Human Papillomavirus Infection as a Possible Cause of Spontaneous Abortion and Spontaneous Preterm Delivery

Table 1

Characteristics of included studies.

References	Country	Inclusion criteria	Gestational age at sample collection (weeks)	Examined tissue type	Sample size	HPV prevalence%	HPV detection method	Study quality
								Study strengths	Potential biases
[34]	Korea	Pregnant women; healthy, ≥18 years of age, sonographically confirmed intrauterine pregnancy	1st, 2nd, or 3rd trimester or postpartum	Cervix	Total: 960; 1st trimester: 380; 2nd trimester: 193; 3rd trimester: 195; Postpartum: 192	Total: 24.3; 1st trimester: 20.5; 2nd trimester: 34.2; 3rd trimester: 23.1; Postpartum: 22.9	DNA chip	Large cohort, multivariant logistic regression analysis, separate analysis for trimesters	Sample collection at different time points, including women with abnormal pap smear
[35]	Korea	PD; healthy, <37 weeks of gestation	6-week postpartum	Cervix	45	15.6	HCA	Multivariant logistic regression analysis	Small sample size, postpartum sampling only, HCA sensitivity limited to 13 HPV-types
[36]	Mexico	SA: healthy, curettage up to week 20; ND: healthy, attending for delivery at term with viable products	SA: <20; ND: before delivery	Cervix	SA: 139; ND: 138	SA: 24.4; ND: 15.2	PCR	Large cohort, risk analysis	Comparison of SA (first trimester) with ND (at term), HPV-related disease history unclear
[37]	Korea	Pregnant women; healthy, singleton, in first trimester	Cervix: 1st, 2nd, and 3rd trimester, postpartum; Placenta, umbilical cord blood: at birth	Cervix, placenta, umbilical cord blood	Cervix: 153; Placenta: 152	Cervix: 24; Placenta: 3.3; Umbilical cord blood: 1.3	DNA chip	Large cohort, longitudinal follow-up, multivariant logistic regression analysis	Sample collection from cervix at different time points
[38]	Poland	Pregnant women; singleton, normal cervical smear	33–41	Cervix	135	16.3	PCR	Large cohort, multivariant logistic regression analysis, confirmation by sequencing	Vaginal and cesarean deliveries included, potential contamination problem (HPV11 present in all positive samples)
[23]	Korea	Pregnant women; healthy, over 36 weeks of gestation	>36	Cervix, placenta, umbilical cord blood	469	Cervix: 15.4; Placenta: 0; Umbilical cord blood: 0	DNA chip	Large cohort, confirmation by in situ hybridization	Vaginal and cesarean deliveries included Umbilical cord blood and placenta were collected from HPV positive mothers
[39]	China	Pregnant women; healthy, asymptomatic	22.5–26.7	Cervix	3139	13.4	DNA chip	Large cohort, logistic regression analysis	Vaginal and cesarean deliveries included, women with abnormal cervical cytology included
[40]	Netherlands	Pregnant women; NA	1st, 2nd, and 3rd trimester, postpartum	Cervix	51	21.6	PCR	Matched groups, detection method with high analytical sensitivity	Small sample size, self-sampling, sample collection at different time points
[41]	Korea	Pregnant women; healthy, over 36 weeks of gestation	>36	Cervix	291	18.9	DNA chip	Large cohort, stratified analysis to test for confounding	Women with abnormal cervical cytology included, vaginal and cesarean deliveries included
[42]	Finland	Pregnant women; healthy, in third trimester	3rd trimester, at birth	Cervix, placenta, umbilical cord blood	Cervix: 329; Placenta: 306; Umbilical cord: 311	Cervix: 16.4; Placenta: 4.2; Umbilical cord blood: 3.5	PCR	Large cohort, regression analysis, multimetrix assay for HPV detection, pap smear at baseline	—
[43]	Poland	SA: healthy; ND: healthy, delivering at term	SA: 6–16; ND: at birth	Aborted products of conception, placenta	SA: 51; ND: 78	SA: 17.7; ND: 24.4	PCR	—	Small sample size, comparison of SA with ND, HPV-related disease history unclear
[44]	Mexico	Pregnant women; healthy, in third trimester, delivering at term	3rd trimester	Cervix, placenta	72	Cervix: 75; Placenta: 47.2	PCR	PCR process was blinded	Potential contamination problem (HPV18 present in all positive placenta samples), vaginal and cesarean deliveries included
[45]	Lithuania	Pregnant women; NA	1st and 3rd trimester	Cervix	1st trimester: 213; 3rd trimester: 146	1st trimester: 17.8; 3rd trimester: 10.3	PCR	Large cohort, risk analysis, separate analysis for trimesters	Big proportion with history of gynecological diseases, exclusion of 67 women due to change of residency/miscarriage/ premature delivery, no inclusion and exclusion criteria, commercial HPV PCR kit
[46]	Japan	Pregnant women; NA	1st, 2nd, or 3rd trimester or postpartum	Cervix	151	35.8	PCR	Large cohort, pap smear at study entry	Sample collection at different time points, unclear how and when women deliver
[21]	USA	PD; <37 weeks of gestation, available HPV-test results	NA	Cervix	70	67.1	HCA	Risk analysis (age, race), data from over 11 years	Sampling method and time point not mentioned, study including African Americans, HCA restricted to 13 HPV-types only
[47]	Turkey	Pregnant women; NA	18–22	Cervix	134	2.2	PCR	Large cohort	22 with abnormal ultrasound findings, other virus types being in focus, HPV-related disease history unclear, no inclusion and exclusion criteria, outpatient clinic (low socioeconomic group)
[32]	Belgium	Pregnant women; assigned for abdominal CVS, mainly due to high risk for chromosomal abnormalities	11–13	Placenta	35	5.7	PCR	Transabdominal sampling (no birth canal contamination), highly sensitive detection method, confirmation by sequencing	Small sample size, highly selected group of women, limited amount of placenta material (actual HPV prevalence higher?), HPV-related disease history unclear
[48]	USA	Pregnant women; healthy, in third trimester, 18 and above	3rd trimester	Cervix	333	28	PCR	Large cohort, logistic regression analysis, confirmation by sequencing	Vaginal and cesarean deliveries included, unclear if deliveries are at term, 25% of women with history of HPV-related lesions
[49]	Brazil	Pregnant women; NA	2–37	Cervix	371	35.3	HCA	Large cohort, multivariant logistic regression analysis	Inclusion at ambulatories for patients suspected to infectious diseases, no inclusion and exclusion criteria, sample collection at different time points, women with genital warts included
[50]	Brazil	Pregnant women; NA	NA	Cervix	40	25	PCR	—	Small sample size, inclusion at outpatient clinic (low socioeconomic group), no inclusion and exclusion criteria, HPV-related disease history unclear, sampling time point not mentioned
[51]	Spain	Pregnant women; unselected	29–33	Cervix	828	6.5	PCR	Large cohort, multivariant logistic regression analysis	Goal to find HPV positive women for prospective cohort study on mother-to-child transmission, HPV-related disease history unclear, no inclusion and exclusion criteria, vaginal and cesarean deliveries
[27]	Finland	Pregnant women; third trimester	31.6–42.5	Placenta, Umbilical cord blood	Placenta: 306; Umbilical cord blood: 311	Placenta: 4.2; Umbilical cord blood: 3.5	PCR	Large cohort, multivariant regression analysis, pap smear at study entry, confirmation by sequencing	Included women delivering before week 37, part of women showing genital warts or cervical lesions, no HPV status examination before recruitment
[20]	USA	PD: spontaneous, <37 weeks of gestation; ND: delivering at term	PD: 21–36; ND: 37–42	Placenta	PD: 30; ND: 30	PD: 50; ND: 20	PCR	Comparison of PD to ND (best possible control), confirmation by sequencing	Small sample size, study including mostly African Americans, HPV-related disease history unclear, type-specific PCR only
[29]	USA	SA: singleton, in second trimester; IA: singleton, for congenital anomalies or maternal medical indications	16.7–23.6	Placenta	SA: 84; IA: 16	SA: 57; IA: 31	PCR	Multivariable logistic regression analysis, comparison of SA to IA (best possible control), confirmation by sequencing	Small sample size, imbalance between cases and controls, study including African Americans, HPV-related disease history unclear, gestational age of controls being greater
[52]	Japan	Pregnant women; healthy, unselected	1st, 2nd, or 3rd trimester	Cervix	1183	12.5	PCR	Large cohort	HPV-related disease history unclear, sample collection at different time points
[53]	USA	Pregnant women; clinically indicating amniocentesis, intact membranes	NA	Amniotic fluid	142	0	PCR	Large cohort, transabdominal sampling (no birth canal contamination)	HPV-related disease history unclear, sampling time point not mentioned, highly selected group of women, unclear how/when they deliver
[54]	Mexico	Pregnant women; healthy	1st, 2nd, or 3rd trimester	Cervix	274	37.1	HCA	Large cohort, unconditional/conditional logistic regression	Self-sampling, HPV-related disease history unclear, sample collection at different time points, HCA restricted to 13 HR-types
[55]	China	Pregnant women; asymptomatic (cervical)	1st, 2nd, or 3rd trimester	Cervix, amniotic fluid, umbilical cord blood	116	Cervix: 36.2	PCR	Large cohort	Sample collection at different time points
[13]	Austria	Pregnant women; healthy, uncomplicated pregnancy, undergoing cesarean section	37.1–40.2	Cervix, placenta, amniotic fluid, umbilical cord blood	153	Cervix: 36.6; Placenta: 5.2; Amniotic fluid: 0; Umbilical cord blood: 0	HCA, PCR	Large cohort, univariant/multivariant logistic regression analysis	Highly selected group of women, placenta swabs (quality of material)
[56]	USA	Pregnant women; unselected	35 and 39	Cervix	577	29	PCR	Large cohort, logistic regression analysis, confirmation by sequencing, pap smear at study entry	No inclusion and exclusion criteria, women with history of HPV-related lesions included
[28]	Croatia	SA; normal cervix	4–19	Placenta	108	7.4	PCR	Large cohort, only women with normal cervix	49.1% having a miscarriage before, 35.2% having abnormal karyotype, possible contamination due to curettage, positive results only with HPV16 and 18 specific primers
[57]	China	Pregnant women; unselected, regardless of sexual history or cervical disease	1st, 2nd, or 3rd trimester	Cervix	308	10.1	PCR	Large cohort, confirmation by sequencing, age-matched controls	Sample collection at different time points, inclusion of women regardless of sexual history or cervical diseases
[22]	Austria	Pregnant women; assigned for CVS or placental biopsy	9.6–31.3	Cervix, placenta	Cervix: 179; Placenta: 147	Cervix: 24.6; Placenta: 0	HCA, PCR	Large cohort, univariant/multivariant logistic regression analysis, transabdominal sampling (no birth canal contamination)	Highly selected group of women, unusual PCR primers (E6), unclear how/when they delivered, analysis of placenta by PCR, cervix by HCA
[58]	France, Switzerland, Germany	Pregnant women; assigned for amniocentesis due to maternal or fetal abnormalities	14–25	Amniotic fluid	238	12	PCR, Southern blot	Large cohort, transabdominal sampling (no birth canal contamination), confirmation by Study strength	Highly selected group of women, HPV-related disease history unclear, samples collected in three countries, unclear how/when they deliver
[59]	Italy	Pregnant women; healthy, negative pap smear at first trimester	36–39	Cervix	711	5.2	PCR	Large cohort, pap smear at study entry, no history of HPV-related lesions	Sampling method not mentioned, vaginal and cesarean deliveries
[60]	Greece	SA; <20 weeks of gestation	6–20	Aborted product of conception	102	0	PCR	Large cohort	11 women have had previous SA, 3 cases with other diseases, GP5/6 primer (low sensitivity?), HPV-related disease history unclear
[61]	China	Pregnant women; singleton	36–40	Cervix	301	22.6	PCR	Large cohort, confirmation by Study strength	Study including vaginal and cesarean deliveries, women with abnormal pap smear included, used specific E6 PCR primers only
[62]	France, Germany	SA: NA; IA: for social indication	NA	Aborted product of conception	SA: 27; IA: 1	SA: 70.4; IA: 100	PCR	—	Small sample size, HPV-related disease history unclear, sampling time point not mentioned, no inclusion and exclusion criteria, PCR primer with low sensitivity
[63]	Italy	Pregnant women; healthy, negative pap smear at entry	36–39	Cervix	752	5.4	PCR	Large cohort, control for confounders, logistic regression analysis, confirmation by Study strength	Sampling method not mentioned
[64]	Finland	Pregnant women; healthy	At birth	Cervix	86	30.2	PCR	Confirmation by Study strength and sequencing	Possible sampling error, contamination, multiple HPV infection, inclusion of women with signs of cervical HPV infection, vaginal and cesarean deliveries
[18]	USA	SA and IA; first trimester	1st trimester	Aborted product of conception	SA: 25; IA: 15	SA: 60; IA: 20	PCR	Comparison of SA to IA (best possible control), confirmation by dot blot hybridization	Small sample size, possible contamination from cervix and vagina, HPV-related disease history unclear
[65]	USA	Pregnant women; healthy	NA	Cervix	114	34.2	Southern blot	Large cohort, logistic regression analysis	History of CIN not used as exclusion criteria, sampling time point not mentioned, study mostly including African Americans and Hispanics, Bronx → low socioeconomic group, Southern Blot (HPV11, 16, 18 only), unclear how/when they deliver
[66]	Germany	Pregnant women; uncomplicated pregnancies	1st, 2nd, and 3rd trimester, postpartum	Cervix	108	13.9	HCA	Large cohort, logistic regression analysis, age-frequency matched controls	Specimens instead of patients, sample collection at different time points, commercial HPV detection kit (6 HPV-types only)
[67]	Hungary	Pregnant women; cytologically and colposcopically healthy	1st, 3rd trimester, postpartum	Cervix	39	31	PCR	Cytologically and colposcopically healthy women	Small sample size, 8 deliveries being preterm, HPV-related disease history unclear, sample collection at different time points, outpatient clinic → low socioeconomic group
[68]	USA	Pregnant women; healthy, in first trimester, ≥18 years of age	1st trimester	Cervix	245	31	HCA	Large cohort, univariant risk analysis/multiple logistic regression analysis, confirmation by Study strength	Study including African-Americans, HCA sensitivity limited to 14 HPV-types

ND = normal deliveries, PD = preterm deliveries, IA = induced abortion, SA = spontaneous abortion.