Using logistic regression, the relation of treatment interval and spontaneous preterm birth remained significant (P=.015) when adjusting for race and dimension of the excised cervical specimen. If treatment interval is dichotomized the odds ratio (OR) for spontaneous preterm birth is 20.2 (95% confidence interval 2.0–207.2). Treatment interval was dichotomized at 12 months, with short interval defined as less than 12 months and long interval as 12 months or more.
Women undergoing treatment for cervical dysplasia are a heterogeneous group with different individual risk profiles for preterm birth. Identifying those factors associated with conization procedures that may place women at higher risk for preterm delivery is important for both patient counseling and risk modification. This idea was illustrated by a recent study published by Sadler et al,3 who reported birth outcomes among women treated for cervical dysplasia. This study did not show an association between treatment for cervical dysplasia and overall preterm birth. It did, however, find a statistically significant increased risk of preterm PROM in women who had laser conization or LEEP and showed an increasing risk of preterm PROM with increasing cone size. Thus, the subset of women with larger cervical excisions were at higher risk for preterm delivery after conization. The findings of our study identify another subset of women—those women who conceive within 2–3 months of LEEP or large loop excision of the transformation zone—who may be at higher risk for preterm delivery. This possible risk factor for preterm birth after LEEP or large loop excision is modifiable, making it a potentially important issue to discuss with patients.
The mechanism by which a short treatment interval predisposes to preterm birth is unclear. The structural integrity of the cervix may be diminished immediately after a cone procedure, limiting the ability of the cervix to support a pregnancy. With time, the cervix may scar or regenerate, minimizing the structural weakness of the cervix. Certainly, the association between shortened cervical length and preterm birth is well established.13,14 Additionally, there are numerous studies examining cervical length as determined by transvaginal ultrasonography after conization that reveal a shortened cervix after conization procedures.15,16 Mazouni et al16 found a mean cervical length after LEEP (within 7 days of procedure) of 24.3±6.7 mm. Interestingly, there are conflicting results about whether this shortening persists after LEEP. Some investigators have noted a trend toward cervical regeneration at 3–12 months after conization, which might minimize the risk of preterm birth after this period.17,18 The mechanisms by which a short cervix after conization might lead to subsequent preterm birth are not well understood. It is important to note that a short cervix by transvaginal ultrasonography is not unequivocally equivalent to a structurally weak cervix. A cervix that is short may be structurally quite sound. In fact, studies that have examined the efficacy of ultrasonography indicated that cerclage for shortened cervix has not shown benefit to cerclage.19,20
More plausibly, perhaps the immunologic milieu of the cervix is altered by a cone procedure. A cone procedure is associated with a significant inflammatory infiltrate. This inflammatory process may alter the cytokine environment early in pregnancy, predisposing a woman to ascending infection. Alternatively, perhaps the cone procedure itself introduces a low-grade infection that ultimately leads to an ascending infection. The cervix is not simply an anatomic barrier between the vagina and the uterus, but also an immunologic barrier that protects the uterus from ascending microbial invasion. A cervix that is surgically shortened may have an altered capacity to provide immune protection. Alternatively, a cervix that is surgically shortened may be more responsive to biochemical stimuli promoting preterm birth than a longer cervix. There are few data regarding the specific immunological and inflammatory processes involved in healing from conization, but, in general, wound healing, whether cutaneous or mucosal, is an intrinsically inflammatory process. Proinflammatory cytokines, matrix metalloproteinases, and prostaglandins are all increased in healing tissues. The nature and degree of inflammation in a healing wound abates over time.21,22 Perhaps establishing a pregnancy while the cervix is in the midst of healing inflammation has adverse functional consequences. Although the mechanism is not clear, there are biologically plausible reasons to support the idea that a short time interval from cone procedure to conception would increase a woman's risk for preterm delivery.
The disparity in preterm birth between white and African-American women is well established in the obstetric literature and remains poorly understood.23–26 Importantly, many confounders of preterm birth, such as prior preterm birth or tobacco use, were controlled for in our study, making the racial difference identified more compelling. Today's understanding of the biology of the racial disparity in preterm birth does not afford us the opportunity to explain this finding in our study. The persistence of risk for preterm birth among African-American women may have a real biological basis, or it may be an epiphenomenon with its underlying explanation in some other gene-environment interaction. To draw further conclusions in this regard would just be speculation.
The small number of women who underwent a cone procedure followed by a delivery is the most significant limitation of this study. Because of this small sample size, we are unable to characterize the magnitude of effect of a short treatment interval on subsequent pregnancy outcomes with as high a degree of precision as we would like. Consequently, we are unable to comment on whether there is a meaningful opportunity for intervention to decrease a woman's risk of preterm birth after LEEP or large loop excision by delaying her time to conception. Additionally, given the concern for second-trimester losses after cervical conization procedures, the inclusion of women after only 20 weeks gestation is another limitation of this study.
Finally, it is important to address the impact of short interpregnancy interval on preterm birth. The magnitude of increased risk of preterm birth with interpregnancy interval less than 6 months is estimated to be 30–60%.27–30 The relationship between short interpregnancy interval and preterm birth has been noted to be similar in magnitude and significance for African-Americans and white women.31,32 In the general obstetric population at low risk for adverse pregnancy outcomes, Adams et al33 found that short interpregnancy intervals are rare and are weak risk factors among low-risk women. In the segment of our cohort that did not undergo conization, there was no relation between short interval and subsequent preterm birth (data not shown). Thus, in this cohort short interpregnancy interval is unlikely to be a significant confounder of our finding of the relation between conization-to-conception interval and preterm birth.
In conclusion, this study identifies a subset of women who may be at higher risk of preterm delivery after their cone procedures. Future studies investigating the association between a short interval from conization to pregnancy would be helpful because this is a potentially modifiable risk factor for preterm birth.
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