1. Clinical Considerations for Anthrax in Pregnant and Postpartum Women
Dana Meaney-Delman, MD MPH
Assistant Professor of Gynecology and Obstetrics
Emory University School of Medicine
Consultant
Division of Reproductive Health
Centers for Disease Control and Prevention
Thank you Tracee for the introduction and thank you Dr Kadalani for your description of the two cases of pregnancy-related anthrax. This talk will complement your presentations and will provide a broader view of the clinical considerations in pregnant and postpartum women.

2. Overview Review unique features of pregnant women
Comprehensive review of reported clinical experience with anthrax in pregnancy and the postpartum period
My task this afternoon is to outline the clinical considerations of anthrax in pregnancy. An important point to state upfront is that is that although pregnant women do differ from non-pregnant adults, it is important to examine how their unique features would impact to the approach to prophylaxis and treatment for anthrax in these patients. My intention is to discuss the unique aspects of pregnancy and examine the clinical experience to date related to anthrax in pregnancy and the postpartum period. This review will hopefully frame some of the future discussions this afternoon and in the small groups sessions tomorrow.

3. Pregnant and Postpartum Women
Approximately 7 million pregnancies/year
Population that is not well studied
Recent H1N1 pandemic experience
Complex clinical management decisions
Pre-event planning essential to ensure an efficient public health response and minimize the burden of disease
There are almost 7 million pregnancies per year in the US and this is a population that is not well studied- there are many barriers to research in this population. This could be the subject of a 30 minute talk in and of itself.
The recent H1NA Pandemic demonstrated how complex the clinical management decisions can become when treating severely ill pregnant women and clearly demonstrated the benefit of pre-event planning for this population.
As we have heard this morning, the biology of anthrax is such, if an event were to occur, the clinical and public health response will need to be very rapid. There will be little time to debate the choice of antibiotics to use, the administration of antitoxins, the recommendations for breastfeeding and other health care planning issues. The CDC, recognizes that advance planning is critical to minimize morbidity and mortality among pregnant and lactating women, which is why we have invited you all here to help us sort through the pertinent issues and develop clinical guidance.
Ventura et al. National Vital Statistics Report 2009: 58(4): 1-13
Cono et al. Emerg Infect Dis 2006;12:
Pandemic and All-Hazards Preparedness Act. Public Law December 19, 2006.

4. Considerations for Infectious Disease in Pregnancy
Maternal
Susceptibility
Severity
Obstetrical Issues
Access to appropriate treatment
Adherence
Fetal
Complications from maternal infection
Congenital infection
Risks from diagnostic testing and treatments
As you will see later in the talk, there is limited information about anthrax in pregnancy and much of what we know dates back to the 19th century except for the few recent cases, including the two you have just heard presented.
However, the is a wealth of knowledge about other infectious diseases in pregnancy and here I have listed some of the most relevant considerations for infectious diseases in pregnancy. In terms of maternal concerns, there is evidence that pregnant and postpartum women may be more susceptible and do develop more severe disease when infected with specific microbes. Access to appropriate treatment for many infectious diseases is also a concern, with-traditional barriers to care that many non-pregnant individuals face but also with the added barrier of the reluctance to use certain antimicrobials and other treatments, resulting from the lack of data and perhaps even medical legal concerns. Adherence to treatments may also be an additional issues for a multitude of reasons in pregnant women, not the list of which is that they often are already feeling sick from the pregnancy itself.
In terms of fetal considerations, complications from maternal infections, including possible perinatal transmission of the infection, are a major concern and these are intimately tied to the appropriate treatments for the mother. One of the underlying tenets of all obstetrical practice is that a healthy fetus relies on having a healthy mother. Although this major tenet drives our approach to obstetrical care, it can present a dilemma when there are fetal risks, either from diagnostic testing or antimicrobial treatments. The basic premise to address this issues is to weight the risks and benefits, and included in that must be an evaluation of the risks of not intervening for the pregnant woman. For anthrax, it is important that we recall the mortality statistics presented earlier- this is often a lethal disease

5. Major Physiologic Characteristics of Pregnancy
Organ System
Physiologic Change
Immunologic
shift away from cell-mediated immunity and toward humoral immunity
Respiratory
increased tidal volume
decreased maternal oxygen reserve
decreased lung compliance
Cardiovascular
increased blood volume
decreased intravascular oncotic pressure
increased volume of distribution
Gastrointestinal
decreased function and motility
Renal
increased glomerular filtration
Increased renal secretion
Paramount to some of these considerations are the underlying physiologic changes pregnant women experience. RUN Through them here
Immunologic changes can relate to the issues of increased susceptibility and severity to infection, as pregnant women experience a shift towards humoral immunity and away from cell mediated immunity. As we have heard today, anthrax is a toxin mediated disease and the role of humoral immunity may be especially important.
Respiratory changes are especially important for infectious diseases that may affect the respiratory tract and these changes increase as the pregnancy progresses with the increasing size of the gravid uterus. This may be a something we need to keep in mind with inhalation anthrax.
Cardiovascular changes including increased intravascular blood volme and decreased intravascular oncotic pressure predispose pregnant women to fluid shifts, which is a major concern with anthrax, given the toxin mediated fluid shifts.
The increased volume of distribution, decreased GI function and motility, as well as the increased in renal function can result in differences in antibiotic response.
Jamieson et al. Emerg Infect Dis ; 2006: 12:11
Cono et al. Emerg Infect Dis; 2006: 12:11

6. Choice of Antimicrobial Agents in Pregnancy
Efficacy of drug
Pharmacokinetics
Maternal risks
Fetal risks
Other concerns
Availability
Tolerability
Adherence
Obviously for bacterial infectious diseases, antibiotics are the mainstay of treatment. Antibiotic choice during pregnancy is based on similar factors as for the general population, the efficacy of the drug for the likely pathogen, and the severity of the disease. However, for a pregnant woman, the maternal and fetal risks also enter into the decision-making process. Fetal risks are best summarized in databases that continually collect data such as : REPRORISK and TERIS which provide updated peer-reviewed information.
One issue that is clear from the literature is that both clinicians and patients tend to overestimate fetal risk which can create a barrier to the use of antibiotics or other medications during pregnancy. This is true even for life threatening diseases.
A second barrier to the use of some antibiotic regimens, such as those for anthrax prophylaxis, is the lack of data on long-term use. The concern is not only the impact on the pregnant woman but also potential long term effects on the newborn.
Cono et al. Emerging Infectious Diseases; 2006: 12:
Lagoy et al. J Women’s Health;2005:14:

7. What do we know about anthrax in pregnancy?
Before we can develop recommendations for pregnant and postpartum women, we need to understand the natural history of anthrax in this population. As my MPH thesis, I conducted a systematic review of the worldwide literature, dating back to the 19th century, in efforts to identify all known cases of anthrax among pregnant or postpartum women to inform our policy efforts.

8. Systematic Review of Worldwide Experience
Extensive search dating back to 1886
14 articles
7 articles translated from Italian and German
Submitted to Obstetrics & Gynecology for publication
We searched 4 databases using a search strategy developed in consultation with an expert CDC librarian. You see this strategy depicted here – it was designed to be as broad as possible to find all reported cases.
Of note, 6 articles required formal translation, 4 from German and 2 from Italian.

9. Findings 20 cases total Anthrax reported in 8 countries 1 in US
17 pregnant , 3 postpartum
9/20 cases reported in the 19th century
Anthrax reported in 8 countries
1 in US
Poland, Iran, Iraq, Turkey, India, Italy
Greatest number in Germany
In total we identified 19 cases of anthrax, 16 in pregnant women and 3 in postpartum women, dating back to the 19th century, the earliest was case from These were naturally-occurring cases of anthrax and we believe that the number of cases is small, for 3 possible reasons. 1) Few cases of animal anthrax due to the success of animal vaccination- recall that exposure to animals is the major source of naturally occurring infection 2) underreporting 3)less exposure among pregnant women.
Cases were reported in 7 countries with only 1 case from the US from dating back to The most recent cases were from Turkey and Iran.

10. Anthrax by Location Location Author(Year) # of Cases Turkey
Kadalani(2003) 2
India
Sujatha(2002) 1
Poland
Tomasiewicz(1998)
Iran
Handjani(1976), Dutz(1971), Deneshbod (1970), Kohout(1964), 5
U.S.
Regan(1923)
Germany
Rostowzew(1897), Eppinger (1888), Paltauf(1888), Vogt (1927), Marchand (1886) 8
Italy
Romano(1888), Morisani(1886)
As you can see here, anthrax infection among PG and PP women was reported in 7 countries, with the greatest number in Germany and the 2nd greatest in Iran.

11. Anthrax Anthrax Form # of cases Suspected Exposure Inhalation (3)
Unknown
Cutaneous 13
“flaying a dead cow”, “slaughtering a sick cow”, wool sorting, contact with infected “rags”
Gastrointestinal 2
Ingestion of spores, ingestion of improperly cooked beef
Uterine 1
Attempted abortion with contaminated instrument
“Horse-hair sorting”
Four different forms of anthrax were reported, but the overwhelming majority were cutaneous, stemming from exposure to sick animals- flaying of a dead cow, wool sorting. A similar trend is noted in non-pregnant patients, with a predominance of cutaneous cases. 2 of the cases were GI, and 1 was actually a uterine case, resulting from an attempted abortion with a contaminated “stick”. Interestingly, there are no confirmed reports of inhalational anthrax but one suspected case based purely on autopsy findings.

12. Clinical Presentations
Cutaneous
Red painless papule black eschar
Significant edema including facial and neck respiratory compromise
Fever, increased WBC
Enlarged regional lymph nodes
Difficulty swallowing
IUFD, labor

13. Clinical Presentations
Gastrointestinal
Abdominal pain, vomiting, bloody diarrhea, abdominal bloating, ascites, pallor, hypotension, vaginal bleeding, vulvar edema, anuria
Uterine
Endometritis, massive hemorrhage, ascites
No clinical information from inhalation cases

14. Case Author Age Gestational Age Form Maternal Death Fetal or
Neonatal Death 1
Kadalani (2003) 33
32 weeks
cutaneous N 2 29
33 weeks 3
Sujatha (2002) 44 NR
gastrointestinal Y Y* 4
Tomasiewicz (1998)
31 weeks 5
Handjani (1976) 20
16-20 weeks 6
Dutz (1971)
uterine 7
Kohout (1964) 30
9 months 8
Regan (1923) 22
5-6 months 9
Rostowzew (1889) 34
8 months 10 36
7 months 11
Rostowzew (1897) 35
4 months 12
Eppinger (1888)
(inhalation) 13 14
Paltauf (1888)
5 months 15
Romano (1888)
“full term” 16
Morisani (1886) 40 17
Marchand (1886) 32
Unknown*
16 cases were identified in pregnant women, with average age of 32 in the cases where ages were reported. Gestational age varied from 2nd trimester to full term with no cases documented in 1st trimester of pregnancy. The years in which the cases were published ranged from

15. Postpartum Cases Case Author Age Time from Delivery ( at Presentation)
Maternal Death
Fetal/Neonatal Death 18
Daneshbod (1970) NR
3 days Y N 19 20
Vogt (1927) 32
5 months
3 cases were identified in postpartum women, which we defined as women who had delivered within 6 months of the report. In all cases, symptoms developed after the delivery with time frames that ranged from 3 days to 5 months.

16. Maternal Death Proportion = 80%
Maternal Outcomes
n=4
Of the 19 total cases, 15 resulted in maternal death for a case fatality proportion of 78%, much higher than would be expected in the general population. In addition the cutaneous case fatality proportion was 7/13 (54%) much higher than the general population between 1% with tx and 20% without treatment. The fatality proportions here for untreated cutaneous infection is probably most relevant and does appear higher than the general population.
Maternal Death Proportion = 80%

17. Penicillin/Streptomycin 6 Dutz (1971) U NR 7 Kohout (1964) C 9 months*
Case
Year
Form
Gestational Age
Treatment
Fetal Death 3
Sujatha (2002) GI
unknown
Cefotaxime
metronidazole Y 5
Handjani (1976)
GI*
16-20 weeks
Penicillin/Streptomycin 6
Dutz (1971) U NR 7
Kohout (1964) C
9 months*
Penicillin
N (transient asphyxia) 8
Reagan (1923)
5-6 months
Antiserum in wound, disinfectants 9
Rostowzew (1897)
8 months 10
7 months 11
4 months 12
Eppinger (1888)
(I) 13 14
Paltauf (1888)
5 months 15
Romano (1888)
“full term”*
Incision, cautery, disinfectants N 16
Paltauf (1886)
“close to term”
Cautery 17
Marchand (1886)
“full term”
This is a list of all the cases that resulted in Maternal and fetal deaths. Notice that treatment is unknown for over half. Although there was an overall 78% maternal fatality proportion, it is unclear what treatment they received if any . For cases before 1964, antibiotics were not available.
Also of note, is that is in one case the pregnant condition was felt to contribute to a delay in accurately diagnosing the disease, as reported by the authors.

18. Fetal/Neonatal Deaths among Pregnancy Cases
The fetal death proportion was also very high at 62.5%- 10 out of the 16 pregnant cases resulted in a confirmed fetal death, and all of these fatalities were associated with maternal mortalities. There were no cases of fetal death with maternal survival in this series. In only 1 case was there documentation that the mother received antibiotics.
Fetal Death Proportion = 64.7%

19. Preterm Deliveries (PTD)
Author/Year
Anthrax
Gestational Age
Clinical
Kadalani/2003
Turkey
Cutaneous
(submandible)
32 weeks/34 weeks
Preterm delivery 13 days after presentation and 3 days after “infection resolved” with antibiotics
(elbow)
33 weeks/34 weeks
Preterm delivery 7 days after presentation despite tocolysis, treated with antibiotics
Tomasiewicz/1998
Poland
(eyelid)
31 weeks/34 weeks
Preterm delivery 3 weeks after presentation
This chart represents the 3 cases of anthrax which resulted in preterm deliveries. You will note that these are more recent cases, all involving cutaneous anthrax, with labor occurring anywhere from 7 days to 3 weeks after initial presentation and in all 3 cases antibiotics were received. All deliveries occurred at 34 weeks and all infants were healthy without evidence of congential infection.
Additionally n 2 other full term cases, delivery occurred at the time of clinical anthrax pressentationRomano and Kohout

20. Anthrax and Breastfeeding
Vogt et al. 1927
Maternal case 5 months postpartum
Cutaneous anthrax on hand fever debridement  sepsis
Continued breastfeeding
No evidence of transmission despite the lack of antibiotic treatment and severe disease
The only case involving breast feeding was that of a 5 month pp woman with anthrax on her hand. In this case, the infection resolved without antimicrobials and there was no evidence of neonatal anthrax
{Antibiotics were not discovered until 1928 by Alexander Flemming through his experiments with staphylococcus where the growth plate was contaminated with mold. Florey and Chain 1938 was not used until 1941 (Fletcher)}

21. Anthrax in Fetal Tissues
Author
Maternal Anthrax
Fetal Tissues
Regan (1923)
Cutaneous
Placenta, amniotic fluid, lungs, liver, heart
Rostowzew (1897)
Placenta, umbilical vessels, liver
Placenta, umbilical cord liver, spleen, kidneys, adrenals
Rostowzew(1897)
Placenta, liver, spleen adrenals
Paltauf (1888)
(Inhalation)
Placenta, lungs heart
Marchand (1886)
Unknown*
Blood, lungs, kidneys, adrenals, liver, spleen
The most surprising finding in our review was that we identified 5 cases in which the fetal autopsies identified anthrax bacilli in the fetal tissues. You can see that not only was the anthrax present in the placenta, but also in the fetal liver lungs heart and other organs. etc. Of special note, these are old cases dating back to 1800s, and at least 4 of them are the cutaneous form These all predate treatment with antibiotics. Nevertheless, the identification of anthrax in the fetal tissues is concerning

22. Maternal & Neonatal Anthrax
32 year old P2 experienced spontaneous labor, resulting in the delivery of a male infant who appeared healthy at birth. Two hours after delivery, the patient developed weak pulse and lethargy, and experienced 1 episode of vomiting. Her respiratory status rapidly deteriorated and she expired 7 hours after delivery. Maternal autopsy revealed mesenteric edema, ascites and mesenteric lymph glands infiltrated with anthrax bacilli. On day of life 3, infant developed “blue-red” rash over entire body, lethargy, a bloated abdomen and ultimately respiratory failure. Fetal autopsy revealed “enormous numbers of anthrax bacilli” in fetal blood, liver, spleen, kidneys adrenal glands and lungs.
Marchand 1886

23. Results Summary
20 cases of naturally-occurring anthrax in pregnant and postpartum women
Most were cutaneous
High maternal mortality proportion overall and higher than expected with cutaneous infections
Obstetrical complications
High fetal/neonatal death proportion
PTD reported
Labor coincided with presentation in 3 cases
Delayed diagnosis may have contributed to disease severity
Perinatal Transmission
6/11 fetal/neonatal deaths demonstrate anthrax in fetal tissues
No evidence of passage of anthrax via in one case of anthrax sepsis
This is the results summary. 19 cases 16 PG 3PP. Only 1 us case. Mostly cutaneous. High maternal mortailty but very little treament known. High fetal death rate, Some PTD and coincident. But most interesting is this issue of possible placental transmission.

24. Limitations All naturally-occurring Very old case reports
Few women received antibiotics
Delays (or failure) to make diagnosis until autopsy

25. Discussion
Are pregnant and postpartum women more or less susceptible to anthrax than the general population?
Unclear from this review
Is anthrax infection more severe in pregnant and postpartum women than in the general population?
High proportion of maternal deaths but limited antibiotic use
Higher rate of death in cutaneous anthrax than reported for general population
Is there an increased risk of adverse obstetrical outcomes in women infected with anthrax?
Deliveries- both preterm and full term
High proportion of fetal death
Is there a risk of congenital infection in infants whose mothers are infected with anthrax?
Evidenced of anthrax in fetal tissues
Is there a risk of anthrax transmission through breast milk?
No evidence to date
So in terms of our research objectives, did we answer the questions?
Are ….more susceptible? The small number of cases limits our ability to answer this question. It may be that PG women are less likely to develop infection with so few cases or they may be less likely to be naturally exposed to the bacterium. In addition, there may be reporting bias whereby thee severe cases could over-reportedy . Alternative there may be additional cases whereby the pregnancy status was not recorded. So basically we don’t know but PG women do develop anthrax infection.
Is.. anthrax more severe? There is a high proportion of maternal deaths but limited antibiotic use- again this is uncertain
It is interesting though that there are higher rates of death than would be expected from untreated cutaneous anthrax so maybe perhaps is a greater risk of severe disease answer maybe but we cannot say for certain.
Is there an….There may be an increased risk of labor and perhaps even preterm labor depending upon gestational age at exposure. This has been shown in other infections whereby by inflammation releases inflammatory mediators- This may be associated with severe anthrax infection but it is hard to say because anthrax infection can lead to death pretty quickly, and there may be no time for inflammatory changes to impact the placenta. And as mentioned there were a lot of fetal deaths but most of these cases predate the use of antibiotics. The 2 most recent cases in who receive appropriate treatment did survive.
Is there a risk of CI As evidenced by 5 cases this may be an important issue. Although there is no evidence of CI in the infants that survived, so perhaps it is only with an issue fulminant infections. This has very important implications for treatment.
Is there evidence of Anthrax transsmission through Breast milk There is only 1 case reported of cutaneous anthrax on the arm in PP woman BF and no there is no evidence of infection despite her being systematically ill. So this remains unclear. Of note, there is some animal data of anthrax identified in the milk of infected cows but how that translates to humans remains unknown.

26. Implications
Anthrax has substantial morbidity and mortality in the obstetrical population
Medical countermeasures for pregnant and postpartum women
should maximize maternal (and fetal) survival
may involve the use of medications that are not typically used this population
may need to include antimicrobials with transplacental passage

27. Acknowledgements Denise Jamieson Marianne Zotti Sonya Rasmussen
Tracee Treadwell
Reina Turcios-Ruiz
George Wendel
Sean Shadomy
Deborah Dee
Willie Bower
Etobssie Wako
Mirelys Rodriguez
Finally I would like to acknowledge all the individuals who have brought me to this place over the past 5 years. But especially I want to thank Denise Jamieson for her tirelss efforts, teaching me how to conduct public health reseach. Sheryl Strasser who has held my hand through the process of completing an MPH thesis as well as Marianne Zorri and Sonja Rasmussen who were integral in the process of this coming together. I could not have achieved this without all 4 of those people. Nor could I let the opportunity go past to thank those at the Institute of Public health, GSU School of Nursing and other individuals at CDC who have guided me. And last but not least my personal friends and my family whose support has been unwavering and so much appreciated.

28. Animal Data On Anthrax in Pregnancy
Paucity of data
Reports of increased rates of spontaneous abortions in cattle (F de Lalla 1992)
Reports of maternal to fetal transmission in guinea-pigs, dogs, pigs (Regan 1923)
Reports of anthrax detected in milk from dairy cattle (WHO 1993)

29. Anthrax in the 1880s
1829 Regnier describes “anthrax” transmissibility from mother to fetus
1855 Pollender discovered bacilli
1858 Brauell, Davaine & Koch 1867 innoculated pregnant animals--> no fetal infections
1882 Strauss/Chamberland & Koubassoff innoculated pregnant animals: fetal infections
Other studies documenting perinatal transmission in animals
Perroncito, Walley 1889, Simon1889, Malvoz 1888, Rosenblath 1889, Latis 1891, Lubarsch, Birch-Hirschfeld 1891