Smallpox during Pregnancy and Maternal Outcomes, Appendix 2

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Vol. 12, No. 7
July 2006

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•	Additional Data and Discussion
•	Appendix 2 References
•	Appendix 2 Table 1
•	Appendix 2 Table 2
•	Appendix 2 Table 3
•	Appendix 2 Table 4
•	Appendix 2 Table 5
•	Appendix 2 Table 6
•	Appendix 2 Table 7
•	Appendix 2 Table 8
•	Appendix 1
•	Back to article

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Smallpox during Pregnancy and Maternal Outcomes

Hiroshi Nishiura*†
*University of Tübingen, Tübingen, Germany; and †Hiroshima University, Hiroshima, Japan

Appendix 2 Additional Data and Discussion

Additional Data and Results

Appendix 2 Tables 1 and 2 stratify case fatalities and the proportion of miscarriage or premature birth by the clinical classification of smallpox. Appendix 2 Tables 3 and 4 compare the frequency of death among pregnant and nonpregnant patients and stratify the frequency by vaccination history.

Appendix 2 Table 5 shows the frequency of miscarriage or premature birth by clinical stage of smallpox among 27 patient in Philadelphia in 1878 (9); all patients miscarried or delivered prematurely at the given date of the illness. Fourteen patients (51.9%) miscarried or delivered prematurely within 5 days after rash appeared, while the frequency among the remainder showed a long-tailed distribution. Appendix 2 Tables 6–8 provide anonymous individual records of 46, 19, and 23 pregnant smallpox patients in Philadelphia (10), Paris (5), and New South Wales (7), respectively. The investigated variables differed by outbreak.

Supplementary Discussion: Validity and Reliability

A few specific limitations of this study must be addressed. The first is related to the underdiagnosis of pregnancy, especially in the early gestational period. Moreover, the definition of pregnancy-related deaths is difficult to grasp, even at present (11). Whereas this limitation could have led to overestimation of miscarriage, case fatality is not thought to have been substantially influenced, especially since the sample size was large. Second, regarding the reliability of the data, some of the earliest epidemiologic studies were performed before maturation of both the epidemiologic and statistical methods used in current epidemiologic observations. For example, technical problems arose when precise epidemiologic interpretation was needed: 1) adjusting confounding variables was extremely difficult, and I refrained from further stratifying for adjustment or multivariate analysis with the limited number of cases, and 2) the cases classified as variola sine eruptione shown here did not follow virologic confirmation, and diagnosis of this type was made mainly on the basis of probable contacts. Nevertheless, other types of variola major can be confidently diagnosed compared to other infectious diseases, and historical records remain a useful tool as long as the literature appropriately documents the necessary data. This study was motivated by the relatively high reliability of diagnosis and determination of both fatality and miscarriage or premature birth, obvious events compared to fetal vaccinia, which is extremely difficult to diagnose, and fetal and neonatal outcomes, which could be biased by progress in obstetrics and medicine on a whole. Although adhering to formal methods of metaanalysis and showing combined estimates of maternal outcomes with adjustment was difficult, this study successfully confirmed that smallpox is more severe with pregnancy and characterized several features of maternal outcomes.

Appendix 2 References

Meyer L. Über Pocken beim weiblichen Geschlecht. Beiträge zur Geburtshülfe und Gynäkologie / hrsg. von d. Gesellschaft für Geburtshülfe in Berlin (Berlin: Crede). 1873;2:186–98.
Sangregorio G. Vaiuolo e gravidanza. Cenni statistici (1). Guardia Ostetrica di Milano. I Morgagni. 1887;29:793–6.
van der Willigen AM. Pokken in de Zwangerschap, 80 gevallen van variolae gravidarum. Ned Tijdschr Geneeskd. 1895;11:485–99.
Charpentier JB. Variole et vaccine dans la grossesse [thesis]. Paris: Université de Paris; 1900.
Queirel. Variole et grossesse. Annales de Gynecologie et d'Obstetrique. 1907;4:137–47.
Rao AR. Haemorrhagic smallpox: a study of 240 cases. J Indian Med Assoc. 1964;43:224–9.
Robertson DG. Small-pox epidemic in New South Wales, 1913. Melbourne: issued under the authority of the Minister for Trade and Customs; 1914.
Rao AR. Smallpox. Bombay: Kothari Book Dept; 1972.
Fenner F, Henderson DA, Arita I, Ladnyi ID. Smallpox and its eradication. Geneva: World Health Organization; 1988 [cited 2006 May 4]. Available from http://whqlibdoc.who.int/smallpox/9241561106.pdf
Welch WM. Smallpox in the pregnant woman and in the foetus. Philadelphia Medical Times. 1877–1878;8:390–8.
Deneux-Tharaux C, Berg C, Bouvier-Colle MH, Gissler M, Harper M, Nannini A, et al. Underreporting of pregnancy-related mortality in the United States and Europe. Obstet Gynecol. 2005;106:684–92.

Table 1. Case fatality among pregnant women with smallpox by clinical types of variola major, according to data from 19th- and early 20th-century outbreaks*

Reference	Hemorrhagic		Confluent		Discrete		VSE

	D/C	CF (95% CI)	D/C	CF (95% CI)	D/C	CF (95% CI)	D/C	CF (95% CI)

Meyer (1), 1868–1872	13/13	100.0 (NC)	9/26	34.6 (16.3–52.9)	–	–	0/37	0.0 (NC)
Sangregorio (2), 1887	3/3	100.0 (NC)	20/22	90.9 (78.9–100.0)	3/40	7.5 (0.0–15.7)	0/7	0.0 (NC)
van der Willigen (3), 1893–1894	6/6	100.0 (NC)	4/4	100.0 (NC)	2/10	20.0 (0.0–44.8)	0/60	0.0 (NC)
Charpentier (4), 1898	13/13	100.0 (NC)	17/34	50.0 (33.2–66.80	4/45	8.9 (0.6–17.2)	–	–
Queirel (5), 1906	8/8	100.0 (NC)	2/3	66.7 (13.3–100.0)	0/8	0.0 (NC)	–	–
Rao (6), 1959–1962	14/14	100.0 (NC)	12/32	37.5 (20.7–54.3)	0/48	0.0 (NC)	–	–

Hemorrhagic, widespread hemorrhages in the skin and mucous membranes; confluent, confluent rash on the face and arms; discrete, areas of normal skin visible between pustules, even on the face; VSE, variola sine eruptione, fever without rash caused by variola virus, also known as varioloid (8,9*); D/C, Smallpox deaths/cases; CF, case fatality; CI, confidence interval; NC, not calculable.

Table 2. Miscarriage or premature birth among pregnant women with smallpox by clinical types of variola major, according to data from 19th- and early 20th-century outbreaks

Reference	Hemorrhagic		Confluent		Discrete		VSE

	L/C	PL (95% CI)	L/C	PL (95% CI)	L/C	PL (95% CI)	L/C	PL (95% CI)

Meyer (1), 1868–1872	13/13	100.0 (NC)	14/26	53.8 (34.7–73.0)	–	–	4/37	10.8 (0.8–20.8)
Sangregorio (2), 1887	3/3	100.0 (NC)	17/22	77.3 (59.8–94.8)	10/40	25.0 (11.6–38.4)	1/7	14.3 (0.0–40.2)
Charpentier (4), 1898	13/13	100.0 (NC)	18/34	52.9 (36.2–69.7)	9/45	20.0 (8.3–31.7)	–	–
Queirel (5), 1906	8/8	100.0 (NC)	3/3	100.0 (NC)	0/8	0.0 (NC)	–	–

Hemorrhagic, widespread hemorrhages in the skin and mucous membranes; confluent, confluent rash on the face and arms; discrete, areas of normal skin visible between pustules, even on the face; VSE, variola sine eruptione, fever without rash caused by variola virus, also known as varioloid (8,9*); L/C, miscarriage or premature birth/cases; PL, proportion of miscarriage or premature birth; CI, confidence interval; NC, not calculable.

Table 3. Comparison of the frequency of deaths among pregnant and nonpregnant patients, according to data from 19th- and early 20th-century outbreaks*

Reference	Nonpregnant		Pregnant		p value*	OR (95% CI)†

	Cases	Deaths	Cases	Deaths

Meyer (1), 1868–1872	1116	163	76	23	<0.01	2.5 (1.5–4.3)
van der Willigen (3), 1893–1894	352	39	80	12	0.33	1.4 (0.7–2.8)
Rao (6), 1959–1962	348	29	94	26	<0.01	4.2 (2.3–7.6)

*2-sided.
†OR, odds ratio; CI, confidence interval.

Table 4. Comparison of the frequency of deaths stratified by vaccination history, according to data from 19th- and early 20th-century outbreaks

Reference	Unvaccinated		Vaccinated		p value*	OR (95% CI)†

	Cases	Deaths	Cases	Deaths

Welch (10), 1878	7	7	39	7	<0.01	NC
van der Willigen (3), 1893–1894	2	2	78	10	0.02	NC
Rao (6), 1959–1962	12	9	82	17	<0.01	11.5 (2.8–47.1)

*2-sided.
†OR, odds ratio; CI, confidence interval; NC, not calculable.

Table 5. Frequency of miscarriage or premature birth with smallpox by clinical stage of symptoms, Philadelphia, 1878 (10)

Stage of illness	n

Prodromal period	1
Eruption day 1	4
Day 2	2
Day 3	3
Day 4	2
Day 5	2
Days 6–10	1
Days 11–20	1
Days 21–30	3
Day 31 onwards	3
No precise description	5
Total	27

Table 6. Anonymous records of 46 pregnant women with smallpox, Philadelphia, 1878 (10)

Patient identification	Age	Classification*	Vaccination history	Gestational age (mo)	Dates of smallpox at miscarriage or premature birth†	Maternal outcome

1	23	Variola	Vaccinated	4	Day 4 of eruption	Recovered
2	27	Variola	Vaccinated	3	Day 4 of eruption	Died
3	35	Varioloid	Vaccinated	3	Day 18 of eruption	Recovered
4	21	Variola	Vaccinated	2	Week 3	Recovered
5	32	Varioloid	Vaccinated	5	After discharge	Recovered
6	24	Variola	Vaccinated	8	Day 1 of fever	Died
7	30	Variola	Vaccinated	5.5	Day 1 of fever	Recovered
8	26	Varioloid	Vaccinated	3	5 wks after discharge	Recovered
9	22	Variola	Unvaccinated	7.5	Day 1 of eruption	Died
10	35	Varioloid	Vaccinated	3		Recovered
11	15	Variola	Unvaccinated	3		Died
12	23	Varioloid	Vaccinated	2	Day 10 after discharge	Recovered
13	22	Varioloid	Vaccinated	5.5	Day 26 of eruption	Recovered
14	18	Varioloid	Vaccinated	8.5	Day 9 of eruption	Recovered
15	21	Varioloid	Vaccinated	3		Recovered
16	29	Varioloid	Vaccinated	5		Died
17	30	Varioloid	Vaccinated	9	Early stage	Recovered
18	30	Variola	Vaccinated	5.5	Day 2 of eruption	Died
19	27	Varioloid	Vaccinated	7	Day 2 of eruption	Recovered
20	27	Variola	Vaccinated	3	Day 1 of eruption	Died
21	26	Variola	Unvaccinated	7 or 8	Day 3 of eruption	Died
22	32	Varioloid	Vaccinated	8		Recovered
23	20	Variola	Unvaccinated	6		Died
24	17	Variola	Unvaccinated	4	6 wks after discharge	Recovered
25	24	Variola	Vaccinated	3	6 wks after discharge	Died
26	19	Varioloid	Vaccinated	6	1 mo after discharge	Recovered
27	26	Variola	Vaccinated	5	Day 3 of eruption	Died
28	22	Varioloid	Vaccinated	3	Day 2 of eruption	Recovered
29	30	Variola	Vaccinated	5.5	Day 4 of eruption	Recovered
30	20	Varioloid	Vaccinated	8	Day 1 of eruption	Recovered
31	25	Variola	Vaccinated	5.5	Day 1 of eruption	Recovered
32	25	Variola	Vaccinated	4	Day 5 of eruption	Recovered
33	45	Varioloid	Vaccinated	6		Recovered
34	19	Varioloid	Vaccinated	6		Recovered
35	26	Variola	Unvaccinated	7.5	Day 1 of eruption	Died
36	18	Varioloid	Vaccinated	3.5	Day 1 of eruption	Recovered
37	26	Variola	Unvaccinated	8	Early stage	Died
38	41	Varioloid	Vaccinated	8	Day 3 of eruption	Recovered
39	28	Varioloid	Vaccinated	4.5		Recovered
40	30	Varioloid	Vaccinated	6		Recovered
41	25	Varioloid	Vaccinated	3	Day 1 of eruption	Recovered
42	20	Variola	Vaccinated	6.5	Day 5 of eruption	Died
43	22	Varioloid	Vaccinated	5		Recovered
44	28	Varioloid	Vaccinated	6		Recovered
45	21	Varioloid	Vaccinated	5	During maturation	Recovered
46	25	Varioloid	Vaccinated	6	During maturation	Recovered

*Variola includes a rash (hemorrhagic, confluent, and discrete), while varioloid is equivalent to variola sine eruptione.
†Clinical stage of smallpox when miscarriage or premature birth occurred. Those reports that did not document the outcomes have been left blank.

Table 7. Anonymous records of 19 pregnant women with smallpox, Paris, 1906 (5)

Patient identification	Gestational age (mo)	Miscarriage or premature birth*	Maternal outcome

1	3	Yes	Died
2	4	Yes	Died
3	5	Yes	Died
4	5	Yes	Died
5	5	Yes	Died
6	6	Yes	Died
7	6	Yes	Died
8	7	No	Died
9	2	Yes	Recovered
10	2.5	No	Recovered
11	3	Yes	Died
12	4	Yes	Died
13	5	No	Recovered
14	6	Yes	Recovered
15	6.5	No	Recovered
16	7	No	Recovered
17	8	No	Recovered
18	9	No	Recovered
19	9	No	Recovered

*Distinction between miscarriage and premature birth was not made.

Table 8. Anonymous records of 23 pregnant women with smallpox, New South Wales, 1913 (7)

Patient identification	Age (y)	Previous miscarriage?	Gestational age (mo)	Miscarriage or premature birth?

1	20	No	3	Yes
2	27	Yes	6	Yes
3	19	No	4	Yes
4	34	No	4	Yes
5	20	No	7.5	No
6	29	No	8	No
7	35	No	5	No
8	25	No	7	No
9	24	Yes	7	No
10	25	No	7	No
11	22	No	8	No
12	26	No	8	No
13	28	No	5	No
14	30	No	Late stage	Yes
15	28	No	6	No
16	21	No	8	No
17	32	No	3.5	Yes
18	26	No	2	No
19	38	No	7	No
20	24	No	7	No
21	24	No	3.5	Yes
22	20	No	8	0
23	27	Yes	6	Yes

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Hiroshi Nishiura, Department of Medical Biometry, University of Tübingen, Westbahnhofstrasse 55, Tübingen, D-72070, Germany; email: nishiura.hiroshi@uni-tuebingen.de

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