Are there adverse effects of periconceptional spermicide use?

Vol. 43, No.3, March 1985 Printed in U.SA.

FERTILITY AND STERILITY Copyright ' 1985 The American Fertility Society

Are there adverse effects of periconceptional spermicide use?

James L. Mills, M.D., M.S.* Gilorge F. Reed, Ph.D. Robert P. Nugent, M.P.H. Ernest E. Harley, M.S. Heinz W. Berendes, M.D., M.H.S. Epidemiology and Biometry Research Program, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland

Recent studies have suggested that spermicide exposure around conception may cause congenital malformations, reduced birth weight, or spontaneous abortion. This large, prospective study examined the risk for multiple malformations, patterns of malformations, low birth weight, preterm delivery, and spontaneous abortion in infants whose mothers used spermicides only before or after their last menstrual period, compared with a control group using other contraceptive methods. The multiple malformation rates in women using spermicides only before or after their last menstrual period were 3.8 and 4.8 per thousand, respectively. For the control groups, the corresponding rates were 5.4 and 6.4 (not significant). No pattern of malformations was found in spermicide-exposed infants. The risk of preterm delivery, the risk for producing a low-birth-weight « 2500 gm) infant, and the risk of spontaneous abortion were no higher in women exposed to spermicides than in women using other methods of contraception. This study finds no evidence that spermicide exposure around the time of conception is dangerous to the fetus. Fertil Steril 43:442, 1985

Although spermicides are generally considered to be a safe method of contraception, several recent reports have raised questions about their use around the time of conception. Congenital malformations/,2 reduced birth weight,3 and increased fetal losses 4 , 5 have been attributed to maternal spermicide exposure during or shortly before pregnancy. Other studies have reported no increase in congenital malformations following maternal spermicide use. 6 -8 The reported effects on birth weight and fetal losses have not been examined in detail, nor has any study looked for Received September 4, 1984; accepted October 30,1984. *Reprint requests: James L. Mills, M.D., M.S., NICHD, NIH, Landow Building, Room 8A04, Bethesda, Maryland 20205. 442

Mills et Ill. Periconceptional spermicide exposure

clusters of malformations. This study examines the effects of maternal spermicide use around the time of conception on infant birth weight, preterm delivery, fetal losses, and patterns of malformations. MATERIALS AND METHODS

Data for this study were gathered by KaiserPermanente of Northern California under contract to the National Institute of Child Health and Human Development. All women having a confirmation of pregnancy examination in a Kaiser-Permanente facility between 1974 and 1977 were asked to complete a prenatal questionnaire at their first prenatal visit. The. women were asked what type of contraception they had used Fertility and Sterility

during each of the preceding 12 months. For each month, both the type of contraceptive and the brand name were recorded. The women were also asked specifically whether or not they had used any type of contraceptive after their last menstrual period (LMP) and, if so, when they had stopped. Gestational age was calculated from the first day of the LMP with correction if the LMP and obstetricians' due date did not agree. Information on other risk factors for fetal losses and for producing malformed, low-birth-weight, or preterm infants was obtained from the questionnaire and from a review of hospital records. Information on pregnancy outcomes, including infants' birth weights and the presence or absence of congenital malformations, was obtained from discharge diagnoses, physicians' notes, and autopsy reports from the infants' hospital charts. All pregnancy outcomes for which information on malformations was available were included. Study physicians (who were unaware of the mothers' contraceptive histories) conducted an independent review of a sample of records to verify the diagnosis and coding of malformations. Pregnancy outcomes in the offspring of spermicide users were compared with pregnancy outcomes in the offspring of users of other types of contraception: oral contraceptives, condom (alone), diaphragm (alone), intrauterine device, or the rhythm method. The two groups were divided into those using contraception only before the LMP and those exposed after the LMP. Spermicide users were compared with users of other methods of contraception for other risk factors for congenital malformations, low birth weight, preterm delivery, and spontaneous abortion: race, maternal age, parity, smoking, alcohol use, previous spontaneous abortions, previous malformed infants, maternal weight-for-height percentile, and socioeconomic status (education). In order to investigate possible patterns of congenital malformations, 57 types of malformations were examined in pairs in the two study groups to see whether any pairs were significantly more common in the offspring of spermicide users. Individuals having three or more malformations were examined to determine whether (1) multiple malformations were more common in spermicide users versus other methods and (2) whether spermicide use caused a specific "syndrome" or pattern of malformations. Next, mean birth weight, fetal loss, and preterm delivery rates in the two groups were compared by pre-LMP and post-LMP Vol. 43, No.3, March 1985

exposure. Finally, the ratio of male to female offspring in the two groups was examined. The chi-square test was used to examine differences in sociodemographic variables, birth weight, fetal losses, length of gestation, and ratios of male to female offspring. Multiple logistic regression was used to examine the effect of spermicides on birth weight, gestational age, and fetal losses after adjusting for multiple confounding factors.

RESULTS A total of 34,660 women participated in this study; 3146 had used spermicides before their LMP but not after; 2282 were exposed to spermicides after their LMP; 13,148 had used other forms of birth control before their LMP only; and 2831 were exposed after their LMP. Seventy-one percent of the participants were Caucasian, 9% were black, 9% were Hispanic, and 11 % belonged to other races. Five percent were older than 34 years of age; 5% were younger than 20 years of age. Data were collected early in pregnancy in the majority of cases. Forty-eight percent of the women registered and completed questionnaires by the 12th week of pregnancy, 79% by the 16th week, and 89% by the 20th week. Spermicide users were significantly older, of higher parity, and more educated than women using other contraceptive techniques (P < 0.0001). They drank less alcohol and smoked fewer cigarettes than users of other contraceptives (P < 0.0001). The two groups did not differ significantly in number of previous spontaneous abortions, previous malformed infants, or maternal weight for height. The percentages of Caucasians and blacks in the two groups were not significantly different. When the 57 types of malformations were examined in pairs, no pair was significantly more common in the spermicide group than in the control group. Three or more congenital malformations were present in 12 of3146 infants of sperm icide users (0.38%) and 77 of 13,148 infants of users of other methods (0.59%) in the group exposed only before the LMP. Among those exposed after the LMP, there were 11 of 2282 infants of spermicide users (0.48%) and 18 of2831 infants of users of other methods (0.64%) with three or more malformations. The malformation rates in spermicide users and users of other methods were not significantly different. Among infants having Mills et al. Periconceptional spermicide exposure

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Table 1. Birth Weight of Infants by Maternal Contraceptive Exposure < 2500 gm

Before the LMP only Spermicide (n = 3146) Other methods (n = 13,148)

;3

131 (4%) 640 (5%)

Table 3. Fetal Loss Rates by Maternal Contraceptive Exposure Q

2500 gm

2880 (96%) 11,953 (95%)

Before the LMP only Spermicides Other methods

Fetal loss

Live birth

142 (4.5%) 587 (4.5%)

2995 (95.5%) 12,533 (95.5%) 0.90)

(p =

0.11)

(690 unknowns)

108 (5%) 165 (6%) = 0.09)

2060 (95%) 2518 (94%) (262 unknowns)

(p =

After the LMP Spermicide (n = 2282) Other methods (n = 2831) (p

three or more malformations, those exposed to spermicides showed no excess of hypospadias, chromosomal anomalies, or limb defects. The specific anomalies in the offspring of spermicide users were reviewed to determine whether a pattern of malformations was present. In no instance did two or more infants whose mothers used spermicides have the same three (or more) malformations. Next, the effect of spermicide exposure on the risk of producing a low-birth-weight « 2500 gm) infant was examined. The results are shown in Table 1. Among those practicing contraception only before their LMP, 4% of the infants in the spermicide group and 5% of the infants in the other methods group weighed < 2500 gm. In the group exposed after the LMP, 5% of the infants in the spermicide group and 6% of the infants in the other methods group weighed < 2500 gm. The differences were not statistically significant. The risk of preterm delivery was examined next (Table 2). Among women practicing contraception only before their LMP, 10% of the spermicide users and 11 % of the users of other methods delivered before 37 weeks. In the group exposed after the LMP, the corresponding percentages were 12 and 13, respectively. Again, the differences between spermicide users and the control group were not statistically significant. Table 2. Preterm Delivery by Maternal Contraceptive Exposure

After the LMP Spermicides Other methods

112 (4.9%) 159 (5.6%) (p =

QInduced abortions excluded.

Fetal losses, including spontaneous abortions, late fetal deaths, ectopic pregnancies, and hydatidiform moles, were reviewed. As shown in Table 3, spermicide use was not associated with a higher risk of having an unsuccessful pregnancy, regardless of the time of exposure. When spontaneous abortions (including missed abortions) before 20 weeks and ectopic and molar pregnancies were examined separately, there was no increase seen in conjunction with spermicide use. Table 4 shows the proportion of male and female births to users of spermicides and other methods of contraception. The male/female ratio in spermicide users was 52:48 regardless of whether exposure extended beyond the LMP. In the control group, the male/female ratios were 51:49 in the group using contraceptives only before the LMP and 53:47 in the group exposed after the LMP. Spermicide exposure did not cause a statistically significant shift in the ratio of male to female infants in either case. Because it has been suggested 3 that exposure to spermicides after the LMP decreases birth weight in female offspring, low-birth-weight rates were examined by sex of offspring (Table 5). Spermicide exposure either before or after the LMP did not increase the risk of producing a low-birthweight infant of either sex. The risk of producing a low-birth-weight infant was slightly (but not Table 4. Sex of Offspring by Maternal Contraceptive Exposure

Delivery before Delivery at 37 37 weeks or more weeks

Before the LMP only Spermicide (n = 3146) Other methods (n = 13,148)

321 (10%) 1476 (11%) (p =

After the LMP Spermicide (n = 2282) Other methods (n = 2831)

273 (12%) 368 (13%) (p =

444

2825 (90%) 11,672 (89%)

Before the LMP only Spermicide (n = 3146) Other methods (n = 13,148)

0.11) 2009 (88%) 2463 (87%) 0.29)

Mills et al. Periconceptional spermicide exposure

2166 (95.1%) 2664 (94.4%) 0.28)

Male

Female

1570 (52%) 6471 (51%)

1447 (48%) 6140 (49%)

(p =

After the LMP Spermicide (n = 2282) Other methods (n = 2831)

0.49)

(666 unknowns)

1051 (48%) 1122 (52%) 1252 (47%) 1434 (53%) (p = 0.24) (254 unknowns)

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Table 5. Rates of Low Birth Weight « 2500 gm) by Sex and Maternal Contraceptive Exposure < 2500 gm

Exposure before the LMP only Girls 61 (4.2%) Spermicides 334 (5.5%) Other methods (p = 0.07) Boys 70 (4.5%) Spermicides 305 (4.7%) Other methods (p = 0.72) Exposure after the LMP Girls 63 (6.0%) Spermicides 88 (7.0%) Other methods (p = 0.36) Boys 45 (4.0%) Spermicides 77 (5.4%) Other methods (p = 0.13)

;" 2500 gm

1383 (95.8%) 5797 (94.5%) (12 unknowns) 1497 (95.5%) 6156 (95.3%) (13 unknowns) 985 (94.0%) 1162 (93.0%) (5 unknowns) 1075 (96.0%) 1356 (94.6%) (3 unknowns)

significantly) lower among spermicide users than among control subjects. The risks of pre term delivery, fetal loss, and the risk of delivering a low-birth-weight « 2500 gm) infant were examined by multiple logistic regression. When maternal age, parity, smoking, alcohol use, weight-for-height percentile, race, education, and previous spontaneous abortions were taken into account, spermicide use did not contribute significantly to either low birth weight or preterm delivery. DISCUSSION

Previous articles have suggested several deleterious effects of spermicide exposure around the time of conception. Jick et al. l reported that women who filled prescriptions for spermicides within 600 days of delivery were more likely to produce children with limb reduction defects, chromosomal abnormalities, hypospadias, or neoplasms. These findings have been questioned, however, because it is uncertain whether the women actually used spermicides around the time of conception. Rothman 2 reported an association between spermicide use and Down's syndrome in a population of infants with congenital heart disease and control subjects. However, spermicide use was significantly more common only when Down's cases were compared with normal control subjects, not other malformed infants. This suggests that recall bias may have caused the higher rate of spermicide exposure reported in the Down's group. Our previous study and others Vol. 43, No.3, March 1985

demonstrated no increased risk of any single malformation in infants of spermicide users. 6 -8 The present study found no association between spermicide use and any patterns of malformations, including limb defects, chromosomal abnormalities, and hypospadias. Because many teratogens (alcohol, phenytoin, rubella) produce recognized constellations of defects, it is important to establish that spermicides do not. This study is the first to address this issue. Polednak et al. 3 have found a significant reduction in birth weight in girls, but not boys, whose mothers reported using spermicides after their LMP. This study fails to confirm their findings. Neither girls nor boys whose mothers used spermicides before or after their LMP were significantly lighter than the offspring of users of other contraceptive methods. In keeping with the finding that birth weight was not reduced by spermicide exposure, the study also found that the risk of preterm delivery was not higher in women exposed to spermicides either before or after their LMP. Two studies4, 5 have found an increase in fetal losses associated with maternal spermicide use. In one,4 an increased female/male birth ratio was found; the authors suggested that spermicides might cause selective abortion of male conceptuses. In the present study, spermicide exposure did not result in an increased fetal loss rate, nor were sex ratios in the spermicide group significantly different from those in the control group. This study has a number of advantages over previous reports. The timing of spermicide exposure was well documented at the first prenatal visit. Documenting contraceptive exposures before delivery eliminates the risk of recall bias. The large number of pregnancies studied makes it possible to look for patterns of malformations and to determine effects of exposure on birth weight, fetal losses, and length of gestation with precision. The results of our study are reassuring to women using spermicides, particularly those who might accidentally be exposed after conception. This first search for a pattern of malformations showed no evidence of a "fetal spermicide syndrome." Maternal spermicide use either before or after the LMP was not associated with lower birth weight or preterm delivery. Finally, this study found no increase in spontaneous abortions in women using spermicides regardless of the time of exposure. Mills et al. Periconceptional spermicide exposure

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While no one would recommend that a woman continue to use spermicides after conception, such accidental exposure is likely to continue to occur .. This study's findings of no adverse effects will help the clinician to allay women's concerns about periconceptional spermicide exposure. Acknowledgments. We would like to thank Ms. Beverly J. Trainor and Ms. Diane Wetherill for preparing the manuscript. REFERENCES 1. Jick H, Walker AM, Rothman KJ, Hunter JR, Holmes LB, Watkins RN, D'Ewart DC, Danford A, Madsen S: Vaginal spermicides and congenital disorders. JAMA 245:1329, 1981 2. Rothman KJ: Spermicide use and Down's syndrome. Am J Public Health 72:399, 1982

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3. Polednak AP, Janerich DT, Glebatis DM: Birth weight and birth defects in relation to maternal spermicide use. Teratology 26:27, 1982 4. Scholl TO, Sobel E, Tanfer K, Soefer E-F, SaidmanB: Effects of vaginal spermicides on pregnancy outcome. Fam PI ann Perspect 15:244, 1983 5. Jick H, Shiota K, Shepard TH, Hunter JR, Stergachis A, Madsen S, Porter JB: Vaginal spermicides and miscarriage seen primarily in the emergency room. Teratogenesis Carcinog Mutagen 2:205, 1982 6. Mills JL, Harley EE, Reed GF, Berendes HW: Are spermicides teratogenic? JAMA 248:2148, 1982 7. Cordero JF, Layde PM: Vaginal spermicides, chromosomal abnormalities and limb reduction defects. Fam Plann Perspect 15:16, 1983 8. Shapiro S, Slone D, Heinonen OP, Kaufman DW, Rosenberg L, Mitchell AA, Helmrich SP: Birth defects and vaginal spermicides. JAMA 247:2381, 1982

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