Cervical Cancer and Risk for Delivery of Small-for-Gestational Age Neonates

Abstract

Objective:

To determine if cervical intraepithelial neoplasia grade 3 (CIN-3) and cervical cancer are associated with adverse obstetrical outcomes.

Methods:

Women with diagnoses of CIN-3 and cervical cancer were first identified from the University of Pittsburgh Medical Center (UPMC) Network Cancer Registry by using respective ICD-3 codes. Identified records were then linked to the Magee Obstetrical Maternal and Infant (MOMI) database to identify women who subsequently delivered pregnancies at Magee-Womens Hospital. Women with cervical disease were compared with women without known disease to determine the impact of cervical disease on various maternal and neonatal outcomes. The latter group consisted of those women who delivered singleton pregnancies at our institution, as determined by the MOMI database, but who did not have any matching records in the UPMC Cancer Registry. Statistical significance was defined by a p value <0.05.

Results:

We identified CIN-3 (n = 52) and cervical cancer patients (n = 83) who later had documented pregnancies delivered at Magee-Womens Hospital between 1989 and 2006. Women with cervical cancer and CIN-3 were at greater risk to deliver small-for-gestational age (SGA) neonates compared with women without known cervical disease (RR 1.54, 95% confidence interval [CI] 1.0-2.46). A secondary analysis of risk factors for SGA neonates demonstrated a significant association with cervical cancer (p = 0.04). After accounting for variables known to be risk factors for SGA, cervical cancer was associated with a 1.9-fold increased risk of a SGA delivery (OR 1.9, 95% CI 1.1-3.4).

Conclusions:

Cervical cancer is a risk factor for delivery of an SGA neonate in a subsequent pregnancy.

Introduction

Cervical cancer is the second most common cancer among women.¹ The American Cancer Society (ACS) estimated that there were 11,150 new cases of cervical cancer diagnosed in the United States during 2008.² According to the National Cancer Institute's (NCI) Surveillance, Epidemiology and End Results (SEER) program, the average age of cervical cancer diagnosis is 47 years; however, >40% of cases are diagnosed in women ≤44 years of age.³

Up to 48% of reproductive-age women may seek fertility-sparing treatment for cervical cancer.⁴ However, candidates are generally limited to those with early stage disease (IA1 to nonbulky IB1) and to those from developed nations.⁵ Excisional treatment modalities, including cervical conization and radical trachelectomy, are feasible options for the treatment of IA1 and IA2–IB1 nonbulky cancers, respectively.^6

–9 Ablative treatment modalities, such as cryoablation, may be used in the treatment of cervical intraepithelial neoplasia (CIN).¹⁰

Several retrospective studies have examined the impact of treatment for cervical disease, including CIN and cervical cancer, on reproductive outcomes.^{11

–19} Kyrgiou et al.²⁰ conducted a meta-analysis of 27 retrospective studies and stratified their analysis by treatment modality. Excisional procedures, such as loop electrosurgical excision procedure (LEEP) or cold knife conization, were significantly associated with adverse obstetrical outcomes, specifically preterm delivery, low birth weight neonates, and higher cesarean section rates. An additional meta-analysis by Arbyn et al.²¹ reported an increased risk in adverse pregnancy outcomes associated with the treatment of CIN by cold knife conization, laser conization, or radical diathermy. Based on these findings, the authors of both studies recommended that women should be counseled about these risks before treatment.

Although it is known that surgical treatment for cervical disease is linked to adverse obstetrical outcomes, little is known about the potential effects of these disease processes on future pregnancies. In this study, we reviewed pregnancy outcomes at our institution following a diagnosis of CIN-3 or cervical cancer to identify any consequences to the mother and neonate that may be associated with these disease processes.

Materials and Methods

Following Institutional Review Board approval, we performed a historical cohort study by merging data from the University of Pittsburgh Medical Center (UPMC) Network Cancer Registry with data from the Magee Maternal and Infant (MOMI) database. The former is designed to report people with various cancer types to the Pennsylvania Department of Health; the latter is a database containing information on all women who delivered at our institution between 1989 and 2006. Preliminary analysis revealed 1206 matches between the two databases; of the 205 women identified with any cancer preceding a delivery, the largest group consisted of those with CIN or cervical cancer or both.

Subsequently, using the UPMC Network Cancer Registry, reproductive-age women (18–45 years of age) with a history of CIN-3 or cervical cancer were identified using respective ICD-3 codes (CIN-3: 8077; cervical cancer: 8010, 8070, 8072, 8140, 8260, 8380). Identified records were then linked to the MOMI database by variables common to both datasets, including patient name, date of birth, medical record numbers, and social security number, in order to identify which women later delivered a singleton pregnancy at our institution between 1989 and 2006. For women who had more than one pregnancy during this interval, analysis was restricted to the first singleton pregnancy following a diagnosis of CIN-3 or cervical cancer. Second or third pregnancies were also excluded in the data for control women. Fifty-two women with CIN-3 and 83 women with cervical cancer were identified who later delivered singleton pregnancies at our institution. Our control cohort consisted of more than 78,000 women who delivered singleton pregnancies between 1989 and 2006 at our institution, as determined by the MOMI database, but who did not have any matching records in the UPMC Cancer Registry. Further, our control group had no reported malignancies as determined by a field in the MOMI database; thus, these women essentially had no known cervical disease or other malignancy. Following the merging process, data were then deidentified for further analysis.

Maternal outcomes were examined, including preterm delivery (PTD, <37 weeks of gestation), preterm premature rupture of membranes (PPROM, rupture of membranes <37 weeks of gestation), cesarean section, gestational diabetes mellitus (GDM), and gestational hypertensive disorder (GHTN). Neonatal outcomes were also examined, including low birth weight (LBW, < 2500 g), small-for-gestational age (SGA), congenital anomalies (CA), and fetal mortality. The impact of each maternal or fetal characteristic was assessed for those women with CIN-3 and cervical cancer and expressed as relative risk (RR) values, with 95% confidence intervals (CI), compared with a designated reference group.

Because prior studies have not identified SGA as an adverse outcome for women with CIN-3 or cervical cancer,^20,21 we performed an in-depth analysis of the case and control groups for their relationship to SGA. SGA was determined by an algorithm that identified neonates who were below the 10th percentile of weight for their respective gestational ages.²² Chi-square analyses were used to identify risk factors for SGA deliveries. Maternal as well as neonatal factors were examined, including maternal age, race, insurance type, marital status, gravidity, parity, GDM, GHTN, cervical disease status, neonatal gender, gestational age, and CA.

Logistic regression modeling was performed to identify significant and independent risk factors associated with delivery of an SGA neonate. The model was constructed via forward building by adding variables that appeared on univariate analysis to be related to SGA. Variables were removed if they were not significantly related to SGA or did not create a significant change in other variables' odds ratios (ORs). Data were analyzed using SPSS 15.0 statistical software (SPSS, Inc., Chicago, IL), and p < 0.05 was considered statistically significant.

Results

During the period 1989–2006, 52 women with CIN-3 and 83 women with cervical cancer delivered a subsequent singleton pregnancy (n = 135). Analysis of maternal and fetal characteristics (Table 1) revealed that women with CIN-3 and cervical cancer were more frequently between the ages of 25 and 29 years (RR 1.65, 95% CI 1.02-2.66), unmarried (RR 2.38, 95% CI 1.70-3.33), and insured by Medicaid (RR 3.03, 95% CI 2.13-4.17) compared with the designated reference groups. Women with CIN-3 and cervical cancer had significantly increased risks of LBW (RR 1.65, 95% CI 1.03-2.65) and SGA births (RR 1.54, 95% CI 1.0-2.46). There were no significant differences in risk, however, for PTD, PPROM, cesarean section rates, GDM, GHTN disorders, CA, or fetal mortality in women with CIN-3 and cervical cancer compared with women with no known cervical disease.

Table 1.

Demographic Characteristics and Pregnancy Outcomes for Women With a Diagnosis of CIN-3 and Cervical Cancer Compared With Those Without Known Cervical Disease

Characteristic	Without CIN-3 or cancer (%) n = 78,087	CIN-3 and cervical cancer (%) n = 135	RR (95% CI) ^a
Maternal age, years
≤24	22.7	19.2	1.0
25–29	25.4	35.6	1.65 (1.02–2.66)^*
30–34	31.8	31.8	1.18 (0.73–1.92)
≥35	20.0	13.4	0.78 (0.43–1.43)
Race
Caucasian	80.5	77.8	1.0
African American	19.5	22.2	1.18 (0.79–1.78)
Insurance type
Medicaid	25.5	50.2	3.03 (2.13–4.17)^*
Insured/self-pay	74.5	49.8	1.0
Marital status
Unmarried	31.2	51.9	2.38 (1.70–3.33)^*
Married	68.8	48.1	1.0
Gravidity
Primigravid	41.3	31.3	1.28 (0.91–1.80)
Multigravid	58.7	68.6	1.0
Neonate sex
Male	51.4	52.6	1.0
Female	48.6	45.9	0.92 (0.66–1.30)
Gestational Age
Preterm	11.6	16.3	1.48 (0.94–2.34)
Term	88.4	83.7	1.0
Route of delivery
Vaginal	80.1	80.0	1.0
Cesarean section	19.9	20.0	1.01 (0.66–1.53)
PPROM	3.1	6.7	1.19 (0.49–2.90)
Gestational diabetes	2.5	1.5	0.61 (0.15–2.46)
Gestational hypertensive disorder	9.3	8.9	0.95 (0.52–1.72)
Congenital anomalies	4.3	1.5	0.33 (0.06–1.4)
Low birth weight	9.6	14.8	1.65 (1.03–2.65)^*
Fetal mortality	0.4	1.5	3.63 (0.90–14.7)
SGA	10.7	15.6	1.54 (1.0–2.46)^*

Table values represent the percentage of the study groups with the indicated characteristics.

RR, relative risk of women with CIN-3 and/or cervical cancer having the indicated variable.

Denotes a statistically significant relationship.

CI, confidence interval; CIN, cervical intraepithelial neoplasia; PPROM, preterm premature rupture of membranes; RR, relative risk; SGA, small-for-gestational age.

Based on findings from our primary analysis, we next performed a post hoc analysis of all singleton pregnancy SGA neonates delivered at our institution. Approximately 1 in 10 singleton pregnancies resulted in an SGA neonate. Table 2 compares characteristics of women who delivered SGA neonates with those who did not deliver SGA neonates. Demographic characteristics significantly associated with SGA neonates included younger maternal age (p < 0.001), African American race (p < 0.001), Medicaid insurance (p < 0.001), unmarried (p < 0.001), multigravid (p < 0.001), and primiparous (p < 0.001). Significant maternal variables included PTD (p < 0.001), PPROM (p < 0.001), GDM (p < 0.001), and GHTN disorders (p < 0.001). Significant neonatal variables included female gender (p < 0.001) and CA (p < 0.001).

Table 2.

Demographic Characteristics and Pregnancy Outcomes for Women (n = 77,928) with Singleton Deliveries Between 1989 and 2006

Characteristic	All singleton deliveries n = 77,928	SGA deliveries n = 8,326 (%)	p value ^a
Maternal age, years			<0.001
≤24	17,668	2,675 (31.3)
25–29	19,839	2,049 (10.3)
30–34	24,816	2,146 (8.6)
≥35	15,605	1,456 (9.3)
Teenager			<0.001
Yes	5,468	927 (17.0)
No	72,460	7,399 (10.2)
Race			<0.001
Caucasian	62,279	5,780 (9.3)
African American	15,023	2,478 (16.5)
Insurance type			<0.001
Medicaid	19,081	3,092 (16.2)
Insured/self-pay	55,980	4,988 (8.9)
Marital status			<0.001
Unmarried	24,274	3,818 (15.7)
Married	53,654	4,508 (8.4)
Gravidity			<0.001
Primigravid	22,779	3,069 (13.5)
Multigravid	54,983	5,109 (18.6)
Parity			<0.001
Primiparous	32,104	4,480 (14.0)
Multiparous	45,814	3,844 (8.4)
Cervical status			0.04
Normal	77,793	8,305 (10.7)
CIN-3	52	6 (11.5)
Cervical cancer	83	15 (18.1)
Neonate sex			<0.001
Male	39,844	3,151 (7.9)
Female	37,684	4,775 (12.7)
Gestational age			<0.001
Preterm	8,848	1,230 (13.9)
Term	69,080	7,096 (10.3)
Route of delivery			0.32
Vaginal	62,420	6,635 (10.6)
Cesarean section	15,508	1,691 (10.9)
PPROM	4,827	403 (8.3)	<0.001
Gestational diabetes	1,902	146 (7.7)	<0.001
Gestational hypertensive disorder	7,237	1,209 (16.7)	<0.001
Congenital anomalies	3,301	491 (14.9)	<0.001

Table values represent the absolute values or percentages of the study groups with the indicated characteristics.

All p values were determined by Pearson chi-square analysis. A p value <0.05 was considered statistically significant.

PPROM, preterm premature rupture of the membranes; SGA, small-for-gestational age.

A history of cervical cancer was also a significant demographic variable for delivery of an SGA neonate (p = 0.04) (Table 2). Treatment modalities for cervical cancer did not impact this relationship; however, this analysis was limited to general categories of treatment (i.e., excisional or ablative). In addition to maternal age 12–19 years and 20–24 years, African American race, Medicaid insurance, and GHTN disorders, logistic regression modeling (Table 3) revealed that women with a history of cervical cancer were 1.9 times (95% CI 1.1–3.4) more likely to have an SGA neonate compared with women without cervical cancer.

Table 3.

Significant Risk Factors for Delivery of Small-for-Gestational Age Neonates

Risk factor	Odds ratio	95% confidence interval
Cervical cancer	1.9	1.1–3.4
Maternal age, years
12–19	1.3	1.2–1.4
20–24	1.2	1.1–1.3
25–29	1.0	0.9–1.1
30–34	0.9	0.8–1.0
≥35	1.0
African American	1.5	1.4–1.6
Medicaid	1.5	1.4–1.6
Gestational hypertension disorder	1.3	1.1–1.6

Discussion

A fertility-sparing approach to cancer treatment is a growing trend and is receiving increased media attention, although the long-term ramifications of the disease process or fertility-sparing management are not well known for many cancers. Prior studies examining risk have been centered on risk to the index patient; there are few studies of risks to the fetus (or neonate) in a subsequent pregnancy after cancer diagnosis or treatment.^23,24 Knowledge of these risks will help to counsel patients in deciding about therapies and fertility, as well as providing information to healthcare providers to identify high-risk pregnancies requiring additional antenatal management.

Findings of this study demonstrate a significant association between SGA neonates and a maternal history of cervical cancer, a result not previously reported. Women with a history of cervical cancer were 1.9 times more likely to deliver an SGA neonate than women without cervical cancer. SGA neonates are traditionally defined as those with an estimated weight less than the 10th percentile for gestational age.²² A diagnosis of SGA can have severe ramifications, including an increase in perinatal mortality and long-term neurodevelopmental problems and adult cardiovascular disease.^25
–27 Fetal surveillance may be recommended for women with risk factors for SGA neonates.²⁸

The exact pathophysiology connecting cervical cancer and SGA is unclear. Cervical cancer is a known end result of persistent infection with oncogenic forms of the human papilloma virus (HPV).²⁹ Host immunological responses, including T cell-mediated pathways, have been identified and are believed to play a central role in cervical carcinogenesis.²⁹ It could be possible for women with a history of cervical cancer to have persistent immunological processes that may cause SGA. It could also be possible that the vascular supply to the uterus is altered by prior HPV infection or by prior treatment for cervical cancer. Either immunological or vascular changes could cause alterations in placental development associated with SGA.³⁰

Although the current study defines a relationship between cervical cancer and delivery of an SGA neonate, there are several limitations to the interpretation of our data. This is a retrospective study and, therefore, has limitations related to this type of study, including reporting and referral bias, inaccuracy of recorded medical information, and inability to control for all bias and confounding factors.³¹ For example, it is likely that cases of CIN-3 are underreported in the UPMC Cancer Registry; this could account for the fact that CIN-3, although typically more prevalent in the general population, occurred less frequently than invasive cervical disease in our cohort. Alternatively, CIN-3 may be falsely low because of treatment of patients outside of the UPMC health system (i.e., referral bias).

Further, this study is a secondary analysis of two preexisting independent databases that were not created for our inquiries. We were unable to control for tobacco use because this variable was not consistently reported in the MOMI database until after 1995. The relationship of tobacco use to SGA has been defined,³² has an association between tobacco use and cervical carcinogenesis.³³ Thus, tobacco use is a potential confounding variable and should be addressed in future prospective studies.

We are also unable to examine the surgical interventions patients received prior to pregnancy. In our cohort, CIN-3 or cervical cancer was diagnosed before pregnancy, but the treatment may have occurred before or after pregnancy. Eighty-four percent of women received treatment before delivery, and 13.3% received treatment after delivery. Overall, 53.3% received excisional treatment, 24.0% received ablative treatment, and 22.2% did not have any documented treatment performed. Our analysis, however, did not reveal any statistically significant relationships due to the overall small numbers of treated patients in our cohort. Kyrgiou et al.,²⁰ in their meta-analysis, concluded that excisional procedures for CIN or early invasive cervical lesions were significantly associated with adverse obstetrical outcomes; in contrast, ablative treatment modalities did not have any significantly increased obstetrical risks. These findings were supported by an additional study pertaining to severe obstetrical adverse outcomes following treatment for CIN.²¹ Our lack of information about the timing of treatment modality limits our ability to make specific statements about cervical cancer treatment and future reproductive risks.²⁰

Further, our institution is a regional referral center for high-risk obstetrics. It is feasible that some women in our study cohorts who initially received obstetrical care in the community may have returned to our institution because of a high-risk pregnancy with a suspected SGA fetus. Our population of SGA neonates in women with a history of cervical cancer may, therefore, be enriched and may account for this relationship being statistically significant. Future studies accounting for selection bias and stratifying obstetrical outcomes by treatment type are necessary to fully inform women with cervical cancer of the risks in a subsequent delivery.

Conclusions

Our findings demonstrate a significant relationship between a history of cervical cancer and the subsequent delivery of an SGA singleton pregnancy. These results are supported by the linkage of 20 years of data from two large databases.

Fertility-sparing procedures and technologies are rapidly becoming available to cancer patients, but the risks to future pregnancies are not well defined at present. Further prospective studies are needed to help clarify risks after treatment of malignancy to enable more specifically tailored preconception counseling and antenatal care.

Footnotes

Acknowledgments

We thank the University of Pittsburgh Medical Center Network Cancer Registry team of William Eppinger, Sharon Winters, and Louise Mazur, who were crucial in the data sharing and subsequent linkage to the MOMI database.

Financial support for this study was provided by the Department of Obstetrics, Gynecology and Reproductive Sciences, Magee-Womens Hospital, University of Pittsburgh Medical Center. This study was presented at the 2007 American College of Obstetricians and Gynecologists (ACOG) District III meeting in Santo Domingo, Dominican Republic, and at the 2008 annual ACOG meeting in New Orleans, Louisiana.

Disclosure Statement

The authors have no conflicts of interest to report.

References

Parkin

, Bray

, Devesa

. Cancer burden in the year 2000. The global picture. Eur J Cancer, 2001; 37,Suppl 8:S4–66.

Jemal

, Siegel

, Ward

, Murray

, Xu

, Thun

. Cancer statistics, 2007. CA Cancer J Clin, 2007; 57:43–66.

National Cancer Institute Surveillance, Epidemiology, End Results (SEER) program

2009 November 1

http://www.seer.cancer.gov/statfacts/html/cervix.html

Duggan

, Muderspach

, Roman

, Curtin

, d'Ablaing

3rd , Morrow

. Cervical cancer in pregnancy: Reporting on planned delay in therapy. Obstet Gynecol, 1993; 82:598–602.

Segnan

. Socioeconomic status and cancer screening. IARC Sci Publ, 1997; 369–376.

Committee on Practice

B-G

. ACOG practice bulletin. Diagnosis and treatment of cervical carcinomas, number 35. Obstet Gynecol, 2002; 99:855–867.

Covens

, Shaw

, Murphy

et al.

Is radical trachelectomy a safe alternative to radical hysterectomy for patients with stage IA-B carcinoma of the cervix?

Cancer, 1999; 86:2273–2279.

Dargent

, Martin

, Sacchetoni

, Mathevet

. Laparoscopic vaginal radical trachelectomy: A treatment to preserve the fertility of cervical carcinoma patients. Cancer, 2000; 88:1877–1882.

Schorge

, Lee

, Sheets

. Prospective management of stage IA(1) cervical adenocarcinoma by conization alone to preserve fertility: A preliminary report. Gynecol Oncol, 2000; 78:217–220.

10.

Martin-Hirsch

, Paraskevaidis

, Kitchener

. Surgery for cervical intraepithelial neoplasia. Cochrane Database Syst Rev, CD001318. 2000.

11.

Hagen

, Skjeldestad

. The outcome of pregnancy after CO₂ laser conisation of the cervix. Br J Obstet Gynaecol, 1993; 100:717–720.

12.

Kasum

, Kuvacic

. [Pregnancy outcome after conization.] Jugosl Ginekol Perinatol, 1991; 31:31–34.

13.

Kristensen

, Langhoff-Roos

, Kristensen

. Increased risk of preterm birth in women with cervical conization. Obstet Gynecol, 1993; 81:1005–1008.

14.

Paraskevaidis

, Koliopoulos

, Lolis

, Papanikou

, Malamou-Mitsi

, Agnantis

. Delivery outcomes following loop electrosurgical excision procedure for microinvasive (FIGO stage IA1) cervical cancer. Gynecol Oncol, 2002; 86:10–13.

15.

Raio

, Ghezzi

, Di Naro

, Gomez

, Luscher

. Duration of pregnancy after carbon dioxide laser conization of the cervix: Influence of cone height. Obstet Gynecol, 1997; 90:978–982.

16.

Sadler

, Saftlas

, Wang

, Exeter

, Whittaker

, McCowan

. Treatment for cervical intraepithelial neoplasia and risk of preterm delivery. JAMA, 2004; 291:2100–2106.

17.

Samson

, Bentley

, Fahey

, McKay

, Gill

. The effect of loop electrosurgical excision procedure on future pregnancy outcome. Obstet Gynecol, 2005; 105:325–332.

18.

Tan

, Pepra

, Haloob

. The outcome of pregnancy after large loop excision of the transformation zone of the cervix. J Obstet Gynaecol, 2004; 24:25–27.

19.

van Rooijen

, Persson

. Pregnancy outcome after laser vaporization of the cervix. Acta Obstet Gynecol Scand, 1999; 78:346–348.

20.

Kyrgiou

, Koliopoulos

, Martin-Hirsch

, Arbyn

, Prendiville

, Paraskevaidis

. Obstetric outcomes after conservative treatment for intraepithelial or early invasive cervical lesions: Systematic review and meta-analysis. Lancet, 2006; 367:489–498.

21.

Arbyn

, Kyrgiou

, Simoens

et al. Perinatal mortality and other severe adverse pregnancy outcomes associated with treatment of cervical intraepithelial neoplasia: meta-analysis. BMJ, 2008; 337:a1284.

22.

Alexander

, Kogan

, Himes

. 1994–1996 U.S. singleton birth weight percentiles for gestational age by race, Hispanic origin, and gender. Matern Child Health J, 1999; 3:225–231.

23.

Fossa

, Magelssen

, Melve

, Jacobsen

, Langmark

, Skjaerven

. Parenthood in survivors after adulthood cancer and perinatal health in their offspring: A preliminary report. J Natl Cancer Inst Monogr, 2005; 77–82.

24.

Green

, Whitton

, Stovall

et al. Pregnancy outcome of female survivors of childhood cancer: A report from the Childhood Cancer Survivor Study. Am J Obstet Gynecol, 2002; 187:1070–1080.

25.

Barker

, Osmond

, Simmonds

, Wield

. The relation of small head circumference and thinness at birth to death from cardiovascular disease in adult life. BMJ, 1993; 306:422–426.

26.

Fattal-Valevski

, Leitner

, Kutai

et al. Neurodevelopmental outcome in children with intrauterine growth retardation: A 3-year follow-up. J Child Neurol, 1999; 14:724–727.

27.

Williams

, Creasy

, Cunningham

, Hawes

, Norris

, Tashiro

. Fetal growth and perinatal viability in California. Obstet Gynecol, 1982; 59:624–632.

28.

Mari

, Hanif

. Intrauterine growth restriction: How to manage and when to deliver. Clin Obstet Gynecol, 2007; 50:497–509.

29.

Sheu

, Chang

, Lin

, Chow

, Huang

. Immune concept of human papillomaviruses and related antigens in local cancer milieu of human cervical neoplasia. J Obstet Gynaecol Res, 2007; 33:103–113.

30.

Althabe

, Labarrere

, Telenta

. Maternal vascular lesions in placentae of small-for-gestational-age infants. Placenta, 1985; 6:265–276.

31.

Mantel

, Haenszel

. Statistical aspects of the analysis of data from retrospective studies of disease. J Natl Cancer Inst, 1959; 22:719–748.

32.

Kramer

. Determinants of low birth weight: Methodological assessment and meta-analysis. Bull WHO, 1987; 65:663–737.

33.

Plummer

, Herrero

, Franceschi

et al. Smoking and cervical cancer: Pooled analysis of the IARC multi-centric case-control study. Cancer Causes Control, 2003; 14:805–814.