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Dispatch
Smallpox during Pregnancy and Maternal Outcomes
Hiroshi Nishiura*†
*University of Tübingen, Tübingen, Germany; and †Hiroshima University, Hiroshima,
Japan
Appendix 1
Methods
Search Strategy
Since most documented large-scale outbreaks of smallpox were
written before the mid-20th century, this study could not follow formal methods
of systematic review, i.e., by using MEDLINE or other databases. Consequently,
this study first tracked selected references in major specialized books (1–4) and articles on smallpox or viral
diseases after the mid-20th century (5–8).
These references (9–12) were
subsequently reviewed, and their references were further tracked, regardless of
language, to search for potentially useful articles. This task was repeated as
many times as necessary until no further references were identified (Appendix 1
Figure). Consequently, references dating back to the 19th century were
reviewed.
Study Selection Criteria
All publications reporting either of the defined maternal
outcomes, i.e., case fatality and miscarriage or premature birth, were
selected. Second, the obtained publications were limited by the following
inclusion criteria: the publication must 1) document >8 smallpox cases
during pregnancy (exclusion of case reports), 2) clarify the time and place of
the outbreak, 3) report an outbreak of variola major
(not variola minor), and 4) explicitly define and
describe either of the outcomes as a major topic of discussion.
Statistical Analysis
Since crude case fatalities and frequencies of miscarriage
and premature birth could be biased by several serious underlying factors,
e.g., vaccination and progress in obstetrics and medicine as a whole, the
heterogeneity of which cannot be methodologically adjusted, interpreting
findings after combining the data after statistical adjustment was deemed
inappropriate in this study. Thus, data analysis did not follow usual methods
of metaanalysis for estimation of combined case
fatality and the proportion of miscarriage and premature birth. Rather, the
outcomes, except overall crude estimates, were investigated by each publication
separately when possible. The χ2 and Fisher exact tests were used to evaluate univariate associations. Confidence intervals (CI) for a proportion, p, were obtained by using the standard error,  , where N is the sample size.
Identification of Historical Records
First, 13 studies were excluded: 8 were clinical case
reports (13–20), 1 did not clarify
the time and place of the outbreak and showed the same number of cases and
deaths documented in another study included for analysis (21), 2 documented variola minor outbreaks
(6,9), and the remaining 2 were
review articles that did not provide outcomes (22,23). Further, a more recent study by Dixon in Tripolitania was
also excluded because only approximate case fatalities (40% and 11% for
pregnant and nonpregnant patients, respectively) were
given (24). Four patients in the New
South Wales report (25) were excluded
from the analyses because disease onset was observed after delivery.
Consequently, as noted in the main text, 19 outbreaks were identified. Half
originated from a review article published in 1932 (10). The original reports were written in Dutch, English, French,
German, and Italian.
Appendix 1 References
- Fenner F, Henderson DA, Arita I, Ježek Z, Ladnyi ID. Smallpox and its eradication. Geneva: World Health Organization.
1988 [cited 2006 May 3]. Available from http://whqlibdoc.who.int/smallpox/9241561106.pdf
- Dixon CW. Smallpox. London:
Churchill; 1962.
- Rao AR. Smallpox. Bombay: Kothari
Book Dept; 1972.
- Hanshaw JB, Dudgeon JA. Viral diseases of the fetus and newborn. Philadelphia:
Saunders; 1978.
- Rao AR, Prahlad I, Swaminathan M, Lakshmi A. Pregnancy and smallpox. J Indian Med Assoc. 1963;40:353–63.
- Megale P, Angulo JJ, Pederneiras CA. Variola minor in Braganca Paulista county, 1956. Observations on the clinical course of variola minor and on pregnancy in women with the disease. Bull Soc Pathol Exot Filiales.
1979;72:11–20.
- Marsden JP. Variola minor; a personal analysis
of 13,686 cases. Bull Hyg (Lond).
1948;23:735–46.
- Saxen L, Cantell K, Hakama M. Relation between smallpox vaccination and outcome of pregnancy. Am J Public Health Nations Health. 1968;58:1910–21.
- Marsden JP, Greenfield CRM. Inherited smallpox. Arch Dis Child. 1934;9:309–14.
- Lynch FW. Dermatologic conditions of the fetus with
particular reference to variola and vaccinia. Arch Derm Syphilol. 1932;26:997–1019.
- Bancroft IR. Clinical observations on variola. Journal of Medical
Research. 1904;11:322–44.
- Voigt L. Über den Einfluss der Pockenkrankheit auf Menstruation, Schwangerschaft, Geburt und Fötus. Sammlung Klinischer Vortraege/Gynaekologie. 1894–1897;112:249–72.
- Lop PA. Variole et vaccine dans la grossesse [thesis]. Paris: Université de Paris; 1893.
- Jenner E. Two cases of Small-pox infection communicated to
the foetus in utero under
particular circumstances, with additional remarks. Medico-Chirurgical
Transactions. 1809;1:269–75.
- Davidson W. Small-pox in utero. Lancet. 1837–1838;2:628.
- Marsden JP, Chir B. Metastatic calcification. Notes
on twins born shortly after an attack of smallpox in the mother. Br J
Child Dis. 1930;27:193–200.
- Rigden G. Influence of maternal small-pox on the fetus. BMJ. 1877;1:229–30.
- Robinson H. Occurrence of confluent
small-pox at the seventh month of pregnancy. BMJ. 1877;1:163.
- Cowie JM, Forbes D. Intrauterine
influence of the fetus in small-pox. BMJ. 1904;1:1485.
- Paranjothy D, Samuel I. Pregnancy associated with haemorrhagic smallpox. J Obstet Gynaecol Br Emp. 1960;67:309–13.
- Pfeiffer L. Behandlung und Prophylaxe der Blattern. Handbuch der speciellen Therapie. Jena (Germany): Fischer; 1894.
- von Jarrier. De la menstruation dans la variole [thesis]. Paris: Université de Paris; 1880.
- von Obermeier. Beiträge zur Kenntnis der Pocken. Virchows Arch.
1872;IV:S345.
- Dixon CW. Smallpox in Tripolitania, 1946: an epidemiological
and clinical study of 500 cases, including trials of penicillin treatment. J Hyg (Lond). 1948;46:351–77.
- Robertson DG. Small-pox epidemic in New
South Wales, 1913. Melbourne, Australia: Minister for Trade and Customs;
1914.
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