review Gynecol Ostet. 2015;128(3): doi: /j.ijgo Epu 2014 Nov Lumignon P, Piggio G, Villr J, Pinol A, Bkkteig L, Bergsjo P, et l. The epidemiology of syphilis in pregnncy. Int J STD AIDS. 2002;13(7): Stroup DF, Berlin JA, Morton SC, Olkin I, Willimson GD, Rennie D, et l. Metnlysis of oservtionl studies in epidemiology: proposl for reporting. Met-nlysis Of Oservtionl Studies in Epidemiology (MOOSE) group. JAMA. 2000;283(15): doi: /jm PMID: Moher D, Lierti A, Tetzlff J, Altmn DG; PRISMA Group. Preferred Reporting Items for Systemtic Reviews nd Met-Anlyses: The PRISMA Sttement. Int J Surg. 2010;8(5): doi: /j.ijsu Epu 2010 Fe McFrlin BL, Bottoms SF, Dock BS, Isd NB. Epidemic syphilis: mternl fctors ssocited with congenitl infection. Am J Ostet Gynecol. 1994;170(2): Centers for Disese Control nd Prevention (US). Epidemic of congenitl syphilis Bltimore, MMWR Mor Mortl Wkly Rep. 1998;47(42): Alexnder JM, Sheffiled JS, Snchez PJ, Myfield J, Wendel GD Jr. Efficcy of tretment for syphilis in pregnncy. Ostet Gynecol. 1999;93(1): Ingrhm NR Jr. The vlue of penicillin lone in the prevention nd tretment of congenitl syphilis. Act Derm Venereol Suppl (Stockh). 1950;31(Suppl 24): World Helth Orgniztion. The glol elimintion of congenitl syphilis: rtionle nd strtegy for ction. Genev: WHO; Slkhov E, Tikhonov L, Southwick K, Shkrishvili A, Ryn C, Hillis S, et l. Congenitl syphilis in Russi: the vlue of counting epidemiologic cses nd clinicl cses. Sex Trnsm Dis. 2004;31(2): Wtson-Jones D, Chngluch J, Gumdok B, Weiss H, Rusizok M, Ndeki L, et l. Syphilis in pregnncy in Tnzni. I. Impct of mternl syphilis on outcome of pregnncy. J Infect Dis. 2002;186(7): Hong FC, Yng YZ, Liu XL, Feng TJ, Liu JB, Zhng CL, et l. Reduction in mother-tochild trnsmission of syphilis for 10 yers in Shenzhen, Chin. Sex Trnsm Dis. 2014;41(3): Folgos E, Osmn NB, Gonzlez C, Hägerstrnd I, Bergström S, Ljungh A. Syphilis seroprevlence mong pregnnt women nd its role s risk fctor for stillirth in Mputo, Mozmique. Genitourin Med. 1996;72(5): Gomez GB, Km ML, Newmn LM, Mrk J, Broutet N, Hwkes SJ. Untreted mternl syphilis nd dverse outcomes of pregnncy: systemtic review nd met-nlysis. Bull World Helth Orgn. 2013;91(3): Mnuscript received on 15 Octoer Revised version ccepted for puliction on 26 Ferury resumen Sífilis gestcionl y mortintlidd en l Región de ls Américs: un revisión sistemátic y metnálisis Plrs clve Ojetivo. Llevr co un revisión sistemátic y metnálisis de los cálculos notificdos de l socición entre sífilis gestcionl (SG) y mortintlidd en l Región de ls Américs. Métodos. Se relizó un úsqued en Cochrne Lirry, Emse, LILACS, MEDLINE/PuMed, PLOS y ScienceDirect de estudios de investigción originles que cuntificrn l relción entre l SG y l mortintlidd en l Región de ls Américs. Se seleccionó un muestr finl de ocho estudios. Se efecturon un metnálisis cumultivo y cutro metnálisis de sugrupo de los dtos de estudio sore l socición entre sífilis mtern durnte el emrzo y mortintlidd. Los cutro metnálisis se sron en 1) l definición de csos y del control; 2) el trtmiento de l sífilis (presenci o usenci, eficz o ineficz); 3) l definición de mortintlidd como usenci de signos de vid l ncer ; y 4) l definición de mortintlidd sd en el jo peso l ncer y l edd gestcionl. Se empleron metnálisis de efectos letorios pr clculr ls estimciones cumulds de mortintlidd con exposición l SG, y se comproó l heterogeneidd de cd uno de los nálisis de sugrupo. Resultdos. Ls mujeres con SG presentron myores proiliddes de mortintlidd (rzón de posiiliddes [OR] cumuld: 6,87; IC de 95%: 2,93 16,08). Se oservó un heterogeneidd considerle en los ocho estudios (porcentje de vrición [I2] = 95). El gráfico en emudo no fue estdísticmente significtivo, lo que indic un usenci de sesgo de pulicción. En los cutro metnálisis de sugrupo, tmién se oservron myores proiliddes de mortintlidd en ls mujeres emrzds con sífilis. Conclusiones. L SG es un importnte fctor contriuyente l mortintlidd en l Región de ls Américs. Ls intervenciones dirigids l SG son ltmente eficces en función de los costos y deen ejecutrse en tod l región, junto con ls prues dignóstics de lt clidd en el lugr de sistenci, pr yudr lcnzr l met de eliminción de l sífilis congénit. Mortinto; sífilis; Américs; Améric Ltin; Indis Occidentles. Rev Pnm Slud Pulic 37(6),