. Author manuscript; available in PMC: 2021 Feb 1.

Published in final edited form as: J Pediatr. 2019 Dec 4;217:98–109.e8. doi: 10.1016/j.jpeds.2019.10.046

Table III.

Characteristics of included studies

Study nos.	Publication	Year	Country	Study design	Study period^*	Subject source	Matching/adjusting variables	Sample size	Investigated exposure (agents)	Measurement method and exposure timing

#1	Francis et al¹⁵	2015	USA	Nested case- control^†	1982–2006 (birth year)	Population based	Birth date, race and sex/race, age, and sex	268 ALL and 270 controls	CMV,^‡ EBV (DNA)	Digital droplet PCR in neonatal blood spot
#2	Bogdanovic et al¹⁷	2016	Sweden	Case-control	1992–2006	Population based	Age or birthdate and birthplace	95 ALL and 95 controls	HHV-6,^‡ parvovirus B19, HERV (DNA)	Next-generation sequencing in pooled samples and real-time PCR in individual samples of neonatal blood spots
	Gustafsson et al³¹	2012						50 ALL and 100 controls	KIPyV, WUPyV, MCPyV (DNA)	Nested PCR in neonatal blood spots
	Honkaniemi et al³⁰	2010						243 ALL and 484 controls	Species C adenovirus (DNA)
#3	Bzhalava et al¹⁶	2016	Sweden	Nested case-control	1977–2005	Population based	None	26 ALL cases and 47 controls	Anelloviridae,^‡ viruses from environmental samples, papillomaviridae, “unclassified” viruses (DNA)	Next generation sequencing in first trimester maternal sera
#4	Kumar et al³⁷	2014	India	Case-control	2008–2012	Hospital based	Age, sex and residency	132 leukemia and 132 controls	Infection^‡	Self-report interview on exposure during pregnancy
#5	Tedeschi et al²¹	2009	Finland and Iceland	Nested case-control	1983–2006	Population based	Mother’s country, age at serum sampling, date of specimen collection and children’s birth date and sex/birth order and sibship size	705 leukemia (561 ALL) and 2105 controls	EBV (VCA IgM,^‡ EA and ZEBRA IgG)	ELISA in first trimester maternal sera
#6	Vasconcelos et al³⁹	2008	USA	Case-control	1995–2002	Population based	Birth date, sex, ethnicity, maternal	89 ALL and 100 controls	Species C adenoviruses (DNA)	Seminested PCR in neonatal blood spots
#6	Kwan et al³²	2007					county of residence at birth, or plus maternal race/household income, maternal education, and maternal age at the birth of the child	365 leukemia (311 ALL) and 460 controls	Influenza/pneumonia,^‡ urinary tract infection, sexually transmitted diseases	Self-report interview on exposure from 3 months before pregnancy through the end of pregnancy
#7	Gustafsson et al²⁹	2007	Sweden	Case-control	1980–2001	Hospital based	Birthdate or age and birthplace	49 ALL and 47 controls	Species C adenoviruses DNA^‡	Nested PCR in neonatal blood spots
	Gustafsson et al²⁸	2006						48 ALL and 46 controls	CMV (DNA)
	Bogdanovic et al²⁷	2004						54 ALL and 47 controls	HHV-6, EBV (DNA)
	Isa et al²⁶	2004						54 ALL and 50 controls	Parvovirus B19 (DNA)
	Priftakis et al²⁵	2003						54 ALL and 37 controls	BKV, JCV (DNA)
#8	Leppik et al³³	2007	Finland and Iceland	Nested case-control	1975–1997	Population based	Mothers’ country, age at serum sampling, date of specimen collection and children’s birth date and sex	30 leukemia and 30 controls	TT virus (DNA)	PCR in first trimester maternal sera
	Tedeschi et al²⁰	2007						343 leukemia (304 ALL) and 973 controls	EBV (VCA IgM, EA IgG and IgM, ZEBRA IgG and IgM)	ELISA in first trimester maternal sera
	Lehtinen et al⁴⁰	2005						402 leukemia (341 ALL) and 1212 controls	Mycoplasma pneumoniae, chlamydia trachomatis, helicobacter pylori (IgM and IgG)
	Lehtinen et al⁴¹	2003						403 leukemia (342 ALL) and 1216 controls	HHV-6 (IgM,^‡ IgG); CMV, EBV VCA (IgM, IgG)
#9	Naumburg et al⁴²	2002	Sweden	Case-control	1973–1989	Population based	Sex and birth in the same year and month/adjustments for potential confounders only marginally influenced the risk estimates, such as mothers age, parity, mode of delivery (vaginal or caesarian), maternal smoking, elapsed time from rupture of the membranes to delivery, gestational age at birth, birth weight, birth weight for gestational age, and type of birth (single or multiple).	652 leukemia (578 ALL) and 652 controls	Infection,^‡ lower genital tract infection, urinary tract infection, other infection	Data extracted from medical record on exposure during pregnancy
#10	Dockerty et al⁴⁴	1999	New Zealand	Case-control	1990–1993	Population based	None	121 leukemia and 303 controls	Influenza,^‡ cystitis or kidney infection, cold sores/oral herpes, any other infection	Self-reported questionnaire on exposure during pregnancy or in the 3 months before the pregnancy
#11	McKinney et al⁴³	1999	UK	Case-control	1991–1994	Population based	Age, sex and health board area of residence	144 leukemia (124 ALL) and 271 controls	Any infection,^‡ respiratory tract infection, viral infection, genitourinary infection, fungal infection	Data abstracted from medical record on exposure during pregnancy
#12	Roman et al⁴⁵	1997	UK	Case-control	1962–1992	Hospital based	Hospital catchment area of birth, sex and year and month of birth	143 leukemia (113 ALL) and 286 controls	Viral infection,^‡ influenza, vulvar warts, herpes simplex, rubella	Data abstracted from medical record on exposure during pregnancy
#13	Buckley et al^24,§	1994	USA and Canada	Case-control	1982–1991	Hospital based	Birth year, race, income, geographical region and family size	404 ALL and 440 community controls	Infection	Self-administered questionnaire on exposure during pregnancy
#14	Gardner et al⁴⁶	1990	UK	Case-control	1950–1985	Population based	Sex, birth date and residence	35 leukemia and 103 local controls	Viral infection^‡	Self-reported questionnaire on exposure during pregnancy
#15	McKinney et al^23,§	1987	UK	Case-control	1980–1983	Population based	Sex and age	171 leukemia and 342 controls	Influenza, urinary tract infection	Self-reported interview on exposure during pregnancy
#16	Fine et al⁴⁸	1985	UK	Prospective and retrospective cohorts	1946–1972	Population based	Sex and date and area of birth	6 leukemia (4 ALL) and 5039 nonleukemia	Viral infection,^‡ influenza, varicella, herpes zoster, mumps, rubella, measles, infectious hepatitis, CMV, miscellaneous viruses	Self-reported interview or medical records from general practice, local authority, hospital and virus laboratory sources
#17	Van Steensel-Moll et al⁴⁷	1985	Netherlands	Case-control	1973–1980	Population based	Birth date, sex and municipality/age and sex	519 ALL and 507 controls	Viral infections^‡	Self-administered questionnaires on exposure during pregnancy
#18	Madden et al⁴⁹	1983	USA	Nested case-control	1959–1966	Hospital based	Maternal age, race, date of delivery, hospital, socioeconomic relationships	7 leukemia deaths and 7 controls	BKV IgM	ELISA in maternal sera series
#18	Heinonen et al⁵⁰	1973		Prospective cohort			None	8 leukemia (including 2 ALL^¶) deaths and 50 889 controls	Spontaneous viral infections^‡	Self-reported interview and review of hospital and other records on exposure during pregnancy
#19	Bithell et al²²	1973	UK	Case-control	1953–1967	Population based	None	4219 leukemia deaths and 9074 controls	Influenza,^‡ rubella, varicella, other virus infections	Self-reported interviews and review of antenatal records (whenever possible) on exposure during pregnancy
#19	Stewart et al³	1958					Age (birth in the same month or half year), sex, locality	619 leukemia deaths and 619 controls	Genitourinary tract, virus infection, rubella, mumps, herpes zoster, infective hepatitis
#20	Fedrick and Alberman⁴	1972	UK	Prospective cohort	1958	Population based	Birth date	11 leukemia (10 ALL^**) and 17 739 nonleukemia	Influenza^‡	Self-reported questionnaires on exposure during pregnancy

BKV, BK virus; EBV, Epstein-Barr virus; EA, early antigen; ELISA, enzyme-linked immunosorbent assay; HHV-6, human herpesvirus type 6; HERV, human endogenous retroviruses; JCV, JC virus; KIPyV, Karolinska Institutet polyomavirus; MCPyV, Merkel cell polyomavirus; PCR, polymerase chain reaction; TT virus, Torque teno viruses; VCA, viral capsid antigen; WUPyV, Washington University polyomavirus.

Diagnosis year of cases for case-control study or recruitment year of mothers or babies for cohort study.

^†

This study was categorized as nested case-control study because the cases and controls were drawn from the same source population at birth (Childhood Cancer Record Linkage Program).

^‡

Variables that were selected as the “proxy of any infection” variable in qualitative summary in Figure 2.

^§

The studies of Buckley et al²⁴ in 1994²⁴ and McKinney et al²³ in 1987²³ were not included in any meta-analysis because the effect estimate or 95% CI was not reported and could not be computed.

^¶

Two cases of “leukemia, lymphoblastic” or “leukemia, lymphocytic” in the nonexposed group were treated as ALL.

^**

One case of lymphoblastic leukemia in the non-exposed group was treated as ALL.