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Impact of therapy for cervical intraepithelial neoplasia on fertility
Impact of therapy for cervical intraepithelial neoplasia on fertility E J. Montz, MD Los Angeles, California Cervical intraepithelial neoplasia is endemic in young American women. Because the majority of these women have a strong desire to maintain fertility, the efficacy of treatment modalities for this condition must be weighed against potential negative effects on fertility. Except for cone biopsy, however, the peer-reviewed literature provides little information about the effects of such techniques on fertility. While there are no data demonstrating that the other commonly used therapies (loop electrical excision procedure, cryotherapy, laser vaporization, and diathermy cautery) have a negative impact on fertility, neither has it been definitively proved that they do not have an untoward impact on fertility. Thus further studies are needed, and patients should be educated regarding the limitations of available information when informed consent for treatment is obtained. (Am J Obstet Gynecol 1996;175:1129-36.)
Key words: Cervical intraepithelial neoplasia, fertility, conization, loop electrical excision procedure
When offering a patient a given modality of therapy, all health care providers are obligated to inform the patient of the risks of that therapy. It is only after a patient is adequately informed about potential adverse side effects that he or she can truly grant informed consent for treatment. Unfortunately, the type and probability of occurrence of such side effects are often unclear. This deficiency in the physician's knowledge base may reflect either a lack of existing information or unfamiliarity with the published data. This article will review the information available in the published literature about the effect of treatment for cervical intraepithelial neoplasia (CIN) on fertility.
Definition of fertility According to Stedman's Medical Dictionary, 1 the term "fertile" (L. fertilis; fero, to bear) is defined as "1. Fecund; fruitful; capable of conceiving and bearing young." Therefore, "infertile" would be defined as the inability to conceive and to bear young. Although this is the classic definition of fertility, the functional definition used by reproductive endocrinologists differs and focuses
From the Gynecologic Oncology Service, Department of Obstetrics and Gynecology, University of California at Los Angeles Centerfor Health Sciences. Presented at "Pathogenesis, Management and Detection of Cervical Neoplasia: A Multidisciplinary Perspective," Coronado, Calif., August 20-22, 1995. Reprint requests:E J. Montz, MD, GynecologfcOncologyService,Department of Obstetrics and Gynecology, University of California at Los Angeles Centerfor Health Sciences, CHS 24-127, 10833 Le ConteAve., Los Angeles, CA 90024. Copyright © 1996 by Mosby-YearBook, Inc. 0002-9378/96 $5.00+ 0 6/0/75664
on the second half of the Stedman's definition: "2. Impregnated; fertilized." According to these fertility experts, a woman is truly fertile when an ultrasonographically documented embryo (preferably with a heartbeat) exists. Thus it is evident that we must focus on two aspects of fertility. The first component is the capacity to conceive, and the second, equally important component is the ability to carry the conception to a state and time when a viable infant is born.
Demographics of fertility During the past four decades we have seen important changes in the demographics associated with pregnancy in United States. Most remarkable is the fact that the mean age of the mother at the time of first live birth is persistently increasing at a rate of approximately 1 year per decade. 2 Interestingly, not only are women older at their first term delivery, but the proportion of births accounted for bywomen aged 35 to 49 years is increasing. In 1982, this age group comprised approximately 5% of women bearing children. It has been proposed that by the change of the millennium, 8.6 percent of pregnant women will be between 35 and 49 years of age? Two p h e n o m e n a account for these statistics: Women are delaying having their first child, and the large n u m b e r of "baby boomers" are aging and therefore skewing the mean age higher. As women age, physiologic changes in reproductive function lead to decreasing fertility rates. Infertility rates in women in their twenties range between 7% and 9%. As women mature into their late thirties and forties, infertility rates ascend to 22% to 29%. 4 Interestingly, the base infertility rates have not changed remarkably since the 1129
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1950s. In the 1970s and early 1980s, a transient increase in infertility rates occurred as a result of sexually transmitted diseases. Since then the rates have remained stable. Rates of dysplasia, like those of infertility, are age-related, with high-grade dysplasias most commonly diagnosed late in the fourth and early in the fifth decade of life. 5 As women delay pregnancy, two untoward events occur: The risk of infertility increases simply because of the patient's age, and the probability of developing highgrade cervical intraepithelial neoplasia (CIN) rises. If a therapeutic modality used to treat CIN also impairs fertility, the patient is placed at a further reproductive disadvantage.
CIN therapy may impair fertility GIN therapy may impair fertility in four ways.~ Historically, the most commonly discussed modality is the induction of cervical stenosis. 7' s Theoretically, the stenosis may act as an anatomic barrier to sperm, preventing access to the endometrial cavity and fallopian tubes. It has been proposed that severe stenosis may also inhibit cervical dilatation during labor. Fertility also could he compromised by loss of cervical mucus. 9 When cervical mucus is significantly reduced, sperm transport from the upper vagina into the endometrium may be impeded. CIN therapy may also have an impact on fertility by inducing cervical incompetence. It is believed that resection of a large volume of the cervical stroma will result in difficulties with structural integrity)9 This loss of support may lead to an increase in second trimester abortion and preterm labor. Finally, CIN therapy can potentially cause infertility through treatment-induced tubal dysfunction. Fortunately this is a rare occurrence, because ascending infections, which may lead to the development of a physiologic tubal dysfunction or actual obstruction, are uncommon.~l
Treatment modalities and effects on fertility Cold knife cones. Almost 60 years ago it was proposed that cervical conization not he used for women desiring a subsequent pregnancy because of the high frequency of preterm delivery and other pregnancy-related, complications associated with the procedure) 2 Over the decades a large volume of data, much of it contradictory, has addressed this issue. Not surprisingly, of all the modalities used to treat cervical dysplasias, the largest experience and most cumulative data that we have relate to cone biopsies. Mthough data are available about pregnancy outcome, information about the possible role of conization in inducing secondary infertility is scant. An evaluation of the discussion about the side effects of cone biopsies in the
October 1996 AmJ ObstetGynecol
literature indicates that few peer-reviewed articles attempt to address secondary infertility. In the 1970s Kullander and Sjopberg 13published a report on 134 women of reproductive age who had undergone conization as therapy for cervical intraepithelial neoplasia. During postconization follow-up, which averaged 6 years, the authors found that subsequent infertility (described as the inability to conceive) occurred in 11 cases. However, careful review of the data shows that three of the patients had previously undergone tubal ligation and seven patients had other potential explanations for their infertility, such as male factor incompatibility or abstinence. Therefore, only a single patient had secondary infertility for which the sole etiologic cause could have been a prior conization. In a second significant review of the effects of cone biopsy on fertility, Buller and Jones found no evidence of secondary infertility.1. These investigators evaluated 105 persons who did not become pregnant after conization during an average follow-up period of 3.5 years. It is of interest that the majority of these 105 women either used a method of contraception, were sterilized, or were relatively coitally inactive. Only 13 of the women underwent an infertility evaluation after 1 year of unprotected intercourse failed to lead to a pregnancy. The infertility rate for this population (12.3 %) is consistent with that of a similar-aged segment of the general population. Further evaluation of the data indicates that only three of these 13 patients had potentially unexplained infertilitythat may have been a residual effect of the conization. Many of the patients had demonstrable tubal factors following an ectopic gestation, pelvic inflammatory disease, or use of an intrauterine device. Other causes of infertility included coital inactivit); ovarian failure as a sequelae to combination chemoradiation for Hodgkin's disease, and chronic anovulation as a result of kidney failure. Therefore, although the data are limited, that which does exist fails to support the claim that cone biopsies increase rates of infertility (i.e., inability to conceive). What effect does cone biopsy have on a subsequent pregnancy? In contradistinction to data on secondary infertility, we have a moderate quantity of data regarding this issue. In one of the most valuable reviews, researchers compared 66 women who had undergone cone biopsies with 264 (four each) matched controls. 15 Controls were matched for singleton birth, maternal age (within 5 years), parity, socioeconomic group (with use of United Kingdom standard definitions) and date of delivery (same month or immediately preceding or following month). It was noted that women who had undergone a cone biopsy had an increase in preterm deliveries (prior to 37 weeks) and an associated increase in the n m n b e r of low-birthTweight fetuses (2500 gm) but no change in the n u m b e r of assisted deliveries (Table I).
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Table I. O u t c o m e of p r e g n a n c y after c o n e biopsy Control group (n = 264)
Cone biopsy group (n = 66) Outcome
No.
%
No.
%
Relative risk
Delivery before 37 wk Spontaneously only All assisted deliveries* Cesarean section only Birth weight 2500 gm
12 11 15 7 14
18 17 23 11 21
14 8 37 16 22
5 3 14 6 8
3.4; p < 0.01 5.5; p < 0.01 1.6 (NS) 1.7 (NS) 2.5; p < 0.01
FromJonesJM, Sweetnam P, Hibbm'd BM. The outcome of pregnancy after cone biopsy of the cervix: a case control study. BrJ Obstet Gynecol 1979;86:913-7. NS, Not significant. *Cesarean section, forceps, or ventouse.
Table II. Duration of labor in multigravidae delivered vaginally Duration of labor >2
2.1-6
6.1-12
Group
No. of patients
Mean
No.
%
[ No.
%
Cone biopsy Control
55 205
8.5 &3
5 15
9.1 7.3
15 108
27.3 52.7
No. [ 24 6I
12.1-18
>18
%
No.
%
No.
%
43.6 29.8
8 15
14.5 7.3
3 6
5.5 2.9
FromJonesJM, Sweetnam P, Hibbard BM. The outcome of pregnancy after cone biopsy of the cervix: a case control study. BrJ Obstet Gynecol 1979;86:913-7. In the same study .5 it was n o t e d that a change in the duration of labor o c c u r r e d after a cone biopsy had b e e n p e r f o r m e d . With use of data f r o m multigravid patients only, it was d e m o n s t r a t e d that the m e a n duration of labor subsequent to c o n e biopsy was 8.5 hours, c o m p a r e d with the control group, which had a m e a n duration of labor of 6.3 hours (Table II). In contrast, in the previously r e f e r e n c e d work 14 cone biopsy actually statistically s h o r t e n e d the length of the first stage of labor in primigravid w o m e n (11.3 hours in w o m e n who had n o t had conization verses 8.0 hours after conization, p < 0.05), while having no statistically significant effect on subsequent pregnancies or in multigravid women. O t h e r potential side effects of c o n e biopsy on pregnancy, such as spontaneous a b o r t i o n / m i d trimester p r e g n a n c y wastage, p r e m a t u r e labor and birth, or low birth weight, did n o t increase. However, it must be n o t e d that a remarkably large variation rate between the groups would be r e q u i r e d to appreciate a statistically m e a n i n g f u l difference in abortion rates because of the small n u m b e r of patients who were followed up. In a m o r e r e c e n t report, investigators r e p o r t e d on 170 w o m e n who had u n d e r g o n e cervical conization.~6 Thirtyf o u r w o m e n u n d e r w e n t conization before their first delivery, 62 between their first and second delivery, and 74 subsequent to their second delivery. A comparison of p r e g n a n c y o u t c o m e s in this g r o u p of w o m e n with that in 14,063 controls showed an increased rate of i n d u c e d
abortion and a significantly h i g h e r risk of p r e t e r m delivery in the g r o u p that had u n d e r g o n e conization (odds ratio 4.13, 95% confidence interval 2.53-6.75; p < 0.001). T h e incidence of p r e t e r m birth at first delivery was significantly h i g h e r in w o m e n who u n d e r w e n t conization before their first delivery than in w o m e n who had not had a cervical conization (odds ratio 4.08, 95% confidence interval 1.68-9.88; p < 0.01). T h e rate of p r e t e r m delivery at the subsequent birth was n o t significantly increased. W o m e n who u n d e r w e n t the conization between pregnancies had a numerical increase in the incidence o f p r e t e r m deliveries that was n o t statistically significant. In summarizing these major studies and o t h e r less stringent works, 17-19 it appears that cervical conization may increase the incidence of p r e t e r m delivery and associated rates of low-birth-weight deliveries. It may also increase the mid-trimester abortion rate while lengthening labor time, although data r e g a r d i n g these latter phen o m e n a are conflicting at best. Data indicate that little effect on cesarean section rates can be related to this therapeutic modality. Much of the divergence in the data pertaining to the effects of conization on subsequent pregnancy o u t c o m e may reflect differences in the attitudes of institutions and surgeons toward cone size. Leiman et al) ° p e r f o r m e d a retrospective study of 88 pregnancies that o c c u r r e d in 77 patients after they had u n d e r g o n e cervical conization; in this study, p r e g n a n c y o u t c o m e was c o m p a r e d with cone
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Table III. Pregnancy o u t c o m e related to cone volume and height
i
Term
Premature delivery
Cesarean I section Stillbirth
(%)
(%)
vaginal delivery
Total
Spontaneous abortion Ectopic pregnancy Cone volume (ml) <4 >4 Cone height (cm) <2 >2
(%)
Trimester 1 (%)
Trimester 2
(%)
(%)
1 (3.2) --
4 (12.9) 3 (13.7)
2 (6.5) 4 (18.2)
1 (3.2) 7 (31.7)
5 (16.1) 3 (13.7)
2 (6.5) --
16 (51.6) 5 (22.7)
31 (100) 22 (100)
1 (1.5) --
5 (7.7) 2 (8.7)
8 (12.3) 5 (21.7)
6 (9.2) 7 (30.4)
10 (15.4) 1 (4.4)
2 (3.1) --
33 (50.8) 8 (34.8)
65 (100) 23 (100)
(%)
(%)
Modified from Leiman G, Harrison NA, Rubin A. Pregnancy following conization of the cervix: complications related to cone size. Am J Obstet Gyaaecol 1980;136:14-8.
Table IV. Length of time to conceive r e p o r t e d in questionnaire NO, of ~omen TiTtle to conc6iug
(mo)
Study group
Control group
<3 3-6 6-12 _>12
36 25 6 5
36 15 4 7
From Bigrigg A, Haffenden DK, Sheehan AL, Codling BW, Read MD. Efficacy and safety of large-loop excision of the transformation zone. Lancet 1994;343:32-4. ©1994 by The Lancet Ltd. The 95% confidence interval for difference between study and control groups = -31 to 32 mo.
size. Lateral and anterioposterior diameters and the h e i g h t of specimens were measured, and v o l u m e was calculated on the basis of these parameters. Unfortunately, n o t all three m e a s u r e m e n t s were available for all specimens (30); cone heights, a distance m e a s u r e d in all 77 specimens, were available. Volumes were categorized as large (>4 ml) or small (-<4 ml) and heights as large (>2 cm) or small (-<2 cm). These investigators n o t e d that the patients who had larger cones r e m o v e d were m o r e likely to have a midtrimester p r e g n a n c y loss, prematurity, and a decrease in n o r m a l vaginal delivery rates (Table HI). It is i m p o r t a n t to appreciate that these data are derived from a population that would be considered at high risk for p r e g n a n c y complications regardless of w h e t h e r the patient had u n d e r g o n e a cone biopsy. Regardless, the mid-trimester abortion rates in the large groups that und e r w e n t conization were h i g h e r than those r e p o r t e d for a similar p o p u l a t i o n that had n o t u n d e r g o n e the procedure. O n the basis of their data, L e i m a n et al. recomm e n d prophylactic cerclage in w o m e n who have u n d e r g o n e a " l a r g e " cone removal and subsequently conceive a desired pregnancy.
L o o p electrical excision procedure. A l t h o u g h the n u m ber of loop electrical excision procedures (LEEPs) being p e r f o r m e d is increasing because of the relatively recent widespread acceptance of this p r o c e d u r e by the gynecologic community, the data available regarding the impact of LEEP on subsequent fertility and p r e g n a n c y o u t c o m e are extremely limited. To date there have b e e n two significant reviews of the impact of LEEP on fertility. The first, f r o m Bigrigg et al., ~° r e p o r t e d on 250 m a t c h e d pairs of w o m e n (the patient u n d e r g o i n g the LEEP and a m a t c h e d control with the same date of birth, a t e l e p h o n e at h o m e , and a negative pap smear) who agreed to answer a questionnaire on menstruation, pregnancy, and infertility. The w o m e n in the study g r o u p had u n d e r g o n e a LEEP 3 to 4 years before answering the questionnaire; those in the control g r o u p had n o t received prior cervical treatment. O n e h u n d r e d forty-two of these w o m e n b e c a m e p r e g n a n t d u r i n g the time of the trial (76 in the study group and 66 in the control group). Sixty-nine study group pregnancies and 58 control group pregnancies resulted in live births. Five w o m e n in the study group and six w o m e n in the control group had spontaneous abortions, and two in each group had an ectopic pregnancy. Seventy-two of the w o m e n in the study g r o u p and 62 in the control group could r e m e m b e r how l o n g it took for t h e m to b e c o m e pregnant. T h e r e was no evident difference between the two groups in the time it took to conceive. Because of the limitations of the size of the study, however, only a threefold difference in infertility rates would have b e e n perceptible (Table IV). A similar evaluation that c o m p a r e d p r e g n a n c y rates and o u t c o m e s of a series of 574 w o m e n who had underg o n e LEEP with that of the general population was d o n e in the greater metropolitan Montreal area. 21 In contradistinction to Bigrigg and most o t h e r authors investigating postdysplasia t r e a t m e n t fertility, this group investigated the additive effect of cigarette smoking on pregnancy outcome; this is probably an i m p o r t a n t modifier because cigarette smoking n o t only increases a w o m a n ' s risk of
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Table V. Outcome of pregnancy in women treated with cryosurgery for a cervical intraepithelial neoplasia
Before therapy After therapy
7btal No.
<36 wk gestation (%)
Cesareansection (%)
Perinatal death and stillbirth (%)
Prematurerupture of membranes (%)
Cervical insufficiency (%)
65 115
2 (3) 3 (2.6)
1' (1.5) llj- (9.6)
1 (3) 0
2 (3) 4 (3.5)
0 1 (0.9)
Cervical stenosis
From Hemmingsson E. Outcome of third trimester pregnancies after cryotherapy of the uterine cervix. Br J Obstet Gynaecol 1982;89:675-7. *Diagnosis: Pelvic disproportion (1). tDiagnosis: Pelvic disproportion (5), pathoIogic labor (1), placenta previa (1), suspected fetal growth retardation (1), breech presentation (1), asphyxia (1), and preeclampsia (1). developing cervical dysplasia but increases the risk of a pregnancy complication. Therefore, to accurately evaluate the effect of LEEP on subsequent pregnancies, a multivariate analysis stratifying for cigarette smoking (both "yes" or "no" and number) should be completed. In the LEEP group, 53 women had 54 pregnancies. Remarkably, 47% of these women were smokers. The pregnancy rate was equivalent to that in the Montreal metropolitan region when standardized by age. Pregnancy outcome was not different than that in the control population, with newborn weight being directly related to the mother's smoking history. These data help support file opinion of Bigrigg 2° and others 22 that LEEP has no untoward side effect on subsequent fertility and pregnancy outcome. As further reviews of large numbers of patients who have been followed up for significant time periods are reported, these opinions will be supported or refuted. Cryotherapy. Despite the fact that hundreds of thousands of women have been treated with cryotherapy, extensive data reviewing the impact of this therapeutic modality on fertility and pregnancy outcome do not exist. One of the early studies from Weed et al. 9 evaluated a group of 412 patients who had undergone cryotherapy as treatment for cervical dysplasia. Mthough the follow-up time was not given, the authors report a pregnancy rate of 29 per 1000 women, which was almost equivalent to that reported by the state of North Carolina for a population aged 15 to 44 years (29.8 per 1000 women). Little more can be concluded from this review because of the lack of data. Monaghan 23 reported on a cohort of 204 women who underwent cryotherapy as treatment for cervical dysplasia in an outpatient setting. Data on infertility were not included, although information about pregnancy outcome arising from 34 pregnancies that occurred in 30 patients was given. The study compared the outcomes of the postcryotherapy pregnancies to precryotherapy pregnancies in the same cohort. The authors claim that the pregnancy outcome, gestational age using general categorization, and mode of delivery were not different in the group treated with cryotherapy than in the population as a whole.
Probably one of the most interesting articles that has addressed the issue of cryotherapy and pregnancy outcome is of a study in which patients were used as their own controls; this study focused only on the outcome of third trimester pregnancies. 24 The women in the study population had 65 pregnancies before cryotherapy and 115 thereafter. No difference was found in gestational age at the time of delivery, stillbirth rate, premature rupture of membranes, or cervical incompetence before or after cryotherapy (Table V). Besides the expected difference in mean maternal age, there was an increase in the cesarean section rate in the postcryotherapy pregnancies. I t is probable, however, that this is not a reflection of an underlying effect of the cryotherapy on the ability of the cervix to dilate in labor bnt reflects the increase in the use of cesarean sections in the general community population (a 6% rate in 1973 compared with a 13% rate in 1980). Eighty-six percent of the precryotherapy pregnancies were completed before 1975, whereas 76% of the postcryotherapy pregnancies occurred between 1976 and 1980, during the same time period that use of cesarean sections increased significantly in the community. It is possible that cryotherapy has a positive effect on fertility. Limited data in the literature claim that in women believed to have a cervical environment hostile to sperm and sperm transport, cryotherapy may actually improve the quality of the cervical mucous and subsequently facilitate conception. 2~ In summary, remembering the limitations of the available data, there is no evidence that cryotherapy has a negative impact either on fertility or pregnancy outcome and, in selected patients, may improve the cervical milieu. Laser. As is the case with cryotherapy and fertility, despite the extensive use of laser therapy, minimal data are available to support opinions about its effect on fertility and pregnancy outcome. Nonetheless, it is widely claimed in print and even in major gynecologic oncology texts ~1 that laser therapy has no negative impact on fertility. Studies used to support this contention may not have been optimally designed to address the issue. In one study, 68 third-trimester pregnancies from a group of 68
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women who had undergone laser vaporization conization as therapy for CIN were compared with 70 controls matched for age, race, and n u m b e r of births and abortions? 6 No differences in birth weight, gestational age, duration of labor, or mode of delivery were noted. Although data regarding pre-third trimester pregnancy outcomes were included in the report, no comparison was made with the control population, nor was there any attempt to evaluate rates of infertility after laser treatment. As was demonstrated with cold knife conization,1° one could propose that increasing the volume of cervical stroma vaporized would lead to increasing risk of infertility, preterm births, and low-birth-weight infants. Because depth of vaporization appears to be related to the cure rate of the dysplasia, this is more than a theoretical consideration. Although study data have been used to support the contention that increasing the amount of cervix destroyed by vaporization does not have a negative impact on fertility and pregnancy outcome, the reader must be careful as to the conclusions that are derived from this data. 27 No attempts were made to compare patients with controls or to determine rates of infertility. Two groups (deep vaporization, i.e., >10 mm, versus vaporization of" <10 mm) were compared and differences in pregnancy outcomes were reported. Although only 10 completed pregnancies were reported in the group with vaporization of less than 10 mm, the conclusion was made that depth of vaporization has no effect on pregnancy outcome. Statistically, the small sample size would preclude detection of significant differences in pregnancy outcomes. The report of the Laser Study Group from the Royal College of Obstetricians and Gynecologists reviewed the merits of laser therapy in the treatment of CIN. 2s In this report, 97 pregnancies of 96 women who underwent laser vaporization to a depth of 8 mm for CIN were compared with pregnancies of 97 controls matched for age, parity, singleton pregnancy, race, and year of delivery. Not surprisingly, and as previously noted in patients who underwent LEEP procedures in Montreal, 21 the women who had cervical dysplasia and were subsequently treated with laser therapy were more likely to be cigarette smokers. Information regarding the outcome of first trimester pregnancies was not collected. There was no difference between the two groups with regard to pregnancy or labor duration, mode of delivery, mid-trimester pregnancy wastage, the rate of premature ruptured membranes, gestationat age between 28 and 37 weeks, and the n u m b e r of infants with a birth weight of less than 2.5 kilos. As with all so labeled "negative" studies, the power of the study to demonstrate a difference between the two groups must be considered. On the basis of the fertility and pregnancy outcome
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data available from reviews of other therapeutic modalities, it would be rational to postulate that laser vaporization and laser conization, which destroy or remove significan@ less volume of the cervix than cold knife conization, may not have the same negative effect on pregnancy outcome that is found with cold knife conizati0n. It is unlikely that this theory will ever be proved, however, because the frequency with which laser is used for the treatment of cervical dysplasia has significantly dropped during the past 5 years. Electrocoagulation diathermy. Although use of electrocoagulation diathermy is u n c o m m o n in North America, it has been widely used to treat cervical dysplasia in other industrialized countries, such as Australia. The data evaluating effects of this modality on fertility and pregnancy outcome are minimal. In a review from South Australia, investigators reported on 108 patients who attempted to become pregnant after undergoing electrocoagulation diathermy. 29 Ninety-six patients (89%) were able to conceive during a mean follow-up period of just over 3 years. These rates, as well as pregnancy outcomes, were equivalent to what was expected for members of the population as a whole who were of similar demographics and age. Remarkably, only four women had postdiathermy infertility, and one of them had previously undergone a tubal sterilization.
Conclusion The most important conclusion to be drawn from this review is that the data regarding the impact, if any, of the treatment of CIN on future fertility and pregnancy outcome is severely limited and at times contradictor},. In many of the studies performed to date, too few women have been enrolled to appreciate any but the most remarkable differences in treatment-related side effects. To effectively answer these questions, larger and better designed trials should be undertaken. Because decreasing numbers of patients are being treated with certain modalities (cold knife conization and laser vaporization), it is probable that the information presently available is the best that can be obtained. The potential still exists to complete well-designed and well-executed trials evaluating LEEP and cryotherapy. Considering the aforementioned limitations, one can make the following conclusions: 1. Cold knife cone biopsies probably have limited impact on the ability of a patient to conceive after undergoing the therapy. Any difficulty that occurs as a result of cervical stenosis or mucous deficiency should be readily surmounted with intrauterine insemination. Once pregnancy has occurred, however, data from multiple, i n d e p e n d e n t sources support the theory that women who have undergone cone
Volume 175, Number 4, Part 2 Am J Obstet Gynecol
biopsies have i n c r e a s e d rates o f s e c o n d t r i m e s t e r a b o r t i o n s , p r e t e r m delivery, a n d low-birth-weight infants. T h e i n f o r m a t i o n r e g a r d i n g i m p a c t o n d u r a tion o f l a b o r in s u b s e q u e n t p r e g n a n c i e s is less substantial. M u c h o f t h e d i s c r e p a n c y in t h e p u b l i s h e d l i t e r a t u r e m a y reflect institutional a n d individual surgical t e c h n i q u e s of p e r f o r m i n g c o n i z a t i o n ; t h e l a r g e r t h e c o n e ( e i t h e r volumetrically o r in c e p h a l a d c a u d a l l e n g t h ) , t h e m o r e likely t h a t a negative pregn a n c y o u t c o m e will occur. 2. It has n o t b e e n d e m o n s t r a t e d t h a t LEEPs have untoward side effects o n fertility or s u b s e q u e n t pregn a n c y o u t c o m e . T h i s o b s e r v a t i o n is b a s e d o n linaited b u t w e l l - d e v e l o p e d data. A l o n g - t e r m trial with a c o h o r t large e n o u g h for small b u t clinically i m p o r t a n t d i f f e r e n c e s to b e a p p r e c i a t e d s h o u l d b e u n d e r taken. 3. No negative effects o f c r y o t h e r a p y o n t h e p a t i e n t ' s s u b s e q u e n t ability to conceive or o n p r e g n a n c y outc o m e t h e r e a f t e r have b e e n d o c u m e n t e d . Cryot h e r a p y may have a p o t e n t i a l beneficial effect in selected p a t i e n t s w h o have a hostile cervical environment. 4. Data r e g a r d i n g the use o f lasers m u s t be s e p a r a t e d into d a t a for p a t i e n t s w h o have u n d e r g o n e laser v a p o r i z a t i o n with n o d o c u m e n t e d negative effects a n d data for t h o s e in w h o m t h e laser is u s e d as a n i n s t r u m e n t to p e r f o r m a conization. W h e n t h e laser is used to p e r f o r m a conization, t h e p o t e n t i a l for negative fertility-related side effects would, as is t h e case with cold knife c o n i z a t i o n , relate to t h e v o l u m e o f the cervix r e m o v e d . Because laser c o n e s have b e e n n o t e d to b e statistically smaller t h a n cold knife cones, it may b e this v o l u m e d i f f e r e n c e t h a t p r o t e c t s the r e c i p i e n t f r o m a side effect t h a t impairs fertility. 5. O f all t h e modalities r e p o r t e d , t h e least a m o u n t of data are available r e g a r d i n g d i a t h e r m y cautery. T h i s s c a n t data fails to d o c u m e n t any negative effects o n fertility o r p r e g n a n c y o u t c o m e .
REFERENCES
1. Hansel WR, Oldham JO, editors. Stedman's medical dictionary. 24th ed. Baltimore: Williams and Wilkins, 1984: 52O. 2. Mosher WD, Pratt WF. Fecundity and infertility in the United States: incidence and trends. Fertil Steril 1991;56: 192-201. 3. Spencer G. Projections of the population of the United States by age, sex, and race: t983-2080. In: Current population reports-- population estimates and projections. U:S. Department of Commerce; 1984 May. Series P-25, No. 952. 4. Gindoff PR, Jewelewicz R. Reproductive potential in the older woman. Fertil Steril 1986;46:989-1001. 5. Armstrong BK, Munoz N, Bosch FX. Epidemiology of cancer of the cervix. In: Coppleson M, Monaghan JM, Morrow CP,
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Tattersall MHN, editors. Gynecologic oncologT. 2nd ed. Edinburgh: Churchill Livingstone, 1992;1:13-4. 6. Hammond RH, Edmonds DK. Does treatment for cervical intraepithelial neoplasia affect fertility and pregnancy? Little to worry about. Br MedJ 1990;301:1344-5. 7.. McLaren HC. Conservative management of cervical precancel-. J Obstet Gynaecol Br Commonwealth 1967;74:48792. 8. Pittaway DE, DaniellJ, Maxson W, Boehm K Reconstruction of the cervical canal after complete postconization obstruction: a case report. J Reprod Med 1984;29:339-40. 9. Weed JC, Curry SL, Duncan ID, Parker RT, Creasman WT. Fertility after cryosurgery of the cervix. Obstet Gynecol 1978;52:245-6. 10. Leiman G, Harrison NA, Rubin A. Pregnancy following conization of the cervix: complications related to cone size. A m J Obstet Gynecol 1980;136:14-8. 11. Coppleson M, Atkinson KH, Dalrymple JC. Cervical squamous and glandular intraepithelial neoplasia: clinical features and review of management. In: Coppleson M, MonaghanJM, Morrow CP, Tattersall MHN, editors. Gynecologic oncology. 2nd ed. Edinburgh: Churchill and Livingston, 1992:590-5. 12. Miller NF, Todd OE. Conization of the cervix. Surg Gynecol Obstet 1938;67:265-268. 13. Kullander S, Sjopberg N. Treatment of carcinoma-in-situ of the cervix uteri by conization. Acta Obstet Gynecot Scand 1971;50:153-7. 14. Buller RE, Jones I4~7 III. Pregnancy following cervical conization. A m J Obstet Gynecol 1982;142:506-12. 15. JonesJM, Sweetnam R Hibbard BM. The outcome of pregnancy after cone biopsy of the cervix: a case control study. Br J Obstet Gynecol 1979;86:913-7. 16. Kristensen J, Langhoff-Roos J, Borlmn Kristensen E Increased risk of preterm birth in women ~ith cervical conization. Obstet Gynecol 1993;81:1005-8. 17. Weber T, Obel E. Pregnancy complications following conization of the uterine cervix. Acta Obstet Gynecol Scand 1979; 58:259-63. 18. Lee NH. The effect of cone biopsy on subsequent pregnancy outcome. Gynecol Oncol 1978;6:1-6. 19. McLaren HC,JordanJA, Clover M, Artwood ME. Pregnancy after cone biopsy of the cervix. J Obstet Gynaecol Br Commonwealth 1974;81:383-4. 20. Bigrigg A, Haffenden DK, Sheehan AL, Codling BW, Read MD. Efficacy and safety of large-loop excision of the transformation zone. Lancet 1994;343:32-4. 21. Ferenczy Q, Choukroun D, Faleone T, Franco E. The effect of cervical loop eleetrosurgical excision on subsequent pregnancy outcome: North American experience. Am J Obstet Gynecot 1995;172:1246-50. 22. Keijser KG, Kenemans E van der Zanden PH, Schijf CR Vooijs GR Rolland R. Diathermy- loop excision in the management of cervical intraepithelial neoplasia: diagnosis and treatment in one procedure. AmJ Obstet Gyneco11992;166: 1281-7. 23. MonaghanJM, DavisJA, Edington PT. Treatment of cervical intraepithelial neoplasia by colposcopically directed cryosurgery and subsequent pregnancy experience. B r J Obstet Gynaecol 1982;89:387-92. 24. Hemmingsson E. Outcome of third trimester pregnancies after cryotherapy of the uterine cervix. BrJ Obstet Gynaecol 1982;89:675-7. 25. Baram A, Paz GF, Peyser MR, Schachter A, Homonnai ZT. Treatment of cervical ectropion by cryosurgery: effect on cervical mucus characteristics. Fertil Steril 1985;43:86-9. 26. ~Amderson MC, Horwell DH, Broby Z. Outcome of pregnancy after laser vaporization conization. Colpos Gynecol Laser Surg 1984;1:35-40. 27. Stutter WP, Abernethy FM, Brown VA, Hill AS. Success,
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complications, and subsequent pregnancy outcome relative to the depth of laser treatment of cervical intraepithelial neoplasia. Colpos Gynecol Laser Surg 1986;2:35-42. 28. Saunders N, Fenton DW, Soutter WP, Brown VA, Sharp F, Abernethy F. A case controlled study of the outcome of pregnancy following laser vapourization cone of the cervix. In: Sharp F, Jordan JA, editors. Gynecologic laser surgery
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proceedings of the Fifteenth Study Group of the Royal College of Obstetricians and Gynaecologists: reproductive and perinatal medicine (VI). Ithaca: Perinatology Press, 1986: 121-5. 29. Hollyock VE, Chanen W, Wein R. Cervical function following treatment of iutraepithelial neoplasia by electrocoagulation diathermy. Obstet Gynecol 1983;61:79-81.
Key words: Cervical intraepithelial neoplasia, fertility, conization, loop electrical excision procedure
When offering a patient a given modality of therapy, all health care providers are obligated to inform the patient of the risks of that therapy. It is only after a patient is adequately informed about potential adverse side effects that he or she can truly grant informed consent for treatment. Unfortunately, the type and probability of occurrence of such side effects are often unclear. This deficiency in the physician's knowledge base may reflect either a lack of existing information or unfamiliarity with the published data. This article will review the information available in the published literature about the effect of treatment for cervical intraepithelial neoplasia (CIN) on fertility.
Definition of fertility According to Stedman's Medical Dictionary, 1 the term "fertile" (L. fertilis; fero, to bear) is defined as "1. Fecund; fruitful; capable of conceiving and bearing young." Therefore, "infertile" would be defined as the inability to conceive and to bear young. Although this is the classic definition of fertility, the functional definition used by reproductive endocrinologists differs and focuses
From the Gynecologic Oncology Service, Department of Obstetrics and Gynecology, University of California at Los Angeles Centerfor Health Sciences. Presented at "Pathogenesis, Management and Detection of Cervical Neoplasia: A Multidisciplinary Perspective," Coronado, Calif., August 20-22, 1995. Reprint requests:E J. Montz, MD, GynecologfcOncologyService,Department of Obstetrics and Gynecology, University of California at Los Angeles Centerfor Health Sciences, CHS 24-127, 10833 Le ConteAve., Los Angeles, CA 90024. Copyright © 1996 by Mosby-YearBook, Inc. 0002-9378/96 $5.00+ 0 6/0/75664
on the second half of the Stedman's definition: "2. Impregnated; fertilized." According to these fertility experts, a woman is truly fertile when an ultrasonographically documented embryo (preferably with a heartbeat) exists. Thus it is evident that we must focus on two aspects of fertility. The first component is the capacity to conceive, and the second, equally important component is the ability to carry the conception to a state and time when a viable infant is born.
Demographics of fertility During the past four decades we have seen important changes in the demographics associated with pregnancy in United States. Most remarkable is the fact that the mean age of the mother at the time of first live birth is persistently increasing at a rate of approximately 1 year per decade. 2 Interestingly, not only are women older at their first term delivery, but the proportion of births accounted for bywomen aged 35 to 49 years is increasing. In 1982, this age group comprised approximately 5% of women bearing children. It has been proposed that by the change of the millennium, 8.6 percent of pregnant women will be between 35 and 49 years of age? Two p h e n o m e n a account for these statistics: Women are delaying having their first child, and the large n u m b e r of "baby boomers" are aging and therefore skewing the mean age higher. As women age, physiologic changes in reproductive function lead to decreasing fertility rates. Infertility rates in women in their twenties range between 7% and 9%. As women mature into their late thirties and forties, infertility rates ascend to 22% to 29%. 4 Interestingly, the base infertility rates have not changed remarkably since the 1129
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1950s. In the 1970s and early 1980s, a transient increase in infertility rates occurred as a result of sexually transmitted diseases. Since then the rates have remained stable. Rates of dysplasia, like those of infertility, are age-related, with high-grade dysplasias most commonly diagnosed late in the fourth and early in the fifth decade of life. 5 As women delay pregnancy, two untoward events occur: The risk of infertility increases simply because of the patient's age, and the probability of developing highgrade cervical intraepithelial neoplasia (CIN) rises. If a therapeutic modality used to treat CIN also impairs fertility, the patient is placed at a further reproductive disadvantage.
CIN therapy may impair fertility GIN therapy may impair fertility in four ways.~ Historically, the most commonly discussed modality is the induction of cervical stenosis. 7' s Theoretically, the stenosis may act as an anatomic barrier to sperm, preventing access to the endometrial cavity and fallopian tubes. It has been proposed that severe stenosis may also inhibit cervical dilatation during labor. Fertility also could he compromised by loss of cervical mucus. 9 When cervical mucus is significantly reduced, sperm transport from the upper vagina into the endometrium may be impeded. CIN therapy may also have an impact on fertility by inducing cervical incompetence. It is believed that resection of a large volume of the cervical stroma will result in difficulties with structural integrity)9 This loss of support may lead to an increase in second trimester abortion and preterm labor. Finally, CIN therapy can potentially cause infertility through treatment-induced tubal dysfunction. Fortunately this is a rare occurrence, because ascending infections, which may lead to the development of a physiologic tubal dysfunction or actual obstruction, are uncommon.~l
Treatment modalities and effects on fertility Cold knife cones. Almost 60 years ago it was proposed that cervical conization not he used for women desiring a subsequent pregnancy because of the high frequency of preterm delivery and other pregnancy-related, complications associated with the procedure) 2 Over the decades a large volume of data, much of it contradictory, has addressed this issue. Not surprisingly, of all the modalities used to treat cervical dysplasias, the largest experience and most cumulative data that we have relate to cone biopsies. Mthough data are available about pregnancy outcome, information about the possible role of conization in inducing secondary infertility is scant. An evaluation of the discussion about the side effects of cone biopsies in the
October 1996 AmJ ObstetGynecol
literature indicates that few peer-reviewed articles attempt to address secondary infertility. In the 1970s Kullander and Sjopberg 13published a report on 134 women of reproductive age who had undergone conization as therapy for cervical intraepithelial neoplasia. During postconization follow-up, which averaged 6 years, the authors found that subsequent infertility (described as the inability to conceive) occurred in 11 cases. However, careful review of the data shows that three of the patients had previously undergone tubal ligation and seven patients had other potential explanations for their infertility, such as male factor incompatibility or abstinence. Therefore, only a single patient had secondary infertility for which the sole etiologic cause could have been a prior conization. In a second significant review of the effects of cone biopsy on fertility, Buller and Jones found no evidence of secondary infertility.1. These investigators evaluated 105 persons who did not become pregnant after conization during an average follow-up period of 3.5 years. It is of interest that the majority of these 105 women either used a method of contraception, were sterilized, or were relatively coitally inactive. Only 13 of the women underwent an infertility evaluation after 1 year of unprotected intercourse failed to lead to a pregnancy. The infertility rate for this population (12.3 %) is consistent with that of a similar-aged segment of the general population. Further evaluation of the data indicates that only three of these 13 patients had potentially unexplained infertilitythat may have been a residual effect of the conization. Many of the patients had demonstrable tubal factors following an ectopic gestation, pelvic inflammatory disease, or use of an intrauterine device. Other causes of infertility included coital inactivit); ovarian failure as a sequelae to combination chemoradiation for Hodgkin's disease, and chronic anovulation as a result of kidney failure. Therefore, although the data are limited, that which does exist fails to support the claim that cone biopsies increase rates of infertility (i.e., inability to conceive). What effect does cone biopsy have on a subsequent pregnancy? In contradistinction to data on secondary infertility, we have a moderate quantity of data regarding this issue. In one of the most valuable reviews, researchers compared 66 women who had undergone cone biopsies with 264 (four each) matched controls. 15 Controls were matched for singleton birth, maternal age (within 5 years), parity, socioeconomic group (with use of United Kingdom standard definitions) and date of delivery (same month or immediately preceding or following month). It was noted that women who had undergone a cone biopsy had an increase in preterm deliveries (prior to 37 weeks) and an associated increase in the n m n b e r of low-birthTweight fetuses (2500 gm) but no change in the n u m b e r of assisted deliveries (Table I).
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Table I. O u t c o m e of p r e g n a n c y after c o n e biopsy Control group (n = 264)
Cone biopsy group (n = 66) Outcome
No.
%
No.
%
Relative risk
Delivery before 37 wk Spontaneously only All assisted deliveries* Cesarean section only Birth weight 2500 gm
12 11 15 7 14
18 17 23 11 21
14 8 37 16 22
5 3 14 6 8
3.4; p < 0.01 5.5; p < 0.01 1.6 (NS) 1.7 (NS) 2.5; p < 0.01
FromJonesJM, Sweetnam P, Hibbm'd BM. The outcome of pregnancy after cone biopsy of the cervix: a case control study. BrJ Obstet Gynecol 1979;86:913-7. NS, Not significant. *Cesarean section, forceps, or ventouse.
Table II. Duration of labor in multigravidae delivered vaginally Duration of labor >2
2.1-6
6.1-12
Group
No. of patients
Mean
No.
%
[ No.
%
Cone biopsy Control
55 205
8.5 &3
5 15
9.1 7.3
15 108
27.3 52.7
No. [ 24 6I
12.1-18
>18
%
No.
%
No.
%
43.6 29.8
8 15
14.5 7.3
3 6
5.5 2.9
FromJonesJM, Sweetnam P, Hibbard BM. The outcome of pregnancy after cone biopsy of the cervix: a case control study. BrJ Obstet Gynecol 1979;86:913-7. In the same study .5 it was n o t e d that a change in the duration of labor o c c u r r e d after a cone biopsy had b e e n p e r f o r m e d . With use of data f r o m multigravid patients only, it was d e m o n s t r a t e d that the m e a n duration of labor subsequent to c o n e biopsy was 8.5 hours, c o m p a r e d with the control group, which had a m e a n duration of labor of 6.3 hours (Table II). In contrast, in the previously r e f e r e n c e d work 14 cone biopsy actually statistically s h o r t e n e d the length of the first stage of labor in primigravid w o m e n (11.3 hours in w o m e n who had n o t had conization verses 8.0 hours after conization, p < 0.05), while having no statistically significant effect on subsequent pregnancies or in multigravid women. O t h e r potential side effects of c o n e biopsy on pregnancy, such as spontaneous a b o r t i o n / m i d trimester p r e g n a n c y wastage, p r e m a t u r e labor and birth, or low birth weight, did n o t increase. However, it must be n o t e d that a remarkably large variation rate between the groups would be r e q u i r e d to appreciate a statistically m e a n i n g f u l difference in abortion rates because of the small n u m b e r of patients who were followed up. In a m o r e r e c e n t report, investigators r e p o r t e d on 170 w o m e n who had u n d e r g o n e cervical conization.~6 Thirtyf o u r w o m e n u n d e r w e n t conization before their first delivery, 62 between their first and second delivery, and 74 subsequent to their second delivery. A comparison of p r e g n a n c y o u t c o m e s in this g r o u p of w o m e n with that in 14,063 controls showed an increased rate of i n d u c e d
abortion and a significantly h i g h e r risk of p r e t e r m delivery in the g r o u p that had u n d e r g o n e conization (odds ratio 4.13, 95% confidence interval 2.53-6.75; p < 0.001). T h e incidence of p r e t e r m birth at first delivery was significantly h i g h e r in w o m e n who u n d e r w e n t conization before their first delivery than in w o m e n who had not had a cervical conization (odds ratio 4.08, 95% confidence interval 1.68-9.88; p < 0.01). T h e rate of p r e t e r m delivery at the subsequent birth was n o t significantly increased. W o m e n who u n d e r w e n t the conization between pregnancies had a numerical increase in the incidence o f p r e t e r m deliveries that was n o t statistically significant. In summarizing these major studies and o t h e r less stringent works, 17-19 it appears that cervical conization may increase the incidence of p r e t e r m delivery and associated rates of low-birth-weight deliveries. It may also increase the mid-trimester abortion rate while lengthening labor time, although data r e g a r d i n g these latter phen o m e n a are conflicting at best. Data indicate that little effect on cesarean section rates can be related to this therapeutic modality. Much of the divergence in the data pertaining to the effects of conization on subsequent pregnancy o u t c o m e may reflect differences in the attitudes of institutions and surgeons toward cone size. Leiman et al) ° p e r f o r m e d a retrospective study of 88 pregnancies that o c c u r r e d in 77 patients after they had u n d e r g o n e cervical conization; in this study, p r e g n a n c y o u t c o m e was c o m p a r e d with cone
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Table III. Pregnancy o u t c o m e related to cone volume and height
i
Term
Premature delivery
Cesarean I section Stillbirth
(%)
(%)
vaginal delivery
Total
Spontaneous abortion Ectopic pregnancy Cone volume (ml) <4 >4 Cone height (cm) <2 >2
(%)
Trimester 1 (%)
Trimester 2
(%)
(%)
1 (3.2) --
4 (12.9) 3 (13.7)
2 (6.5) 4 (18.2)
1 (3.2) 7 (31.7)
5 (16.1) 3 (13.7)
2 (6.5) --
16 (51.6) 5 (22.7)
31 (100) 22 (100)
1 (1.5) --
5 (7.7) 2 (8.7)
8 (12.3) 5 (21.7)
6 (9.2) 7 (30.4)
10 (15.4) 1 (4.4)
2 (3.1) --
33 (50.8) 8 (34.8)
65 (100) 23 (100)
(%)
(%)
Modified from Leiman G, Harrison NA, Rubin A. Pregnancy following conization of the cervix: complications related to cone size. Am J Obstet Gyaaecol 1980;136:14-8.
Table IV. Length of time to conceive r e p o r t e d in questionnaire NO, of ~omen TiTtle to conc6iug
(mo)
Study group
Control group
<3 3-6 6-12 _>12
36 25 6 5
36 15 4 7
From Bigrigg A, Haffenden DK, Sheehan AL, Codling BW, Read MD. Efficacy and safety of large-loop excision of the transformation zone. Lancet 1994;343:32-4. ©1994 by The Lancet Ltd. The 95% confidence interval for difference between study and control groups = -31 to 32 mo.
size. Lateral and anterioposterior diameters and the h e i g h t of specimens were measured, and v o l u m e was calculated on the basis of these parameters. Unfortunately, n o t all three m e a s u r e m e n t s were available for all specimens (30); cone heights, a distance m e a s u r e d in all 77 specimens, were available. Volumes were categorized as large (>4 ml) or small (-<4 ml) and heights as large (>2 cm) or small (-<2 cm). These investigators n o t e d that the patients who had larger cones r e m o v e d were m o r e likely to have a midtrimester p r e g n a n c y loss, prematurity, and a decrease in n o r m a l vaginal delivery rates (Table HI). It is i m p o r t a n t to appreciate that these data are derived from a population that would be considered at high risk for p r e g n a n c y complications regardless of w h e t h e r the patient had u n d e r g o n e a cone biopsy. Regardless, the mid-trimester abortion rates in the large groups that und e r w e n t conization were h i g h e r than those r e p o r t e d for a similar p o p u l a t i o n that had n o t u n d e r g o n e the procedure. O n the basis of their data, L e i m a n et al. recomm e n d prophylactic cerclage in w o m e n who have u n d e r g o n e a " l a r g e " cone removal and subsequently conceive a desired pregnancy.
L o o p electrical excision procedure. A l t h o u g h the n u m ber of loop electrical excision procedures (LEEPs) being p e r f o r m e d is increasing because of the relatively recent widespread acceptance of this p r o c e d u r e by the gynecologic community, the data available regarding the impact of LEEP on subsequent fertility and p r e g n a n c y o u t c o m e are extremely limited. To date there have b e e n two significant reviews of the impact of LEEP on fertility. The first, f r o m Bigrigg et al., ~° r e p o r t e d on 250 m a t c h e d pairs of w o m e n (the patient u n d e r g o i n g the LEEP and a m a t c h e d control with the same date of birth, a t e l e p h o n e at h o m e , and a negative pap smear) who agreed to answer a questionnaire on menstruation, pregnancy, and infertility. The w o m e n in the study g r o u p had u n d e r g o n e a LEEP 3 to 4 years before answering the questionnaire; those in the control g r o u p had n o t received prior cervical treatment. O n e h u n d r e d forty-two of these w o m e n b e c a m e p r e g n a n t d u r i n g the time of the trial (76 in the study group and 66 in the control group). Sixty-nine study group pregnancies and 58 control group pregnancies resulted in live births. Five w o m e n in the study group and six w o m e n in the control group had spontaneous abortions, and two in each group had an ectopic pregnancy. Seventy-two of the w o m e n in the study g r o u p and 62 in the control group could r e m e m b e r how l o n g it took for t h e m to b e c o m e pregnant. T h e r e was no evident difference between the two groups in the time it took to conceive. Because of the limitations of the size of the study, however, only a threefold difference in infertility rates would have b e e n perceptible (Table IV). A similar evaluation that c o m p a r e d p r e g n a n c y rates and o u t c o m e s of a series of 574 w o m e n who had underg o n e LEEP with that of the general population was d o n e in the greater metropolitan Montreal area. 21 In contradistinction to Bigrigg and most o t h e r authors investigating postdysplasia t r e a t m e n t fertility, this group investigated the additive effect of cigarette smoking on pregnancy outcome; this is probably an i m p o r t a n t modifier because cigarette smoking n o t only increases a w o m a n ' s risk of
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Montz 1133
Table V. Outcome of pregnancy in women treated with cryosurgery for a cervical intraepithelial neoplasia
Before therapy After therapy
7btal No.
<36 wk gestation (%)
Cesareansection (%)
Perinatal death and stillbirth (%)
Prematurerupture of membranes (%)
Cervical insufficiency (%)
65 115
2 (3) 3 (2.6)
1' (1.5) llj- (9.6)
1 (3) 0
2 (3) 4 (3.5)
0 1 (0.9)
Cervical stenosis
From Hemmingsson E. Outcome of third trimester pregnancies after cryotherapy of the uterine cervix. Br J Obstet Gynaecol 1982;89:675-7. *Diagnosis: Pelvic disproportion (1). tDiagnosis: Pelvic disproportion (5), pathoIogic labor (1), placenta previa (1), suspected fetal growth retardation (1), breech presentation (1), asphyxia (1), and preeclampsia (1). developing cervical dysplasia but increases the risk of a pregnancy complication. Therefore, to accurately evaluate the effect of LEEP on subsequent pregnancies, a multivariate analysis stratifying for cigarette smoking (both "yes" or "no" and number) should be completed. In the LEEP group, 53 women had 54 pregnancies. Remarkably, 47% of these women were smokers. The pregnancy rate was equivalent to that in the Montreal metropolitan region when standardized by age. Pregnancy outcome was not different than that in the control population, with newborn weight being directly related to the mother's smoking history. These data help support file opinion of Bigrigg 2° and others 22 that LEEP has no untoward side effect on subsequent fertility and pregnancy outcome. As further reviews of large numbers of patients who have been followed up for significant time periods are reported, these opinions will be supported or refuted. Cryotherapy. Despite the fact that hundreds of thousands of women have been treated with cryotherapy, extensive data reviewing the impact of this therapeutic modality on fertility and pregnancy outcome do not exist. One of the early studies from Weed et al. 9 evaluated a group of 412 patients who had undergone cryotherapy as treatment for cervical dysplasia. Mthough the follow-up time was not given, the authors report a pregnancy rate of 29 per 1000 women, which was almost equivalent to that reported by the state of North Carolina for a population aged 15 to 44 years (29.8 per 1000 women). Little more can be concluded from this review because of the lack of data. Monaghan 23 reported on a cohort of 204 women who underwent cryotherapy as treatment for cervical dysplasia in an outpatient setting. Data on infertility were not included, although information about pregnancy outcome arising from 34 pregnancies that occurred in 30 patients was given. The study compared the outcomes of the postcryotherapy pregnancies to precryotherapy pregnancies in the same cohort. The authors claim that the pregnancy outcome, gestational age using general categorization, and mode of delivery were not different in the group treated with cryotherapy than in the population as a whole.
Probably one of the most interesting articles that has addressed the issue of cryotherapy and pregnancy outcome is of a study in which patients were used as their own controls; this study focused only on the outcome of third trimester pregnancies. 24 The women in the study population had 65 pregnancies before cryotherapy and 115 thereafter. No difference was found in gestational age at the time of delivery, stillbirth rate, premature rupture of membranes, or cervical incompetence before or after cryotherapy (Table V). Besides the expected difference in mean maternal age, there was an increase in the cesarean section rate in the postcryotherapy pregnancies. I t is probable, however, that this is not a reflection of an underlying effect of the cryotherapy on the ability of the cervix to dilate in labor bnt reflects the increase in the use of cesarean sections in the general community population (a 6% rate in 1973 compared with a 13% rate in 1980). Eighty-six percent of the precryotherapy pregnancies were completed before 1975, whereas 76% of the postcryotherapy pregnancies occurred between 1976 and 1980, during the same time period that use of cesarean sections increased significantly in the community. It is possible that cryotherapy has a positive effect on fertility. Limited data in the literature claim that in women believed to have a cervical environment hostile to sperm and sperm transport, cryotherapy may actually improve the quality of the cervical mucous and subsequently facilitate conception. 2~ In summary, remembering the limitations of the available data, there is no evidence that cryotherapy has a negative impact either on fertility or pregnancy outcome and, in selected patients, may improve the cervical milieu. Laser. As is the case with cryotherapy and fertility, despite the extensive use of laser therapy, minimal data are available to support opinions about its effect on fertility and pregnancy outcome. Nonetheless, it is widely claimed in print and even in major gynecologic oncology texts ~1 that laser therapy has no negative impact on fertility. Studies used to support this contention may not have been optimally designed to address the issue. In one study, 68 third-trimester pregnancies from a group of 68
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women who had undergone laser vaporization conization as therapy for CIN were compared with 70 controls matched for age, race, and n u m b e r of births and abortions? 6 No differences in birth weight, gestational age, duration of labor, or mode of delivery were noted. Although data regarding pre-third trimester pregnancy outcomes were included in the report, no comparison was made with the control population, nor was there any attempt to evaluate rates of infertility after laser treatment. As was demonstrated with cold knife conization,1° one could propose that increasing the volume of cervical stroma vaporized would lead to increasing risk of infertility, preterm births, and low-birth-weight infants. Because depth of vaporization appears to be related to the cure rate of the dysplasia, this is more than a theoretical consideration. Although study data have been used to support the contention that increasing the amount of cervix destroyed by vaporization does not have a negative impact on fertility and pregnancy outcome, the reader must be careful as to the conclusions that are derived from this data. 27 No attempts were made to compare patients with controls or to determine rates of infertility. Two groups (deep vaporization, i.e., >10 mm, versus vaporization of" <10 mm) were compared and differences in pregnancy outcomes were reported. Although only 10 completed pregnancies were reported in the group with vaporization of less than 10 mm, the conclusion was made that depth of vaporization has no effect on pregnancy outcome. Statistically, the small sample size would preclude detection of significant differences in pregnancy outcomes. The report of the Laser Study Group from the Royal College of Obstetricians and Gynecologists reviewed the merits of laser therapy in the treatment of CIN. 2s In this report, 97 pregnancies of 96 women who underwent laser vaporization to a depth of 8 mm for CIN were compared with pregnancies of 97 controls matched for age, parity, singleton pregnancy, race, and year of delivery. Not surprisingly, and as previously noted in patients who underwent LEEP procedures in Montreal, 21 the women who had cervical dysplasia and were subsequently treated with laser therapy were more likely to be cigarette smokers. Information regarding the outcome of first trimester pregnancies was not collected. There was no difference between the two groups with regard to pregnancy or labor duration, mode of delivery, mid-trimester pregnancy wastage, the rate of premature ruptured membranes, gestationat age between 28 and 37 weeks, and the n u m b e r of infants with a birth weight of less than 2.5 kilos. As with all so labeled "negative" studies, the power of the study to demonstrate a difference between the two groups must be considered. On the basis of the fertility and pregnancy outcome
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data available from reviews of other therapeutic modalities, it would be rational to postulate that laser vaporization and laser conization, which destroy or remove significan@ less volume of the cervix than cold knife conization, may not have the same negative effect on pregnancy outcome that is found with cold knife conizati0n. It is unlikely that this theory will ever be proved, however, because the frequency with which laser is used for the treatment of cervical dysplasia has significantly dropped during the past 5 years. Electrocoagulation diathermy. Although use of electrocoagulation diathermy is u n c o m m o n in North America, it has been widely used to treat cervical dysplasia in other industrialized countries, such as Australia. The data evaluating effects of this modality on fertility and pregnancy outcome are minimal. In a review from South Australia, investigators reported on 108 patients who attempted to become pregnant after undergoing electrocoagulation diathermy. 29 Ninety-six patients (89%) were able to conceive during a mean follow-up period of just over 3 years. These rates, as well as pregnancy outcomes, were equivalent to what was expected for members of the population as a whole who were of similar demographics and age. Remarkably, only four women had postdiathermy infertility, and one of them had previously undergone a tubal sterilization.
Conclusion The most important conclusion to be drawn from this review is that the data regarding the impact, if any, of the treatment of CIN on future fertility and pregnancy outcome is severely limited and at times contradictor},. In many of the studies performed to date, too few women have been enrolled to appreciate any but the most remarkable differences in treatment-related side effects. To effectively answer these questions, larger and better designed trials should be undertaken. Because decreasing numbers of patients are being treated with certain modalities (cold knife conization and laser vaporization), it is probable that the information presently available is the best that can be obtained. The potential still exists to complete well-designed and well-executed trials evaluating LEEP and cryotherapy. Considering the aforementioned limitations, one can make the following conclusions: 1. Cold knife cone biopsies probably have limited impact on the ability of a patient to conceive after undergoing the therapy. Any difficulty that occurs as a result of cervical stenosis or mucous deficiency should be readily surmounted with intrauterine insemination. Once pregnancy has occurred, however, data from multiple, i n d e p e n d e n t sources support the theory that women who have undergone cone
Volume 175, Number 4, Part 2 Am J Obstet Gynecol
biopsies have i n c r e a s e d rates o f s e c o n d t r i m e s t e r a b o r t i o n s , p r e t e r m delivery, a n d low-birth-weight infants. T h e i n f o r m a t i o n r e g a r d i n g i m p a c t o n d u r a tion o f l a b o r in s u b s e q u e n t p r e g n a n c i e s is less substantial. M u c h o f t h e d i s c r e p a n c y in t h e p u b l i s h e d l i t e r a t u r e m a y reflect institutional a n d individual surgical t e c h n i q u e s of p e r f o r m i n g c o n i z a t i o n ; t h e l a r g e r t h e c o n e ( e i t h e r volumetrically o r in c e p h a l a d c a u d a l l e n g t h ) , t h e m o r e likely t h a t a negative pregn a n c y o u t c o m e will occur. 2. It has n o t b e e n d e m o n s t r a t e d t h a t LEEPs have untoward side effects o n fertility or s u b s e q u e n t pregn a n c y o u t c o m e . T h i s o b s e r v a t i o n is b a s e d o n linaited b u t w e l l - d e v e l o p e d data. A l o n g - t e r m trial with a c o h o r t large e n o u g h for small b u t clinically i m p o r t a n t d i f f e r e n c e s to b e a p p r e c i a t e d s h o u l d b e u n d e r taken. 3. No negative effects o f c r y o t h e r a p y o n t h e p a t i e n t ' s s u b s e q u e n t ability to conceive or o n p r e g n a n c y outc o m e t h e r e a f t e r have b e e n d o c u m e n t e d . Cryot h e r a p y may have a p o t e n t i a l beneficial effect in selected p a t i e n t s w h o have a hostile cervical environment. 4. Data r e g a r d i n g the use o f lasers m u s t be s e p a r a t e d into d a t a for p a t i e n t s w h o have u n d e r g o n e laser v a p o r i z a t i o n with n o d o c u m e n t e d negative effects a n d data for t h o s e in w h o m t h e laser is u s e d as a n i n s t r u m e n t to p e r f o r m a conization. W h e n t h e laser is used to p e r f o r m a conization, t h e p o t e n t i a l for negative fertility-related side effects would, as is t h e case with cold knife c o n i z a t i o n , relate to t h e v o l u m e o f the cervix r e m o v e d . Because laser c o n e s have b e e n n o t e d to b e statistically smaller t h a n cold knife cones, it may b e this v o l u m e d i f f e r e n c e t h a t p r o t e c t s the r e c i p i e n t f r o m a side effect t h a t impairs fertility. 5. O f all t h e modalities r e p o r t e d , t h e least a m o u n t of data are available r e g a r d i n g d i a t h e r m y cautery. T h i s s c a n t data fails to d o c u m e n t any negative effects o n fertility o r p r e g n a n c y o u t c o m e .
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