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obesity, advanced maternal age, Rh disease, and diabetes mellitusare risk factors for stillbirth. More than half of stillbirths are asso-ciated with or caused by these conditions. An estimated 1025% ofstillbirths can be attributed to various maternal or fetal infections,the majority of which are ascending bacterial in origin.2

late stillbirths (after 28 weeks).4 Birth weight appears to havea similar correlation to stillbirth, with an increasing proportion ofinfection-related stillbirths at lower birth weights. Whereas anaccurate gestational age generally is available for births in devel-oped countries, many developing countries rely on a birth weight of1000 g to dene stillbirth, corresponding tow28 weeks. Because ofthese relationships, studies that only evaluate later fetal deathsoccurring after 28 weeks or >1000 g may miss the large infectiouscontribution to early fetal deaths.

* Corresponding author.

Contents lists availab

Seminars in Fetal &

.e

Seminars in Fetal & Neonatal Medicine 14 (2009) 182189E-mail address: Mcclure@rti.org (E.M. McClure).countries compared with rates approaching 45 per 1000 in somedeveloping countries.1 In recent decades, signicant reductions instillbirths have occurred in many developed countries, primarilydue to improved medical care, while rates in developing countrieshave remained high. Stillbirths are frequently classied bypresumed etiology. Important non-infectious causes of stillbirthinclude congenital anomalies, asphyxia, abruptio placentae, andumbilical cord accidents. Maternal and fetal trauma, maternal

2. Denition of stillbirth

A stillbirth is dened as a birth having no sign of life, such asa heartbeat or spontaneous respiration, after delivery. The lowerlimits of gestational age used to dene a stillbirth have includedlower gestational ages ranging from 20 to 28 weeks. Infection ismore clearly associated with early (2028 weeks) compared withoutcomes, with an estimated 3.2worldwide. Rates are as low as 3 p1. Introduction

Stillbirth is one of the most1744-165X/$ see front matter 2009 Elsevier Ltd.doi:10.1016/j.siny.2009.02.003Ureaplasma urealyticum is usually the most common infectious cause of stillbirth. However, in areaswhere syphilis is prevalent, up to half of all stillbirths may be caused by this infection alone. Malariamay be an important cause of stillbirth in women infected for the rst time in pregnancy. The two mostimportant viral causes of stillbirth are parvovirus and Coxsackie virus, although a number of other viralinfections appear to be causal. Toxoplasma gondii, Listeria monocytogenes, and the organisms that causeleptospirosis, Q fever, and Lyme disease have all been implicated as etiologic for stillbirth. In certaindeveloping countries, the stillbirth rate is high and the infection-related component so great thatachieving a substantial reduction in stillbirth should be possible by reducing maternal infections.However, because infection-related stillbirth is uncommon in developed countries, and because thosethat do occur are caused by a wide variety of organisms, reducing this etiologic component of stillbirthmuch further will be difcult.

2009 Elsevier Ltd. All rights reserved.

on adverse pregnancyn occurring each year00 births in developed

Furthermore, a signicant number of stillbirths are multifactorialand thus infection may contribute to many more. We previouslyreviewed the relationship between infection and stillbirth.3 Here,we update that review, including an additional ve years ofliterature.contribution of infection is much greater. In developed countries, ascending bacterial infection, bothbefore and after membrane rupture, with organisms such as Escherichia coli, group B streptococci, andStillbirth caused by an infection, whereas in developing countries, which have much higher stillbirth rates, theInfection and stillbirth

Elizabeth M. McClure a,*, Robert L. Goldenberg b

aDepartment of Epidemiology, UNC Global School of Public Health, Chapel Hill, North CbDepartment of Obstetrics/Gynecology, Drexel University College of Medicine, 245 N. 15

Keywords:ChorioamnionitisInfection

s u m m a r y

Infection may cause stillbisevere maternal illness.bacteria, viruses, and pro

journal homepage: wwwAll rights reserved.by several mechanisms, including direct infection, placental damage, andious organisms have been associated with stillbirth, including manya. In developed countries, between 10% and 25% of stillbirths may beina, USAtreet, 17th Floor, Room 17113, Philadelphia, PA 19102, USA

le at ScienceDirect

Neonatal Medicine

lsevier .com/locate/s iny

Table 1Maternal infections and stillbirths.

Organism Maternal disease Comment

SpirochetesTreponema pallidum Syphilis Major cause of stillbirth when

maternal prevalence is highBorrelia burgdorferi Lyme disease Conrmed relationship but not

common cause of stillbirthBorrelia recurrentis Tick-borne relapsing

feverRarely associated, of unknownimportance as cause ofstillbirth

Leptospira interrogans Leptospirosis Conrmed as cause of stillbirthbut not common

ProtozoaTrypanosoma brucei Trypanosomiasis Not certain cause of stillbirthTrypanosoma cruzi Chagas disease Conrmed as cause of stillbirth

in South America but ofunknown importance

Plasmodium falciparum,Plasmodium vivax

Malaria Likely important cause ofstillbirth in newly endemicareas or in newly infectedwomen

Toxoplasmosis gondii Toxoplasmosis Conrmed as cause of stillbirthbut not common

Coxiella burnetti Q fever Conrmed as cause of stillbirthbut of unknown importance

VirusesParvovirus (B19) Erythema

infectiosumConrmed as cause of stillbirth,likely most common viraletiologic agent

Coxsackie A and B Variouspresentations

Conrmed as causes ofstillbirth, may be importantcontributor

Echovirus Variouspresentations

Conrmed as cause of stillbirthbut of unknown importance

Enterovirus Variouspresentations

Conrmed as cause of stillbirthbut of unknown importance

Hepatitis E virus Fulminant hepaticfailure

Possibly cause of risk factor,especially in geographic areaswith epidemic outbreaks

Polio virus Polio Historically likely cause ofstillbirth but since routinevaccination no longer seen indeveloped countries

Varicella zoster Chickenpox Conrmed as cause of stillbirthbut not common

Rubella German measles Conrmed, but no longer causeof stillbirth in developedcountries

Mumps Parotitis Possibly cause of stillbirthhistorically but no longer causeof stillbirth in developedcountries

Rubella Measles Possibly cause of stillbirthhistorically

Cytomegalovirus Generallyasymptomatic inadults

Rarely if ever cause of stillbirth

Variola Smallpox Historically cause of stillbirthbut no longer seen

Ljungan virus Diabetes,neurological disease,myocarditis anddeaths

Associated with several casesof stillbirth in a single report

Lymphocyticchoriomeningitis virus

Lymphocyticchoriomeningitis

Not conrmed as cause ofstillbirth, of unknownimportance

Human immunodeciencyvirus

Acquiredimmunodeciencysyndrome

Associated with stillbirth butnot likely causative

BacteriaE. coli Generally

asymptomaticConrmed, probably the mostcommon organism associatedwith stillbirth

Group B streptococcus Generallyasymptomatic

Conrmed as common cause ofstillbirth

Fetal & Neonatal Medicine 14 (2009) 182189 1833. Infection and stillbirth

For various reasons, the relationships between maternal infec-tion and stillbirth are often not very clear. First, knowing exactlywhy a stillbirth occurred may be difcult. In addition, organismssuch as the mycoplasmas/ureaplasmas and certain viruses whichare causal are not easily identied. Finding organisms in theplacenta or on the fetus does not prove causality. Since infectionmay initiate a chain of events leading to stillbirth, its role might notbe appreciated (e.g. parvovirus causing hydrops). Lastly, positiveserologic tests do not prove causality.

Infection may cause stillbirth by a variety of mechanismsincluding severe maternal illness, direct infection, and placentaldamage. First, a maternal infection may lead to a systemic illnesswhere themother is severely ill. Because of the highmaternal fever,respiratory distress, or systemic reactions to the illness, the fetusmay die without organisms ever being transmitted to the placentaor fetus, e.g. increased rates of stillbirth following inuenzapandemics. Second, the placenta may be directly infected, resultingin reduced blood ow to the fetus, e.g. malaria. Third, the fetus maybe directly infected through the placenta or membranes, with theorganisms damaging a vital organ such as the lung, heart, or brain,e.g. fetal pneumonia associated with Escherichia coli. If an infectionoccurs very early in gestation, the fetus may not die immediatelybut have a congenital anomaly with a fetal death occurring later,e.g. rubella. Finally, a maternal infection may precipitate pretermlabor with the fetus unable to tolerate labor and born dead. Ure-aplasma urealyticum may precipitate early preterm labor byinfecting the fetal membranes without causing a fetal infection. Aurinary tract infection with E. coli is a non-genital tract infectionthat might precipitate early preterm labor. Thus, stillbirths havebeen reported in association with virtually all types of infection,including those caused by bacteria, viruses, and many parasites.Nevertheless, of the thousands of infectious agents in the envi-ronment, only relatively few have ever been transmitted to thefetus or associated with stillbirth.

4. Specic infections related to stillbirth (Table 1)

4.1. Spirochete infections

Treponema pallidum is the spirochete responsible for syphilis.The rates of infection among women of reproductive age rangefrom 0.02% in developed countries to as high as 12% among someAfrican populations.5,6 Spirochetes can cross the placenta and infectthe fetus at >14 weeks gestation, with risk of fetal infectionincreasing with gestational age. If the fetus is infected, about 45%will die in utero, with another 3040% born alive but with signs ofcongenital syphilis. The most common cause of fetal death appearsto be placental infection associated with decreasing blood ow tothe fetus; direct fetal infection also plays a role. In a review of 33stillbirths likely caused by syphilis, placental histopathologyrevealed villous enlargement, acute villitis, erythroblastosis, andnecrotizing funisitis indicative of a fetal vasculopathy.7 In a multi-variate analysis, Potter et al. found that African women withconrmed syphilis were more likely than controls to have hada stillbirth (odds ratio: 2.8 for one stillbirth and 4.3 for 25 previousstillbirths, P< 0.0001)8 and in a study from Tanzania, 51% of thestillbirths were attributed to syphilis, with high-titer active syphilisbeing associated with an 18-fold increased risk of stillbirth (relativerisk: 18.1; 95% condence interval: 5.559.6) compared with non-infected women.9

In areas of southern Africa, where 10% of pregnant womenmay be seropositive, between 25% and 50% of all stillbirths are

E.M. McClure, R.L. Goldenberg / Seminars infound in seropositive women, with a population-attributable(continued on next page)

Fetafraction of 2550%.10 Russia experienced an epidemic of syphilis inthe late 1990s with rates increasing from 8 per 100 000 in 1991 to209 per 100 000 in 1999. During that period, stillbirth was signif-icantly associated with maternal syphilis (P< 0.01).11 In anotherexample from Africa, Folgosa et al.12 found a positive specicserologic test for syphilis in 42% of stillbirths versus only 12% ofcontrols. To illustrate the effectiveness of treatment, studies havefound that women treated for syphilis had stillbirth risks similar tothose of non-infected women.13

Another spirochetal infection associated with stillbirth is Lymedisease, a systemic illness caused by the tick-borne spirocheteBorrelia burgdorferi. The rst case of stillbirth associated with Lymedisease was described in 1987.14 In that case, the mother acquiredthe disease in the rst trimester, and at 34 weeks was delivered ofa stillborn infant who had B. burgdorferi in the placenta and internalfetal organs. In other reports, after rst-trimester infection andsubsequent fetal death, spirocheteswere found in fetal liver, spleen,

Table 1 (continued )

Organism Maternal disease Comment

Klebsiella Generallyasymptomatic

Conrmed, common cause ofstillbirth

Enterococcus Generallyasymptomatic

Conrmed

U. urealyticum Generallyasymptomatic

Conrmed

Mycoplasma hominus Generallyasymptomatic

Conrmed

Bacteroidaceae Generallyasymptomatic

Conrmed

Listeria monocytogenes Listerosis Conrmed, generallytransmitted transplacentally

Other bacteria includingbrucellosis, clostridia,Agrobacterium radiobacter,Pseudomonas, etc.

Potentially implicated as causalfor stillbirth by case reports

Chlamydia trachomatis Pelvic infection Suggested as cause of stillbirthby case reports

Neiserria gonorrhoeae Pelvic infection Suggested as cause of stillbirthby case reports

FungiCandida albicans Thrush, vaginitis Conrmed as cause of stillbirth

by case reports

E.M. McClure, R.L. Goldenberg / Seminars in184kidney and brain. Subsequently, small series of stillbirths aftermaternal Lyme disease have been described, with most deathsoccurring in the mid-trimester. However, larger-scale serologicstudies have shown that, except in highly endemic areas, fewstillbirths are associated with Lyme disease.15 In endemic areas inthe USA and Norway, the seropositive rate in pregnant womenis 2%.

Another spirochetal disease associated with adverse pregnancyoutcome, tick-borne relapsing fever, is caused by Borrelia duttoniiand transmitted to humans by the tick Ornithodoros moubata,primarily found in sub-Saharan Africa. Studies have reportedassociations between B. duttonii and adverse pregnancy outcomessuch as increased perinatal mortality rates.16 B. duttonii has alsobeen associatedwith preterm birth and low birth weight. B. duttoniiis predominantly found in sub-Saharan Africa. A study in theDemocratic Republic of Congo found that as many as 6.4% ofpregnant women admitted to a maternity ward were diagnosedwith relapsing fever.17 However, the contribution of this disease tothe overall stillbirth rate in endemic areas is unknown. Case reportsof relapsing fever during pregnancy have also been reported fromthe USA.18 Finally, leptospirosis, still another spirochetal disease,has been associated with transplacental infection and stillbirth.

Although not a spirochetal disease, trypanosomiasis, betterknown as African sleeping sickness transmitted by the tsetse y,has been associated with stillbirth. The parasites, Trypanosomabrucei, have been demonstrated in placentas of stillborns. Howcommonly this occurs is unknown. Another trypanosomal illnesswidespread in South America, Chagas disease, is by T. cruzi andinfects the fetus and placenta, causing hydrops and death.19 As withAfrican sleeping sickness, the extent to which maternal infection islinked to stillbirth is unknown.

4.2. Malaria

Malaria, one of the worlds largest health problems, is caused byone of four intracellular parasites transmitted by various types ofmosquitoes. More than 40% of all births worldwide occur in areaswith endemic malaria.20 While several studies have examined theprevalence of placental parasitemia in areas of stable endemicmalaria in Africa, few have focused on areas with low or unstabletransmission. Malaria is generally associated with a wide range ofadverse pregnancy outcomes, but especially growth restriction. Inendemic areas, malaria approximately doubles the maternal risk ofmoderate to severe anemia, and increases the risk of preterm birthand fetal growth restriction. The effect of malaria on stillbirth hasbeen difcult to demonstrate. The impact of malaria on pregnancyoutcomes varies based on the type of malaria (Plasmodium falci-parum has been most commonly implicated in stillbirth; P. vivaxhas only recently been associated with stillbirth), the mothersparity, and her immune status. For example, in primigravid womenliving within endemic areas, placental malaria occurs in 1663% ofmaternal infections compared with rates of 1233% in multigravidawomen. The clinical presentation of malaria infection duringpregnancy varies based on the immunity that women haveacquired.

With a maternal malaria infection, pregnancy outcome isdirectly related to the extent of placental malaria, and in part to thedegree of maternal anemia. Histologically, placental malaria ischaracterized by parasites and leukocytes in the intervillous spaceand pigment within macrophages. When the parasites infect theplacenta, placental insufciency often results because of lympho-cyte and macrophage accumulation, thickening of the trophoblastbasement membrane, and increased expression of various proin-ammatory cytokines, all of which impede maternal blood owthrough the placenta. Placental malaria infection also decreasesantibody transfer across the placenta, increasing susceptibility toconditions such as neonatal tetanus. Malarial organisms cross theplacenta, and congenital malaria, although not as common asplacental infection, certainly occurs. It is difcult to derive anattributable risk of stillbirth associated with malaria in most pop-ulations because, when the prevalence of malaria is high, malariararely exists in isolation from other risk factors. However, a reviewof hospital studies, primarily from endemic areas, found thatplacental malaria was associated with twice the stillbirth risk.21 Inan Ethiopian study conducted in an area of unstable transmission,Newman et al.22 found a seven-fold increased risk of stillbirthcompared with no increased risk for women living in endemicareas. This suggests that in populations of pregnant women expe-riencing a malaria infection for the rst time, malaria is likely animportant cause of stillbirth. Though a few studies have demon-strated increased risk for stillbirth with malaria in Australia andIndia, most malaria research has focused on Africa. Further researchis needed in geographic areas with low or unstable malarialtransmission, such as Asia and Latin America, to better understandthe global impact of malaria on stillbirth.

4.3. Toxoplasmosis

Toxoplasmosis gondii is passed to humans through contact with

l & Neonatal Medicine 14 (2009) 182189animal feces or from undercooked meat. Past maternal infection,

Fetaindicated by antibodies, generally protects the pregnant womanfrom fetal infection. Toxoplasmosis seropositivity in the USA isw15%, but may be much higher in other geographic areas, e.g. onestudy found that the prevalence of toxoplasmosis antibodies was>80% among pregnant Nigerian women.23,24

If the mother is infected during pregnancy, toxoplasmosis maybe transmitted to the fetus via the placenta. The later the primarymaternal infection, the more likely the infectionwill be transmittedto the fetus. Disseminated toxoplasmosis may cause fetal death. Ina casecontrol study from Jordan, T. gondii was signicantly moreprevalent in women with adverse pregnancy outcomes comparedwith controls (54% vs 12%, P< 0.02),25 while a study fromZimbabwe found that serologic tests for toxoplasmosis were four-fold more common in stillbirths than controls.26 Whethertoxoplasmosis was the etiologic factor is unknown.

4.4. Q fever

Q fever is a rickettsial infection caused by Coxiella burnetti. Inhumans this infection is generally acquired by inhalation of infec-ted aerosols during contact with meat products, although trans-mission has occurred by tick bite and ingestion of infected milk. Innon-pregnant adults, C. burnetti causes pneumonia, meningoen-cephalitis, hepatitis, and endocarditis. Infections may be acute orpersistent, the latter being mostly asymptomatic, except duringpregnancy when the organisms may infect the placenta, leading toabortion, stillbirth, and preterm birth. In a review of cases of acuteQ fever during pregnancy, abnormal pregnancy outcomes werefound in all cases of acute maternal infection, with fetal deathoccurring in two-thirds.27 Organisms were generally isolated bothfrom placental and fetal tissues. Most of the stillbirths occurred inthe second and early third trimester. The overall contributions of Qfever to stillbirths, and the actual geographic distribution of Qfever-associated stillbirths, is unknown. Rocky Mountain spottedfever, another rickettsial disease with widespread distribution inthe USA, has not been associated with intrauterine infection orstillbirth.

5. Viral diseases

Although it is apparent that viruses cause stillbirths, the overallnature of this relationship is unknown. Many viruses are difcult toculture, a positive viral serologic result does not prove causation,and DNA or RNA viral identication, only recently widely available,is technically difcult. That said, the clearest relationship betweenany virus and stillbirth is with parvovirus.

Parvovirus (B19) causes a common childhood exanthem erythema infectiosum or fth disease and aplastic anemia inchildren with sickle cell disease. It was rst associated with fetaldeath in 1984.28 Subsequently, investigators have shown thatparvovirus crosses the placenta and preferentially attacks eryth-ropoietic tissue, causes fetal anemia, non-immune hydrops, andfetal death.2931 The virus also attacks cardiac tissue and may causestillbirth by this mechanism. Most stillbirths occur in the secondtrimester and are associated with hydrops, although parvovirusmay also be an important cause of non-hydropic third-trimesterfetal deaths.

Previous infection elicits an antibody response protectiveagainst subsequent maternal and fetal infection. About half of allpregnant women in the USA have had a previous infection, havecirculating antibodies, and are immune. Of those not immune, withexposurew25% will become infected, and of thesew30% will passthe virus to their fetus. Of the infected fetuses, onlyw10% will havehydrops; most of these will not die. Therefore, even with maternal

E.M. McClure, R.L. Goldenberg / Seminars ininfection, the risk of stillbirth is quite low. On the other hand, ina series reported from Sweden, where polymerase chain reactionfor viral DNAwas used to dene fetal parvovirus infection,15% of allstillbirths were attributed to parvovirus30 with similar results alsoreported from Germany.31

Therefore, the proportion of all stillbirths that may be attribut-able to parvovirus is unclear. Nevertheless, the primary mechanismleading to stillbirth involves the predilection of the virus for bonemarrow, resulting in fetal anemia and hydrops. The infections thatresult in stillbirth are generally acquired before 20 weeks, anddeath usually occurs in the mid-trimester. Overall, in the USA itappears that

FetaFurthermore, in a Swedish study, among 21 women with stillbirth,52% were Coxsackie B virus positive; among controls, only 22%were positive.37 Echovirus and enteroviruses have also beencultured from stillborns at autopsy where the cause of deathappeared to be a fetal viral infection; however, maternal illness anddehydration may have also been factors.38,39 Before polio waseradicated from the USA, occasional stillbirths were thought tooccur because of maternal viral infection, primarily as a result ofsevere maternal illness and respiratory failure.

Cytomegalovirus (CMV) is the most common congenital viralinfection. In the USA, 13% of pregnant women acquire primaryCMV during pregnancy. The highest rate of transmission to thefetus, and the most severe consequences, occur with primaryinfection, probably due to lack of transferred immunity. In manywomen, the CMV infection is chronic. However, despite the pres-ence of maternal antibodies, the fetus is at some risk. CMV affects0.24.0% of newborn infants in the USA, and w11% of these, or1:1000 births, are severely affected with pneumonitis and multipleorgan failure. Placental involvement is well-documented. Grifthsand Baboonian40 in a prospective study of >10 000 women foundincreases in fetal loss associated with early CMV infections.Whether CMV actually causes stillbirth and, if so, themechanism bywhich it does, is not clear.

Herpes simplex viruses rarely, if ever, cause stillbirth, likelybecause the virus rarely causes an intrauterine infection; neonatalinfections are acquired during fetal passage through an infectedbirth canal. Although not seen clinically for more than a quartercentury, Bernirschke and Robb41 note that, before its elimination,maternal smallpox infection frequently caused fatal damage tofetuses, who at the time of autopsy, had extensive necrotic lesionsand destructive placental lesions.

Ljunganvirus, a recently describedpicornavirusof bankvoles,wasoriginally isolated in the Ljungan Valley in Sweden. Since then, it hasbeen reported in Denmark and the USA. A recent study of pregnantwomen found the Ljungan virus in 40% of stillborns but not in any ofthe tissue from normal pregnancies.42 The lymphocytic choriome-ningitis virus has also been implicated as a cause of stillbirth.

Finally, the human immunodeciency virus (HIV) may cross theplacenta and infect the fetus before delivery. Althoughmost studiesshow no relationship between maternal HIV infection and still-birth, in one study, HIV-positive women were signicantly morelikely to have a stillborn infant.43 In another study in Zambia, Chiet al. found that among women who were HIV seropositive,decreasing CD4 cell counts were inversely related to stillbirth(P 0.000), suggesting that worsening maternal HIV disease maybe associated with stillbirth. The authors speculated that HIV-related immunosuppressionmight be a factor in adverse pregnancyoutcomes among these women.13

Studies also have examined the role of HIV co-infection onpregnancy outcome. In one study fromwestern Kenya, womenwithboth HIV and malaria had more adverse pregnancy outcomes thanthose with either infection alone. Stillbirths were more likelyamong womenwith malarial infection, irrespective of HIV status.44

Although the role of co-infections on pregnancy outcomes is ofinterest, especially as HIV becomes a chronic disease, currently itdoes not appear likely that HIV is causal for stillbirths, other than inthose cases where the mother has a severe systemic illnessresulting from the HIV.

5.1. Bacterial infections

More than 130 bacterial species are involved in intrauterineinfection. These may be divided into bacterial infections whichreach the fetal compartment by ascending from the vagina through

E.M. McClure, R.L. Goldenberg / Seminars in186the cervix or hematogenously through the placenta.5.2. Ascending bacterial infections

The organisms that ascend from the vagina and infect the uterusand the mechanism by which they cause fetal death have generallybeen similar over time and across geographic areas. However, theproportion of pregnancies affected by intrauterine bacterial infec-tion is likely to be much higher in developing compared withdeveloped countries. The organisms likely ascend from the vaginainto the uterus during early pregnancy, but some reside in theuterus before pregnancy. They enter the amniotic uid eitherthrough intact choriodecidual membranes or after the membranesrupture and ultimately infect the fetus. The most common pathwayof attack is by way of the fetal lung, associated with fetal breathingof contaminated amniotic uid. This explains why the mostcommon autopsy nding for many bacterial infection-relatedstillbirths is pneumonitis.

Intrauterine bacterial infection has also been related to fetaldeath. The organisms that most frequently infect the fetus are U.urealyticum and Mycoplasma hominis, but a large variety of otherbacteria including Bacteroides spp., Gardnerella spp., Mobiluncusspp., various enterococci, can cause this infection. For themost part,the organisms have low virulence and may reside in the uterus formonths before precipitating preterm labor. Even with the onset oflabor, most women do not have classic signs of infection such asfever, chills, or an elevated white count. Instead, the symptoms ofthis infection seem to be contractions and eventually rupturedmembranes. Occasionally, more virulent organisms follow thissame pathway and infect the uterine cavity before rupture ofmembranes. Organisms such as group B streptococci and E. colihave crossed intact fetal membranes and caused amniotic uidinfection. When infection with these organisms occurs, theinammatory response appears to occur much more rapidly and ismore severe, with labor ensuing within hours.

Whether the amniotic uid infection occurs in the presence ofintact membranes or follows membrane rupture, the organismsmay be aspirated, enter the fetal lung, and cause severe infection.Whether the fetus is stillborn with congenital pneumonitis or isborn alive with pneumonia may depend on the length of timebetween infection and delivery. Romero et al.45 note that a pretermfetal infection generally elicits a fetal inammatory response andultimately initiates preterm labor. They suggest that if the fetuscannot initiate an adequate inammatory response leading to laboror membrane rupture the outcome will likely be a stillbirth.

Amniotic uid infection has been described in manygeographic locations. In most areas, it is a common cause ofpreterm birth and stillbirth. It is also clear that the frequency ofthis infection varies by gestational age. Births before 28 weeks arestrongly associated with amniotic uid infection, whereas latepreterm births and births at term are much less likely to have thisinfection. The evidence that amniotic uid infection is causal forstillbirth comes from several different types of studies. The rstcompares placental histologic features in stillbirths with placentasfrom various control groups. In almost every study, the frequencyof histologic chorioamnionitis in the stillbirth group is severaltimes greater than in a control group. Furthermore, the morestringent the required histologic evidence for infection, the morelikely this nding will be present in the stillbirth group comparedwith the control group. Therefore, the presence of funisitis orchorionic plate inammation is often far greater in stillbirths thanin appropriate controls. More impressive is the nding of organ-isms in internal organs at autopsy. For example, a number ofautopsy studies cultured organisms such as group B streptococcus,E. coli, and Klebsiella and enterococci from fetal heart blood, liver,lung, and brain.4648 These ndings are consistent in studies from

l & Neonatal Medicine 14 (2009) 182189Sweden, Lithuania, the USA, and sites in Africa. From Lithuania, for

Fetaexample, fetal bacteremia was found in 36% of stillbirths but notin controls; half the cases were caused by E. coli. The placentasfrequently showed histologic chorioamnionitis and vasculitis.47 Instudies from Mozambique and Zimbabwe, Bergstrom et al. care-fully studied this phenomenon.4850 They found E. coli in 25% ofheart bloods from stillborns and consistently found organisms ininternal organs at autopsy, with the fetal lung most commonlyinfected. In an Ethiopian study, Tafari et al.51 noted that, althoughE. coli and other bacteria were the organisms most oftenresponsible for fetal death, in 23 of 290 (8%) perinatal deaths(mostly late stillbirths), the only organisms identied as respon-sible for congenital pneumonia and fetal death were myco-plasmas. These infections apparently occurred through intactmembranes. Perhaps the most elegant studies were done byNaeye et al.52 who studied stillbirths in Ethiopia but alsocompared their ndings to the US Collaborative Perinatal Study.They noted that the mechanism of infection (i.e. ascending fromthe vagina to the intrauterine cavity) appeared similar in bothgeographic locations, but that the frequency of stillbirth associ-ated with infection was several times greater in Ethiopia than inthe USA. They observed that the rates of infection in early preg-nancy were similar in the USA and in Africa. However, althoughthe rate of infection-related stillbirth declined as the gestationalage increased in the USA, it persisted at high rates throughoutpregnancy in Ethiopia. They speculated that the difference had todo both with the burden of exposure to infectious organisms,which appears to be much greater in Africa, as well as a decreasedimmune response, believed to be related to the malnutrition soprevalent in African populations. On the basis of histologicobservations from Ethiopia, Naeye et al. concluded that w15% ofall Ethiopian pregnancies were associated with an amniotic uidinfection. In developed countries, the amniotic uid infection rateappears lower than in developing countries but still plays animportant role in stillbirth. For example, in a review of all thestillbirths in Stockholm, Sweden in 1998 and 1999, infectionswere estimated to have caused 24% of all stillbirths.53 The authorsnote that E. coli, group B streptococci, and enterococci were themajor organisms found in internal organs at autopsy. Bergstrom50

noted that in the USA Collaborative Perinatal Study, amniotic uidinfection was the most important cause of perinatal deaths.

Of all the bacterial infections associated with stillbirth, specialemphasis should be given to group B streptococcal infection. In themiddle decades of the 20th century, many reports from developedcountries associated stillbirth with an intrauterine infection withthis organism. Many of these infections occurred in the presence ofintact membranes, but the most common scenario described anintrauterine infection after spontaneous membrane rupture. In onestudy, 11 of 113 (9.3%) consecutive stillborn infants had group Bstreptococci cultured from internal tissues at autopsy.54 In another,at autopsy, 45% of mid-trimester stillbirths were associated witha group B streptococcal infection.55 Stillbirths associated withgroup B streptococcal infection virtually always had congenitalpneumonia. Overbach et al.56 noted that, compared with otherintrauterine infections, fetal infection with group B streptococcimight not involve inammation of the fetal membranes. Theysuggested that, when the organisms enter the uterus aftermembrane rupture, rapid bacterial replication occurs in the amni-otic uid and fetus with little infection in the membranes them-selves. Christensen et al.57 noted that fetal mortality associatedwith group B streptococcal infection often occurred so rapidly thatthere was minimal fetal inammatory response. Although still-births associated with group B streptococci appear to havedecreased substantially in the USA in recent years (but it stilloccurs58), in Sweden, group B streptococcus is the most common

E.M. McClure, R.L. Goldenberg / Seminars inbacterial infection associated with stillbirth.53 In developingcountries, group B streptococcus has consistently been found to beless prevalent.59 In those countries, it is not as important a cause ofstillbirths as E. coli and other Gram-negative bacteria.

Two other organisms should be mentioned, Chlamydia tracho-matis and Neisseria gonorrhoeae. C. trachomatis is the most commonsexually transmitted bacterial pathogen. Although both organismshave been found in internal organs at the time of stillbirth autopsy,neither appears to be a signicant factor in stillbirths.3 In other casereports, a related organism, Chlamydia abortus, which causes fetalwastage among infected sheep, has been attributed to stillbirthamong farm women. The reason for their minimal involvement instillbirths may be related to the fact that, as opposed to many otherbacteria such as U. urealyticum, during pregnancy neither bacte-rium appears routinely to ascend into the uterus. Galask et al.60

suggest that, at least for N. gonorrheae, the reason for failure toascend into the uterus during pregnancy is due to its inability toattach to the fetal membranes.

5.3. Hematogenously acquired bacterial infections

Bacteria also reach the fetus through the placenta. When thatoccurs, the placenta will often have evidence of infection, includinga white blood cell response, microabscesses, and infarction. Theorganisms generally enter the fetus through the umbilical vein; forthat reason the liver is the organ most often infected. Listeriamonocytogenes is an excellent example of a hematogenouslytransmitted organism that causes fetal death. Infection is acquiredby the mother, usually by eating contaminated food. The organismsare transmitted hematogenously to the placenta. In some cases, theorganisms are transmitted to the fetus and the fetal deaths areattributed both to placental dysfunction, often associated withgrowth restriction, and direct infection of the fetus. On rare occa-sions, bacterial infection of the fetal liver and stillbirth has beenreported in association with maternal tularemia, anthrax, typhoidfever, and brucellosis, the plant bacterium Agrobacterium radio-bacter, Haemophilus inuenzae, Pseudomonas pyocyanea, clostridialinfections and Candida albicans.

Referring to the potential mechanisms of death associated withinfection-caused stillbirth, we have so far considered predomi-nantly those amniotic uid infections in which the organismsattack the fetus directly causing pneumonitis and sepsis. However,it is also apparent that many of the earliest stillbirths occur withoutthe organisms actually reaching the fetus. Instead, bacterial infec-tions may cause stillbirth by precipitating preterm labor, andperhaps intrauterine bleeding, with the fetus dying in relationshipto one of those conditions. Placental damage, including thrombosis,resulting from these infections also may cause decreased oxygen-ation, resulting in stillbirth by that mechanism.

Overall, by a number of mechanisms, it appears that in devel-oped countries, between 1 and 2 pregnancies in 1000 end ina stillbirth caused by a bacterial infection. With overall stillbirthrates from 20 weeks through term ranging from 6 to 8 per 1000births in many developed countries, this suggests that between 1and 2 of the 68 per 1000 stillbirths occur in relation to a bacterialintrauterine infection. In developing countries, where the stillbirthrates may be 10 times those in developed countries, it appears thata much larger proportion of stillbirths is related to bacterial intra-uterine infection. The proportion attributed to infection depends inpart upon the classication system used to establish causality.

6. Classifying infection as a cause of stillbirths

More than 30 classication systems have been developed sincethe 1950s to assign cause of stillbirth. Generally, each system uses

l & Neonatal Medicine 14 (2009) 182189 187a set of information available about the maternal and/or fetal

calories, or both, and a reduction in genital tract bacterial exposureby use of antibiotics or vaginal/newborn chlorhexidine washes, andeffective management of both preterm and term PROM. Achievinghigh antiviral vaccination rates (rubella, varicella, polio) shouldreduce these related stillbirths. Most important is monitoring theinfection-related stillbirths in developing countries to learn thenumber of stillbirths associated with specic infections and initiateeffective strategies to reduce their occurrence.

8. Conclusion

In developed countries, themost common intrauterine infectioncausing stillbirths appears to be bacteria ascending from the vagina.In developing countries, most infection-related stillbirths appear tobe caused by T. pallidum, malaria, and intrauterine infection withcommon vaginal organisms. A research agenda (panel) addressing

various vector-borne and other tropical diseases to

Fetaconditions and then applies criteria to assign a cause of stillbirth.Among the systems available are the Wigglesworth, Aberdeen, andthe Relevant Conditions at Death (ReCoDe). The Wigglesworthsystem uses a pathophysiological approach and is combined withstratication by birthweight classes, intending to create functionalgroups. The Aberdeen classication, originally developed by Bairdin 1954, and adapted for use in developing countries, ascribes thedeath to predisposing obstetric events or to the underlyingcause.61,62 The more recently developed ReCoDe system attemptsto identify the relevant conditions at the time of death in utero.63

From all available evidence, the particular classication systemused inuences the percentage of cases in which infection isattributed to stillbirth. Also, it is clear that the quantity and qualityof data are crucial to determining whether infection was involvedin any particular stillbirth. For example, using most classicationsystems the cause of more than half the stillbirths remainsunknown. We suspect that with more vigorous search for infection,this percentage will fall. The best proof of an infectious etiology isa carefully performed autopsy and placental examination withappropriate serologic studies, cultures, and DNA specimens takenfor the organisms discussed in this report. However, even if anautopsy is not performed, a histologic study of the placenta,membranes, and umbilical cord, with appropriate bacterial, viral,and protozoan serologic studies, culture, and DNA isolation tech-niques, will often provide evidence for an infectious etiology.

7. Prevention of infection-related stillbirth

Because of the very low incidence of infection-related stillbirthsin many developed countries, reducing this component still furthermay be quite difcult. Even development of vaccines for some ofthe viral causes of stillbirth (parvovirus, Coxsackie A and B) wouldlikely have only a small impact on the stillbirth rates. Stillbirthsassociated with toxoplasmosis occur so rarely that educationalattention to hand washing will not have a discernible impact inmost places. Greater attention to preventing Lyme disease mightreduce the few stillbirths associated with this condition. However,the largest potential benet appears to be related to stillbirthsassociated with bacterial intra-amniotic infections. In a number ofgeographic areas, health care providers do not screen for or treatgroup B streptococcus, and certainly stillbirths caused by thisorganism occur both before and after membrane rupture. The highpercentage of group B streptococcal-related stillbirths in Sweden,a country that does not routinely screen for this organism, suggestsroom for improvement. On the other hand, although not a consis-tent observation, antibiotic prophylaxis against group B strepto-cocci may be associated with an increase in fetal Gram-negativeand especially E. coli infections. Therefore, it is unknown whethergroup B streptococcal screening and treatment programs willactually reduce the number of stillbirths associated with thisorganism or evenwhether they reduce the overall infection-relatedstillbirth rate because they may substitute stillbirths associatedwith one organism for another. Also, although large numbers ofstillbirths have not been associated with ascending bacterialinfection after premature rupture of the membranes (PROM), thecurrent recommended antibiotic treatment strategies certainlyreduce chorioamnionitis and likely reduce stillbirth as well.Whether treatment of bacterial vaginosis will reduce stillbirths isunknown. However, continued attention to screening and treat-ment of the sexually transmitted infections, including syphilis,chlamydia, and gonorrhea, should minimize stillbirths associatedwith these infections.

In many developing countries, the infectious disease burdenduring pregnancy is extremely high, and the stillbirth rate is high as

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Infection and stillbirthIntroductionDefinition of stillbirthInfection and stillbirthSpecific infections related to stillbirth (Table 1)Spirochete infectionsMalariaToxoplasmosisQ fever

Viral diseasesBacterial infectionsAscending bacterial infectionsHematogenously acquired bacterial infections

Classifying infection as a cause of stillbirthsPrevention of infection-related stillbirthConclusionReferences

Practice points