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Shannon Fleck-Derderian, Christina A Nelson, Katharine M Cooley, Zachary Russell, Shana Godfred-Cato, Nadia L Oussayef, Titilope Oduyebo, Sonja A Rasmussen, Denise J Jamieson, Dana Meaney-Delman, Plague During Pregnancy: A Systematic Review, Clinical Infectious Diseases, Volume 70, Issue Supplement_1, 1 May 2020, Pages S30–S36, https://doi.org/10.1093/cid/ciz1228
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Abstract
Yersinia pestis continues to cause sporadic cases and outbreaks of plague worldwide and is considered a tier 1 bioterrorism select agent due to its potential for intentional use. Knowledge about the clinical manifestations of plague during pregnancy, specifically the maternal, fetal, and neonatal risks, is very limited.
We searched 12 literature databases, performed hand searches, and consulted plague experts to identify publications on plague during pregnancy. Articles were included if they reported a case of plague during pregnancy and at least 1 maternal or fetal outcome.
Our search identified 6425 articles, of which 59 were eligible for inclusion and described 160 cases of plague among pregnant women. Most published cases occurred during the preantibiotic era. Among those treated with antimicrobials, the most commonly used were sulfonamides (75%) and streptomycin (54%). Among cases treated with antimicrobials, maternal mortality and fetal fatality were 29% and 62%, respectively; for untreated cases, maternal mortality and fetal fatality were 67% and 74%, respectively. Five cases demonstrated evidence of Y. pestis in fetal or neonatal tissues.
Untreated Y. pestis infection during pregnancy is associated with a high risk of maternal mortality and pregnancy loss. Appropriate antimicrobial treatment can improve maternal survival, although even with antimicrobial treatment, there remains a high risk of pregnancy loss. Limited evidence suggests that maternal-fetal transmission of Y. pestis is possible, particularly in the absence of antimicrobial treatment. These results emphasize the need to treat or prophylax pregnant women with suspected plague with highly effective antimicrobials as quickly as possible.
Plague is a life-threatening zoonotic illness caused by the gram-negative bacillus Yersinia pestis [1, 2]. Y. pestis is endemic in several countries and continues to cause intermittent cases and outbreaks of plague worldwide [2, 3]. The most common forms of plague are bubonic, pneumonic, and septicemic, all of which can be treated successfully with timely administration of effective antimicrobials [1, 4, 5]. Y. pestis is categorized as a tier 1 select agent by the United States (US) government due to its potential for intentional use as a bioweapon.
Based on national surveillance data, mortality rates among females with plague in the US range from 11% for those treated with antimicrobials to 64% for those who did not receive effective antimicrobial treatment [5]. Information on maternal mortality, pregnancy outcomes, and the response to antimicrobial treatment for pregnant women infected with Y. pestis is lacking. Watson et al [6] briefly described the occurrence of spontaneous abortion, fetal tachycardia, and fetal distress among several pregnant women with plague, highlighting the potential severity of Y. pestis infection during pregnancy. Jennings noted that plague during pregnancy “almost invariably lead[s] to miscarriage and death of both mother and child” [7]. Other infections are known to have unique concerns during pregnancy, including more severe disease, maternal complications, birth defects, pregnancy loss, preterm birth, maternal-fetal transmission, and neonatal infection [8–11].
Previous recommendations for the treatment of plague in adults in the US have included streptomycin, gentamicin, fluoroquinolones (levofloxacin, ciprofloxacin, and moxifloxacin), doxycycline, and chloramphenicol [12]. Due to safety concerns, gentamicin was listed as the preferred choice for pregnant women, while doxycycline and ciprofloxacin were considered alternatives [12, 13].
The objectives of this systematic review were to examine the clinical manifestations and risks of plague during pregnancy to inform updated recommendations for plague treatment and prophylaxis during pregnancy. Key questions that guided the review were as follows: (1) Are pregnant women more susceptible to plague or more likely to present with a certain type of plague? (2) Do pregnant women experience more severe morbidity and mortality, complications or worse outcomes? (3) Is there an increased risk of adverse fetal or neonatal outcomes? (4) Is there evidence for maternal-fetal transmission of Y. pestis? and (5) What is the effectiveness of antimicrobial treatments administered to pregnant women?
METHODS
Data Sources and Search Strategy
We searched Medline Ovid, Embase Ovid, Global Health Ovid, Cumulative Index to Nursing and Allied Health Literature, National Technical Information Service, Cochrane Library, Scopus, ClinicalTrials.gov, and PubMed Central from database inception to May 2019 to identify indexed publications in the literature using search terms related to plague and pregnancy (Figure 1). The search strategy was developed with an expert systematic review librarian (Centers for Disease Control and Prevention Library). We also performed a hand search of the archived Morbidity and Mortality Weekly Report (MMWR) to identify surveillance reports of plague during pregnancy and reviewed any additional articles identified by plague subject matter experts, manuscript coauthors, and from included publication references (Figure 2). This review was registered in the International Prospective Register of Systematic Reviews (PROSPERO; identifier CRD42018080959) and followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines [14, 15].


Preferred Reporting Items for Systematic Reviews and Meta-Analyses flow diagram of article selection.
Study Selection
Four reviewers (D. M.-D., N. L. O., S. F.-D., and Maria I. Rivera) screened titles and abstracts of articles captured in the search to identify those with potential data on human cases of plague during pregnancy. Duplicate articles and those not related to cases of plague during pregnancy were excluded. Full-text reviews were conducted on articles included after title and abstract screening. Non-English articles were initially screened by a native speaker of the language; those with relevant data were professionally translated. All full-text reviews were completed by 2 independent reviewers (K.M.C., N.L.O., S.F.-D., S.G.-C., Z.R., or Maria I. Rivera).
Cases were eligible for inclusion if the author(s) reported plague occurring during pregnancy and at a minimum a description of maternal or fetal outcome. We excluded reports of plague diagnosed in the postpartum period and those that occurred prior to 1894, the year that Y. pestis was discovered as the causative agent of plague [16].
Data Abstraction and Analysis
Data abstracted from articles included maternal demographics; clinical features of plague; maternal treatment; maternal, fetal, and neonatal laboratory testing results; maternal complications, morbidity, and mortality; fetal mortality; neonatal morbidity and mortality; and evidence for maternal-fetal transmission of Y. pestis during pregnancy. Data abstraction was conducted in duplicate by 2 authors (S.F.-D., D.M.-D.) and recorded in Excel and Access databases (Microsoft, Redmond, Washington). Discrepancies between abstracters were resolved through group arbitration.
For cases for which timing of pregnancy loss was reported, pregnancy outcome was categorized as either spontaneous abortion (SAB) or intrauterine fetal demise (IUFD). SABs were defined as fetal losses <20 weeks or ≤4 months gestational age (GA); IUFDs were defined as fetal losses ≥20 weeks or ≥5 months GA [17]. Preterm birth was defined as birth <37 weeks or ≤8 months GA [18]. In the absence of reported GA at delivery, author report of prematurity was relied upon to classify births as preterm. Information on maternal hemorrhage was abstracted and included both postpartum hemorrhage, as well as hemorrhage into tissues discovered at autopsy.
The primary form of plague was abstracted based on author assessment or on a description of clinical manifestations. Further details on clinical case definitions are included in Supplementary Appendix 1. Cases with associated laboratory testing results for Y. pestis reported were categorized as either confirmed, probable, or suspect, based in part on the World Health Organization case definitions [1] (Supplementary Appendix 2). Maternal transmission of Y. pestis to fetus or neonate was defined as follows:
- •
Congenital (ie, transmission from mother to fetus likely occurred in utero): Fetal or neonatal specimens tested positive for Y. pestis within 2 days of delivery.
- •
Postnatal (ie, transmission from mother to baby likely occurred during intrapartum or postpartum period): Neonatal specimens tested positive for Y. pestis ≥3 days after birth.
- •
No transmission: (1) Fetal or neonatal specimens (eg, fetal tissue, cord blood, neonatal blood, or neonatal tissue) tested negative for Y. pestis (irrespective of type of testing performed); or (2) documentation that the infant remained asymptomatic after birth.
Quality of Evidence Assessment
The risk of bias for each case was determined using a modified Newcastle-Ottawa Scale adapted for this review [19]. Each case was evaluated by 2 separate reviewers (Z.R., S.F.-D.) and assigned a score from 0 to 8 (Supplementary Materials). Cases were then sorted into 1 of 3 categories: low risk of bias (score 7–8), serious risk of bias (score 5–6), or very serious risk of bias (score 0–4).
RESULTS
Search Results
Database and hand searches identified 6425 articles, of which 850 were selected for full text review (Figure 1); 59 articles met the inclusion criteria and described a total of 160 cases of plague among pregnant women (Supplementary Materials).
Case Characteristics
Cases occurred from 1897 to 2002; year of illness was unknown for 26 (16.3%) cases. The majority (n = 108 [67.5%]) occurred in the preantibiotic era (<1937). Cases were reported from 20 different countries, with India accounting for the largest proportion of cases (n = 113 [70.6%]), followed by the US (n = 6 [3.8%]), Lebanon (n = 6 [3.8%]), and China (n = 5 [3.1%]). Median age at presentation was 28 years (range, 18–40 years). Among the 82 (51.3%) cases with trimester of maternal infection reported, 12.2% occurred in the first trimester, 35.4% in the second trimester, and 52.4% in the third trimester (Table 1).
Characteristics of Pregnant Women With Plague Reported in the Scientific Literature, 1897–2002
Characteristic . | All Cases (N = 160) . | Cases With Laboratory Evidence of Plague (n = 32) . |
---|---|---|
Age, y | ||
Median (range) | 28 (18–40) | 28 (18–40) |
Not reported | 106 (66.3) | 2 (6.3) |
Trimester of infection | ||
Reported | ||
First | 10 (12.2) | 3 (10.7) |
Second | 29 (35.4) | 9 (32.1) |
Third | 43 (52.4) | 16 (57.1) |
Not reported | 78 (48.8) | 4 (12.5) |
Part of outbreak | 34 (21.3) | 3 (9.4) |
Primary manifestation | ||
Reported | ||
Bubonic | 61 (84.7) | 24 (82.8) |
Pneumonic | 9 (12.5) | 4 (13.8) |
Septicemic | 2 (2.8) | 1 (3.4) |
Not reported | 88 (55.0) | 3 (9.4) |
Laboratory evidence | ||
Confirmed | 1 (0.6) | 1 (3.1) |
Probable | 17 (10.6) | 17 (53.1) |
Suspect | 14 (8.8) | 14 (43.8) |
No laboratory testing reported | 128 (80.0) | Not applicable |
Characteristic . | All Cases (N = 160) . | Cases With Laboratory Evidence of Plague (n = 32) . |
---|---|---|
Age, y | ||
Median (range) | 28 (18–40) | 28 (18–40) |
Not reported | 106 (66.3) | 2 (6.3) |
Trimester of infection | ||
Reported | ||
First | 10 (12.2) | 3 (10.7) |
Second | 29 (35.4) | 9 (32.1) |
Third | 43 (52.4) | 16 (57.1) |
Not reported | 78 (48.8) | 4 (12.5) |
Part of outbreak | 34 (21.3) | 3 (9.4) |
Primary manifestation | ||
Reported | ||
Bubonic | 61 (84.7) | 24 (82.8) |
Pneumonic | 9 (12.5) | 4 (13.8) |
Septicemic | 2 (2.8) | 1 (3.4) |
Not reported | 88 (55.0) | 3 (9.4) |
Laboratory evidence | ||
Confirmed | 1 (0.6) | 1 (3.1) |
Probable | 17 (10.6) | 17 (53.1) |
Suspect | 14 (8.8) | 14 (43.8) |
No laboratory testing reported | 128 (80.0) | Not applicable |
Data are presented as No. (%) unless otherwise indicated.
Characteristics of Pregnant Women With Plague Reported in the Scientific Literature, 1897–2002
Characteristic . | All Cases (N = 160) . | Cases With Laboratory Evidence of Plague (n = 32) . |
---|---|---|
Age, y | ||
Median (range) | 28 (18–40) | 28 (18–40) |
Not reported | 106 (66.3) | 2 (6.3) |
Trimester of infection | ||
Reported | ||
First | 10 (12.2) | 3 (10.7) |
Second | 29 (35.4) | 9 (32.1) |
Third | 43 (52.4) | 16 (57.1) |
Not reported | 78 (48.8) | 4 (12.5) |
Part of outbreak | 34 (21.3) | 3 (9.4) |
Primary manifestation | ||
Reported | ||
Bubonic | 61 (84.7) | 24 (82.8) |
Pneumonic | 9 (12.5) | 4 (13.8) |
Septicemic | 2 (2.8) | 1 (3.4) |
Not reported | 88 (55.0) | 3 (9.4) |
Laboratory evidence | ||
Confirmed | 1 (0.6) | 1 (3.1) |
Probable | 17 (10.6) | 17 (53.1) |
Suspect | 14 (8.8) | 14 (43.8) |
No laboratory testing reported | 128 (80.0) | Not applicable |
Characteristic . | All Cases (N = 160) . | Cases With Laboratory Evidence of Plague (n = 32) . |
---|---|---|
Age, y | ||
Median (range) | 28 (18–40) | 28 (18–40) |
Not reported | 106 (66.3) | 2 (6.3) |
Trimester of infection | ||
Reported | ||
First | 10 (12.2) | 3 (10.7) |
Second | 29 (35.4) | 9 (32.1) |
Third | 43 (52.4) | 16 (57.1) |
Not reported | 78 (48.8) | 4 (12.5) |
Part of outbreak | 34 (21.3) | 3 (9.4) |
Primary manifestation | ||
Reported | ||
Bubonic | 61 (84.7) | 24 (82.8) |
Pneumonic | 9 (12.5) | 4 (13.8) |
Septicemic | 2 (2.8) | 1 (3.4) |
Not reported | 88 (55.0) | 3 (9.4) |
Laboratory evidence | ||
Confirmed | 1 (0.6) | 1 (3.1) |
Probable | 17 (10.6) | 17 (53.1) |
Suspect | 14 (8.8) | 14 (43.8) |
No laboratory testing reported | 128 (80.0) | Not applicable |
Data are presented as No. (%) unless otherwise indicated.
Laboratory testing for Y. pestis was reported in 32 (20.0%) cases. Of these, 1 (3.1%) was categorized as confirmed, 17 (53.1%) were probable, and 14 (43.8%) were suspect cases. Among these 32 cases with any form of laboratory evidence of Y. pestis, we found similar proportions of maternal infection occurring in the first, second, and third trimesters (Table 1).
Clinical Features of Plague
Primary clinical manifestation was reported in 72 cases, of which the majority were bubonic (n = 61 [84.7%]) and pneumonic (n = 9 [12.5%]) plague (Table 1). Signs and symptoms of plague were reported for 48 (78.7%) primary bubonic cases and 4 (44.4%) primary pneumonic cases. Among pregnant women with bubonic plague, fever was most commonly reported (n = 36 [75.0%]), followed by headache (n = 11 [22.9%]), sweats/chills (n = 7 [14.6%]), and nausea/vomiting (n = 7 [14.6%]). Buboes developed in the inguinal/femoral, axillary, or other regions in 34 (70.8%), 11 (23.4%), and 4 (8.5%) women, respectively. Among pneumonic cases, fever was reported in 4 (100%) cases, cough and bloody sputum in 2 (50.0%), and dyspnea in 1 (25.0%) case.
Maternal outcome was reported for 150 (93.8%) cases, of which there were 92 (61.3%) maternal deaths. The median time from illness onset to maternal death was 5 days (range, 2–73 days). Two deaths occurred >1 month after illness onset; both took place during hospitalization for plague. In 1 case, the patient developed pneumonia. In the other case, cause of death was attributed to postpartum complications involving “alterations of the nervous system.” Mortality was highest among pregnant women with primary pneumonic plague (n = 7 [77.8%]). Thirty-four (55.7%) cases of primary bubonic and 1 (50.0%) case of primary septicemic plague resulted in maternal death. Of the 32 cases with laboratory evidence of Y. pestis, maternal mortality was 62.5%; a similar distribution of maternal deaths across primary form of plague was seen among this subset (data not shown).
Information on the occurrence of maternal hemorrhage during infection was reported for 22 cases. Among these, 13 (59.1%) women experienced hemorrhage; 8 experienced postpartum hemorrhage and 7 had evidence of hemorrhage into tissues on autopsy. For 3 (13.6%) additional women, hemorrhage seemed likely, but the information available was too limited to interpret confidently.
Pregnancy Outcomes
Among the 138 (86.3%) cases for which pregnancy outcome was known, fetal loss occurred in 101 (73.2%). The median time from symptom onset to pregnancy loss was 3 days (range, 1–11 days). SABs accounted for 8.9% of losses and IUFDs for 25.7%, whereas for 54.5% of losses gestational dating was not reported. The remaining pregnancy losses (10.9%) were fetal losses coincident with maternal death (Figure 3). Of the 37 live births, 6 (16%) neonates were born preterm and 11 (30%) subsequently resulted in neonatal death. The median time from birth to neonatal death was 2 days (range, 0–12 days) (Figure 3). Limited information was reported on the cause of neonatal deaths; however, 6 of the 11 deaths had evidence of Y. pestis in neonatal specimens and appeared to be directly due to plague. No birth defects were reported among any of the fetuses or neonates. Among the subset of pregnant women with laboratory evidence of Y. pestis, 50% experienced pregnancy loss. Similar proportions of preterm birth and neonatal death were also seen among this subset (data not shown).

Pregnancy and neonatal outcomes among pregnant women with plague reported in the scientific literature, 1897–2002. Abbreviations: IUFD, intrauterine fetal demise; NR, not reported; SAB, spontaneous abortion.
Information related to maternal-fetal transmission of Y. pestis during pregnancy was available for 32 cases. In 23 (71.9%) cases there is no evidence that transmission of Y. pestis occurred, and in 3 cases (9.4%) transmission was considered to have occurred in the postnatal period. In 1 case, there was evidence that maternal antibodies had crossed the placenta and were found to be present in the neonate at birth. In 5 (15.6%) cases, laboratory evidence suggests that maternal-fetal transmission is likely, with Y. pestis reported in fetal (n = 2) or postmortem neonatal tissues and blood examined within 2 days of birth (n = 3). None of these 5 patients received maternal antimicrobial treatment. Maternal infection occurred in the third trimester for 4 of these 5 (80.0%) congenital cases (Table 2). For cases with no evidence of transmission, maternal infection occurred in the second and third trimesters for 34.8% and 39.1% of cases, respectively.
Description . | Maternal Clinical Form . | Maternal Infection Timing . | Pregnancy Outcome . |
---|---|---|---|
Lien-Teh [20], 1926: “B. pestisa was found in the placenta, CSF, pleural exudate, lungs, both chambers of the heart, liver, spleen (only smears were positive, the cultures remaining sterile), ureters, peritoneal fluid and uterine cavity of the child.” | Pneumonic | 9 mo | IUFD |
IPC, 1900 [21]: “The mother aborted and died … The umbilical cord, liver, and spleen of the foetus was examined microscopically; only in the liver were any plague bacilli seen, and these were all found phagocytosed in large mononuclear cells.” | NR | NR | Fetal demise, unknown timing |
Lien-Teh [20], 1926: A “child was born which survived for 5 hours … Blood was taken from the heart of the child and … the bacteriological examination of this blood gave positive results.” | Pneumonic | 8 mo | Live birth |
Jennings [7], 1903: “10 hours after birth … buboes appeared in the child’s groin and axillae, and it died in 28 hours. On post-mortem examination plague bacilli were found in its blood, spleen, retroperitoneal, femoral, and axillary glands.” | NR | 9 mo | Live birth |
Bikov [22], 1926b: After neonatal death at 2 d, “blood seeding confirmed plague septicemia” and “positive cultures were obtained from its blood.” | Pneumonic | 8 mo | Live birth |
Description . | Maternal Clinical Form . | Maternal Infection Timing . | Pregnancy Outcome . |
---|---|---|---|
Lien-Teh [20], 1926: “B. pestisa was found in the placenta, CSF, pleural exudate, lungs, both chambers of the heart, liver, spleen (only smears were positive, the cultures remaining sterile), ureters, peritoneal fluid and uterine cavity of the child.” | Pneumonic | 9 mo | IUFD |
IPC, 1900 [21]: “The mother aborted and died … The umbilical cord, liver, and spleen of the foetus was examined microscopically; only in the liver were any plague bacilli seen, and these were all found phagocytosed in large mononuclear cells.” | NR | NR | Fetal demise, unknown timing |
Lien-Teh [20], 1926: A “child was born which survived for 5 hours … Blood was taken from the heart of the child and … the bacteriological examination of this blood gave positive results.” | Pneumonic | 8 mo | Live birth |
Jennings [7], 1903: “10 hours after birth … buboes appeared in the child’s groin and axillae, and it died in 28 hours. On post-mortem examination plague bacilli were found in its blood, spleen, retroperitoneal, femoral, and axillary glands.” | NR | 9 mo | Live birth |
Bikov [22], 1926b: After neonatal death at 2 d, “blood seeding confirmed plague septicemia” and “positive cultures were obtained from its blood.” | Pneumonic | 8 mo | Live birth |
Abbreviations: CSF, cerebrospinal fluid; IPC, Indian Plague Commission; IUFD, intrauterine fetal demise; NR, not reported.
a The footnote will state: B. pestis refers to ‘Bacillus pestis,’ which was a historical term used for Y. pestis.
bArticle translated from Russian to English.
Description . | Maternal Clinical Form . | Maternal Infection Timing . | Pregnancy Outcome . |
---|---|---|---|
Lien-Teh [20], 1926: “B. pestisa was found in the placenta, CSF, pleural exudate, lungs, both chambers of the heart, liver, spleen (only smears were positive, the cultures remaining sterile), ureters, peritoneal fluid and uterine cavity of the child.” | Pneumonic | 9 mo | IUFD |
IPC, 1900 [21]: “The mother aborted and died … The umbilical cord, liver, and spleen of the foetus was examined microscopically; only in the liver were any plague bacilli seen, and these were all found phagocytosed in large mononuclear cells.” | NR | NR | Fetal demise, unknown timing |
Lien-Teh [20], 1926: A “child was born which survived for 5 hours … Blood was taken from the heart of the child and … the bacteriological examination of this blood gave positive results.” | Pneumonic | 8 mo | Live birth |
Jennings [7], 1903: “10 hours after birth … buboes appeared in the child’s groin and axillae, and it died in 28 hours. On post-mortem examination plague bacilli were found in its blood, spleen, retroperitoneal, femoral, and axillary glands.” | NR | 9 mo | Live birth |
Bikov [22], 1926b: After neonatal death at 2 d, “blood seeding confirmed plague septicemia” and “positive cultures were obtained from its blood.” | Pneumonic | 8 mo | Live birth |
Description . | Maternal Clinical Form . | Maternal Infection Timing . | Pregnancy Outcome . |
---|---|---|---|
Lien-Teh [20], 1926: “B. pestisa was found in the placenta, CSF, pleural exudate, lungs, both chambers of the heart, liver, spleen (only smears were positive, the cultures remaining sterile), ureters, peritoneal fluid and uterine cavity of the child.” | Pneumonic | 9 mo | IUFD |
IPC, 1900 [21]: “The mother aborted and died … The umbilical cord, liver, and spleen of the foetus was examined microscopically; only in the liver were any plague bacilli seen, and these were all found phagocytosed in large mononuclear cells.” | NR | NR | Fetal demise, unknown timing |
Lien-Teh [20], 1926: A “child was born which survived for 5 hours … Blood was taken from the heart of the child and … the bacteriological examination of this blood gave positive results.” | Pneumonic | 8 mo | Live birth |
Jennings [7], 1903: “10 hours after birth … buboes appeared in the child’s groin and axillae, and it died in 28 hours. On post-mortem examination plague bacilli were found in its blood, spleen, retroperitoneal, femoral, and axillary glands.” | NR | 9 mo | Live birth |
Bikov [22], 1926b: After neonatal death at 2 d, “blood seeding confirmed plague septicemia” and “positive cultures were obtained from its blood.” | Pneumonic | 8 mo | Live birth |
Abbreviations: CSF, cerebrospinal fluid; IPC, Indian Plague Commission; IUFD, intrauterine fetal demise; NR, not reported.
a The footnote will state: B. pestis refers to ‘Bacillus pestis,’ which was a historical term used for Y. pestis.
bArticle translated from Russian to English.
Antimicrobial Treatment
Antimicrobials were administered to 24 (15.0%) women: 23 received treatment during pregnancy and 1 during the postpartum period. The most common antimicrobials administered were sulfonamides (n = 18/24 [75.0%]) and streptomycin (n = 13/24 [54.2%]). Penicillins (n = 3), tetracyclines (n = 3), gentamicin (n = 1), and chloramphenicol (n = 1) were also administered; however, the small number of these cases limits interpretation (Table 3).
Maternal Mortality and Fetal Fatality by Treatment Among Pregnant Women With Plague Reported in the Scientific Literature, 1897–2002
Antimicrobial Administereda . | Maternal Mortality, No. (%) . | Fetal Fatality, No. (%) . |
---|---|---|
Untreated (n = 136) | 86/129 (67) | 92/124 (74) |
Treated (n = 24) | 6/21 (29) | 8/13 (62) |
Sulfonamides (n = 18) | 4/15 (27) | 8/8 (100) |
Streptomycin (n = 13) | 1/13 (8) | 1/4 (25) |
Penicillins (n = 3) | 1/3 (33) | 0/3 (0) |
Tetracyclines (n = 3) | 1/3 (33)b | 0/1 (0) |
Gentamicin (n = 1) | 0/1 (0) | 0/1 (0) |
Chloramphenicol (n = 1) | 0/1 (0)c | NA |
Antimicrobial Administereda . | Maternal Mortality, No. (%) . | Fetal Fatality, No. (%) . |
---|---|---|
Untreated (n = 136) | 86/129 (67) | 92/124 (74) |
Treated (n = 24) | 6/21 (29) | 8/13 (62) |
Sulfonamides (n = 18) | 4/15 (27) | 8/8 (100) |
Streptomycin (n = 13) | 1/13 (8) | 1/4 (25) |
Penicillins (n = 3) | 1/3 (33) | 0/3 (0) |
Tetracyclines (n = 3) | 1/3 (33)b | 0/1 (0) |
Gentamicin (n = 1) | 0/1 (0) | 0/1 (0) |
Chloramphenicol (n = 1) | 0/1 (0)c | NA |
Abbreviation: NA, not applicable.
aAntimicrobials listed were given alone or in combination with other antimicrobials.
bAdministered to 2 mothers postpartum, 1 of whom died.
cAdministered postpartum.
Maternal Mortality and Fetal Fatality by Treatment Among Pregnant Women With Plague Reported in the Scientific Literature, 1897–2002
Antimicrobial Administereda . | Maternal Mortality, No. (%) . | Fetal Fatality, No. (%) . |
---|---|---|
Untreated (n = 136) | 86/129 (67) | 92/124 (74) |
Treated (n = 24) | 6/21 (29) | 8/13 (62) |
Sulfonamides (n = 18) | 4/15 (27) | 8/8 (100) |
Streptomycin (n = 13) | 1/13 (8) | 1/4 (25) |
Penicillins (n = 3) | 1/3 (33) | 0/3 (0) |
Tetracyclines (n = 3) | 1/3 (33)b | 0/1 (0) |
Gentamicin (n = 1) | 0/1 (0) | 0/1 (0) |
Chloramphenicol (n = 1) | 0/1 (0)c | NA |
Antimicrobial Administereda . | Maternal Mortality, No. (%) . | Fetal Fatality, No. (%) . |
---|---|---|
Untreated (n = 136) | 86/129 (67) | 92/124 (74) |
Treated (n = 24) | 6/21 (29) | 8/13 (62) |
Sulfonamides (n = 18) | 4/15 (27) | 8/8 (100) |
Streptomycin (n = 13) | 1/13 (8) | 1/4 (25) |
Penicillins (n = 3) | 1/3 (33) | 0/3 (0) |
Tetracyclines (n = 3) | 1/3 (33)b | 0/1 (0) |
Gentamicin (n = 1) | 0/1 (0) | 0/1 (0) |
Chloramphenicol (n = 1) | 0/1 (0)c | NA |
Abbreviation: NA, not applicable.
aAntimicrobials listed were given alone or in combination with other antimicrobials.
bAdministered to 2 mothers postpartum, 1 of whom died.
cAdministered postpartum.
Of those treated, maternal outcome was reported for 21 patients and fetal outcomes were reported for 13 patients. Maternal mortality was 28.6% and fetal fatality was 61.5% for women treated with antimicrobials. In comparison, maternal mortality and fetal fatality was 66.7% and 74.2%, respectively, for the 136 untreated cases (Table 3). Five live births occurred among treated mothers; none reported preterm birth or neonatal death. Of the women treated with sulfonamides, maternal mortality and fetal fatality were 27% (n = 4/15) and 100% (n = 8/8), respectively. Of those treated with streptomycin, maternal mortality and fetal fatality were 8% (n = 1/13) and 25% (n = 1/4), respectively (Table 3). Conversely, among the 32 live births from untreated mothers, 18.8% were born preterm and 34.3% ultimately resulted in neonatal death.
Quality of Evidence Assessment
The majority of cases were given a risk of bias assessment of “very serious” (n = 110 [68.8%]). Forty-six (28.8%) were scored as “serious” and 4 (2.5%) were scored as having a low risk of bias (Supplementary Materials). The 4 cases with a low risk of bias were based on detailed reports of women treated with antimicrobials from 1941 to 1983. Three occurred in the US and 1 in Argentina (Supplementary Materials).
DISCUSSION
In this comprehensive systematic literature review describing worldwide cases of plague during pregnancy, the clinical presentation of plague among pregnant women appears similar to that among nonpregnant adults published in the literature [5, 22]. Maternal mortality and pregnancy loss commonly occurred. In the subgroup of treated pregnant women, antimicrobials were associated with improved maternal survival; however, there was minimal improvement in fetal survival after maternal treatment. These findings, which are based on limited data, suggest the need to ensure pregnant women receive timely and effective treatment with antimicrobials with known clinical efficacy. In this review, sulfonamides did not confer a fetal survival benefit; however, more data are needed to draw firm conclusions about the fetal benefit of specific antimicrobials. Due to the unethical nature of conducting randomized controlled trials in pregnant women, antimicrobial efficacy will need to be further extrapolated from the nonpregnant population. Regardless of the antimicrobials chosen, plague should be considered as a possible diagnosis among women who have potential zoonotic or bioterrorism-related exposures to allow antimicrobial treatment to begin as early as possible.
Interestingly, we identified reports in which some pregnant women survived and delivered a live newborn even without appropriate antimicrobial treatment. Although it is possible for nonpregnant adults to survive bubonic plague in the absence of antimicrobial treatment, this finding is surprising and may represent misdiagnosis or less likely, highly effective critical care. In addition, neonates have survived fatal maternal infection, suggesting that maternal-fetal transmission is not universal and that, despite severe maternal illness, neonates can survive. Unfortunately, some live births did ultimately result in a neonatal death. Preterm birth appears to be common, similar to other severe infections during pregnancy [8–10]. No birth defects were identified in this systematic review; however, given the small number of live births and first trimester exposures, the possibility of an early infection causing birth defects cannot be excluded.
Five cases of likely maternal-fetal transmission of Y. pestis reported were identified. None of these cases received maternal antimicrobial treatment, indicating that without such treatment, and perhaps with high levels of bacteremia, in utero transmission of Y. pestis may occur. We also found evidence suggesting that maternal antibodies can cross the placenta.
Identifying primary bubonic plague as the most common form in this review is not unexpected; it is similar to what is observed in the nonpregnant adult population [23]. Although pregnant women with plague presented with typical signs and symptoms of the bubonic and pneumonic forms of the disease [1], a proportion of pregnant women experienced postpartum hemorrhage or hemorrhage into tissues during their illness. Hemorrhage is a known complication of plague, and hemorrhage of the reproductive organs in females with plague has been reported [20, 22, 24]. However, based on these small numbers and without a direct comparison, we do not know if plague-related hemorrhage is more common during pregnancy. Regardless, obstetricians caring for these women should be prepared to manage hemorrhage as a complication of plague.
This review has several important limitations. First, included articles were case reports, case series, or outbreak reports, and therefore this review is solely based on observational, low-quality data and is likely to be highly subject to publication bias. This may have resulted in the overrepresentation of unusual or more severe cases of plague during pregnancy described in the literature. Many articles contained only brief clinical descriptions resulting in large amounts of missing data. Most notably, the data available on trimester of infection and gestational age limit the ability to examine specific outcomes by gestational timing. Second, the majority of cases occurred in the preantimicrobial era and from a single country. Because very few cases were treated with antimicrobials, we cannot draw conclusions on the efficacy and safety of specific antimicrobial treatments. Moreover, because 70% of cases were reported from India, this may decrease the generalizability of our findings to other settings. Third, Y. pestis laboratory testing results were unavailable for more than three-quarters of cases and therefore some of these cases may not in fact have had plague. However, many cases were reported in association with similar cases in nonpregnant individuals and known exposures to Y. pestis. Also, many patients were reported to have classic buboes and other symptoms associated with the disease. While limitations exist, we did not detect any substantial differences in case characteristics, clinical features of plague, or pregnancy outcomes when comparing those with laboratory evidence reported and those without. We would expect that if cases with other etiologies were included, this would likely skew the outcomes more positively. Last, while the most common form was bubonic, roughly half of cases lacked sufficient information to ascertain primary form. As mortality varies by primary form, extrapolating our findings to other types of plague in pregnant women should be done with caution.
CONCLUSIONS
Untreated Y. pestis infection during pregnancy is associated with a high risk of mortality and, as demonstrated in this review, a high risk of pregnancy and neonatal loss. Appropriate antimicrobial treatment can improve maternal survival, although even with antimicrobial treatment, the risk of pregnancy loss remains. In addition to severe infection and sepsis, preterm birth and hemorrhage are potential complications of plague during pregnancy. Limited evidence suggests that maternal-fetal transmission of Y. pestis is possible, particularly when antimicrobial treatment is absent or delayed. Taken together, these results indicate the need to recognize and treat pregnant women with plague promptly with effective antimicrobials and to monitor for preterm birth and hemorrhage. Given the severe adverse outcomes associated with plague during pregnancy, prophylaxis of pregnant women exposed to Y. pestis and prevention of disease is of paramount public health importance during outbreaks or bioterrorism events involving plague.
Supplementary Data
Supplementary materials are available at Clinical Infectious Diseases online. Consisting of data provided by the authors to benefit the reader, the posted materials are not copyedited and are the sole responsibility of the authors, so questions or comments should be addressed to the corresponding author.
Notes
Acknowledgments. Isabel Sheets assisted with creation of the data abstraction tool. Joanna Taliano conducted the literature database search. Helen Talley-McRae and Maria I. Rivera procured and organized articles for review. Patty Yu, Martina Badell, Jeanne Sheffield, and Brenna Hughes consulted on pregnancy-related questions.
Disclaimer. The findings and conclusions in this report are those of the authors and do not necessarily represent the official position of the Centers for Disease Control and Prevention (CDC).
Financial support. This project was supported by the CDC and the Office of the Assistant Secretary for Preparedness and Response. This project was supported in part by an appointment to the CDC Fellowship Program, administered by the Oak Ridge Institute for Science and Education through an interagency agreement between the US Department of Energy and the CDC.
Supplement sponsorship. This article appears as part of the supplement “Plague and Bioterrorism Preparedness,” sponsored by the Centers for Disease Control and Prevention.
Potential conflicts of interest. The authors: No reported conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest.
References