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Abstract & Commentary
Synopsis: Travel during pregnancy carries some unique risks of infectious disease exposures, but most occur in situations that can be readily avoided. These include remote treks to destinations where medical care is not accessible in an emergency, exposures to environmental and pharmaceutical agents that are not anticipated, and to infectious agents that can do harm to both mother and fetus—some with potentially disastrous results. This study from Riyadh, Saudi Arabia, is important, since it documents and, once again, reminds us about a rate of abortion associated with human brucellosis that far exceeds the rates for any other infectious bacterial pathogen likely to be encountered by pregnant women during their travels.
Source: Khan MY, et al. Brucellosis in pregnant women. Clin Infect Dis. 2001;32:1172-1177.
Khan and colleagues are based at the King Fahad National Guard Hospital in Riyadh, Saudi Arabia, which serves the Saudi National Guard soldiers and extended families at secondary and tertiary levels of medical care. However, many of these soldiers come from Bedouin tribes in which milk is obtained from goats, camels, or sheep and not pasteurized. Many of these animals have been shown to be infected with brucellosis. The known seropositivity rate for human brucella infections in Saudi Arabia runs quite high, at about 15%. In their retrospective review of a medical record database from 1983 through 1995, a total of 545 patients with a discharge diagnosis of brucellosis were identified, of which 92 (17%) infections occurred during pregnancy —a rate of 1.3 cases of brucellosis in pregnant women per 1000 delivered obstetrical discharges. The diagnosis of brucellosis was based upon a compatible clinical history and a serum agglutinin titer of ³ 1:320, or a positive blood culture result. For the purposes of this study, they defined spontaneous abortions as fetal deaths occurring at £ 24 weeks’ gestation. Deaths that occurred at > 24 weeks’ gestation were designated intrauterine fetal deaths. The mean age of women in the study was approximately 27 years; 71 had 3 or more pregnancies prior to this study and 86 had never before experienced a spontaneous abortion. Nearly half of the 92 presented during their second trimester.
Sadly, the results were all too impressive. Among the 92 cases of pregnant women with acute brucellosis, 40 (43%) had spontaneous abortions during the first or second trimesters and 2 additional patients experienced intrauterine fetal deaths in their third trimesters. The occurrence rates for abortions among women with brucellosis in their first and second trimesters were higher than in their third trimester (see Table). The rates, for comparison, among all women in Saudi Arabia were 2.8% in the first and second trimester, as compared to the 52-64% rates of spontaneous abortion during the first and second trimesters among women with acute brucellosis in this study.
|Occurrence of Spontaneous Abortion and Intrauterine Death, According to Trimester of Pregnancy, in 92 Women with Acute Brucellosis in Saudi Arabia|
of Spontaneous Abortions
|Note: Difference in the incidence of abortion was significant for first vs. third trimester (P < .001) and second vs. third trimester (P < .0001), but not for first vs. second trimester.|
| These either were or included intrauterine fetal deaths.|
|Adapted from: Khan MY, et al. Brucellosis in pregnant women. Clin Infect Dis. 2001;32:1172-1177.|
The rate of intrauterine fetal death among all pregnant women in Saudi Arabia during their third trimester was calculated to be approximately 0.3%, whereas pregnant women with brucellosis in this study also experienced 2 intrauterine fetal deaths (8%), likely reflecting a significantly higher risk.
Khan et al showed no relationship between the magnitude of serum agglutinin titers and either the occurrence of bacteremia or spontaneous abortion. Blood cultures were positive in 22/52 (42%) of women who were tested as part of their evaluation and of those characterized as to Brucella spp nearly all were Brucella melitensis. Antepartum treatment, with a combination regimen of antimicrobial agents such as cotrimoxazole and rifampin, appeared to be highly protective against fetal loss. Of the 92 women with acute brucellosis during pregnancy, 41 received antepartum antimicrobial therapy. Among women in this treated group, there were only 3 spontaneous abortions and 1 fetal death out of a total of 42 such events in the entire study (ie, the total incidence of spontaneous abortion and fetal death was 46% but almost all occurred in the untreated group).
Comment by Frank J. Bia, MD, MPH
Referring to his classic monograph on brucellosis, Khan et al quoted Dr. Wesley Spink stating ". . . the passage of time has produced no definitive evidence that the Brucellae produce abortions any more frequently than do other species of bacteria." Reading further into the original text Spink clearly does recognize that " like any other severe bacterial infection with invasion of the blood stream, brucellosis can and does induce abortions and miscarriages, particularly the disease caused by Br. melitensis."1 However, he appears to attribute these adverse effects nonspecifically to a bacteremia that was perhaps no different than any other bacteremia in this regard. Spink also recognized that infection of the human fetus in utero had been reported much earlier in the last century.
The first large series to define a causative relationship between brucellosis and abortions in humans was reported from Spain by Criscuolo and di Carlo in 1954.2 They studied 200 women with active brucella infections, and abortions occurred in 52, for a rate of 26%. Spink had also been aware of and referenced their publication. In 1980, Schreyer and colleagues reported 1 case of maternal Gram-negative septic shock and disseminated intravascular coagulation with intrauterine fetal death in the second trimester caused by B melitensis.3 By 1990, Sharif and colleagues had tested 537 pregnant women from rural Saudi Arabia, 24 of whom were symptomatic with brucellosis.4 Dividing their 42 seropositive women into those with brucella antibody titers above and below 1:160, they demonstrated an abortion incidence rate of 17.6% among the 30 women in the high-titer group. The remaining 12 women with lower titers had an incidence of 7.7%. Recent studies of 400 cases of brucellosis from Kuwait indicated a 31% rate of abortion among 35 pregnant women in that series; a similar 41% rate of abortion occurred among 30 pregnant women reported by Madkour, one of whom had experienced recurrent abortions after 5 normal full-term pregnancies.6 In 1998, Makhseed and colleagues, also from Kuwait, used maternal enzyme-linked immunosorbent assays and conception product cultures for Brucella spp to again demonstrate a correlation between infection and preterm or intrauterine fetal death.7 Hackmon and colleagues presented 7 additional cases of brucellosis in the Hebrew literature from Soroka Medical Center in Beer Sheba.8 One case was complicated by preterm, premature rupture of membranes and preterm delivery in the 20th week; 2 other cases experienced preterm delivery, 1 with associated chorioamnionitis. Of the remaining 4 who delivered at term, 2 developed postpartum endometritis and 1 had preterm premature rupture of membranes.
In 1907, the Mediterranean Fever Commission had documented the isolation of B melitensis for the milk of 2 nursing women without evidence of any resulting infection in the nursing child.9 Recently, Cokca and colleagues reported a pregnant woman in Turkey with bilateral breast abscesses due to B melitensis.10 First reported in Malta during 1907 by E.M. Williams,11 Shamo’on and Izzat again reported a case of congenital brucellosis from Amman, Jordan, in 1999.12
Khan et al correctly point out that there are few data available regarding other microbial bacteremias with which to compare this study. Their search of the literature with regards to other bacteria such as Escherichia coli and Salmonella spp produced a single report of 30 pregnancies complicated by typhoid fever resulting in 3 spontaneous abortions (10%). Similar numbers appeared in a study of 10 pregnant women with Campylobacter jejuni infections during pregnancy in which one patient developed premature labor resulting in neonatal death. In essence, it simply may not be maternal bacteremia alone that represents the risk factor for spontaneous abortions in brucellosis.
The human placenta and fetus do not contain erythritol, a constituent of normal ungulate fetal and placental tissue that promotes overwhelming Brucella infections. Yet, despite the absence of bacteremia, erythritol or histopathological changes in the placenta, active human brucellosis is clearly associated with high rates of spontaneous abortion. The good news in the current study appears to be that early antimicrobial therapy with agents such as combined cotrimoxazole and rifampin, which are safe during pregnancy, may prevent such an outcome.
Travelers to areas where brucellosis is endemic have always been at risk for systemic brucella infections that have been sometimes difficult to diagnose and even gone on for years.12,13 However, travel during pregnancy is another issue, particularly when it comes to brucellosis. The documented rates of abortion, miscarriage, prematurity, and fetal death are far too high and now too well-documented, to take chances with acquiring this disease. No satisfactory vaccines against human brucella infections are available.14 Consumption of unpasteurized dairy products, including raw milk and cheese products, are the most likely sources of infection for pregnant women as opposed to occupational exposures in veterinarians, farmers, and abattoir workers. Pregnant women should first assure themselves that such food sources have clearly undergone pasteurization, or simply avoid them entirely.
1. Spink WW. The Nature of Brucellosis. Minneapolis, Minn: University of Minnesota Press; 1956:87, 188.
2. Criscuolo E, di Carlo FC. El aborto y ostras manifestaciones ginecoobstetricas en el curso de la brucelosis humana. Rev Fac Cien Med Univ Nac Cordoba. 1954; 12:321-330.
3. Schreyer P, et al. Brucella septicemia in pregnancy. Eur J Obstet Gynecol Reprod Biol. 1980;10:99-107.
4. Sharif A, et al. Screening for brucellosis in pregnant women. J Trop Med Hyg. 1990;93:42-43.
5. Lulu AR, et al. Human brocellosis in Kuwait: A prospective study of 400 cases. QJM. 1988;66:39-54.
6. Madkour MM. Pregnancy and brucellosis. In: Madkour MM, ed. Madkour’s Brucellosis. Berlin, Germany: Springer-Verlag; 2001:187-192.
7. Makhseed M, et al. Obstetric and gynecologic implication of brucellosis in Kuwiat. J Perinatol. 1998;18:196-199.
8. Hackmon R, et al. Brucellosis in pregnancy. Harefuah. 1998;135:3-7, 88 [Article in Hebrew].
9. Eyre JWH, et al. Report upon the bacteriological and experimental investigations during the summer of 1906. In: Reports of the Royal Society of London, Mediterranean Fever Commission. London, England: Harrison & Sons; 1907:3. Quoted in Spink: The Nature of Brucellosis.
10. Cokca F, et al. Bilateral mammary abscess due to Brucella melitensis. Scand J Infect Dis. 1999;31: 318-319.
11. Williams EM. Mediterranean fever: Infection in utero. J Roy Army M Corps. 1907;9:59. Quoted in Spink: The Nature of Brucellosis.
12. Shamo’on H, Izzat M. Congenital brucellosis. Pediatr Infect Dis J. 1999;18:1110-1111.
13. Margolis DM, Collins MT. A 74-year-old man with persistent fevers. Md Med J. 1997;46:524-529.
14. Corbel MJ. Brucellosis: An overview. Emerg Infect Dis. 1997;3:213-221.