Obstetric and neonatal outcome after surgical treatment of cervical dysplasia

European Journal of Obstetrics & Gynecology and Reproductive Biology 162 (2012) 16–20

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Obstetric and neonatal outcome after surgical treatment of cervical dysplasia Marie Van Hentenryck a, Jean Christophe Noel b, Philippe Simon a,* a b

Department of Obstetrics and Gynecology, ULB Erasme Hospital, 808 Route de Lennik, 1070 Brussels, Belgium Department of Gynecopathology, ULB Erasme Hospital, 808 Route de Lennik, 1070 Brussels, Belgium

A R T I C L E I N F O

A B S T R A C T

Article history: Received 10 October 2011 Received in revised form 4 January 2012 Accepted 30 January 2012

Objectives: Conization is the gold standard today for the management of severe cervical dysplasia. However, with the increasing delay until first pregnancy, obstetric follow-up of patients with a history of conization is a growing concern. Study design: Retrospective case–control study using data from the electronic database of a university hospital. We compared the obstetric and neonatal outcome of 106 pregnancies delivered after conization with the outcome of 212 pregnancies of patients with no history of conization. Results: A significant reduction in the mean gestational age at delivery (38.23  2.51 weeks vs. 39.15  1.56 weeks) was observed, together with a higher rate of premature rupture of the membrane (9.4% vs. 1.9%), premature onset of labor (9.4% vs. 2.4%), premature delivery (17% vs. 3.8%) and neonatal hospitalization (17.9% vs. 6.6%) in the group of patients with history of conization. Children born to women who had surgery had a significantly lower birth weight (3146.9  611 g vs. 3347.3  502 g) and size (49.1  2.6 cm vs. 50.0 cm  2.2 cm) than those of the control group. Furthermore, these children were more frequently admitted in the neonatal intensive care unit (22.6% vs. 10.4%, p = 0.004). Conclusions: Conization is an important risk factor for premature birth and women with a history of conization require cautious obstetric management during pregnancy. Anti-HPV vaccination and proactive surveillance of low-grade or moderate dysplasia, instead of immediate surgery, should be encouraged in young patients. ß 2012 Elsevier Ireland Ltd. All rights reserved.

Keywords: Cervix Conization Obstetric outcome

1. Introduction Human papillomavirus (HPV) infection is the most common sexually transmitted disease [1]. During their lifetime, more than 75% of sexually active women will contract the virus [2]. There are many different types of HPV, which can be differentiated based on their oncogenic properties, and persistent infection with oncogenic HPV types can cause cervical cancer [3]. HPV types 16 and 18 account for more than 50% of all precancerous lesions of the uterine cervix and more than 70% of all cervical cancers. Factors associated with a persistent infection are cigarette smoking, high parity, simultaneous herpes simplex virus type 2 or Chlamydia trachomatis infection, and immunodeficiency. An association with prolonged oral contraceptive use is still a matter of debate [2]. The time of progression from severe dysplasia to invasive cancer is shorter in women with oncogenic HPV types than in women with

Abbreviations: CIN, cervical intraepithelial neoplasia; HPV, human papillomavirus; NICU, neonatal intensive care unit; OR, odds ratio; PROM, premature rupture of membranes; RR, relative risk. * Corresponding author. Tel.: +32 25 55 36 85. E-mail address: [email protected] (P. Simon). 0301-2115/$ – see front matter ß 2012 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.ejogrb.2012.01.019

no HPV infection. The risk of developing cervical cancer from highgrade dysplasia (CIN3) is estimated at 31% after 30 years [4]. Cervical cancer is the second most common cause of cancerrelated death among women worldwide. Eighty percent of these deaths occur in developing countries, with a peak of mortality between 35 and 55 years of age. HPV infection, however, is more frequent in adults younger than age 25 [1]. This can be explained by the greater exposure of the junctional zone and the greater number of sexual partners among this population [5]. Fortunately, this young population is characterized by a high HPV clearance rate, and the infection is usually limited to six to 18 months [6,7]. In some developed countries, well-organized screening programs and adequate treatments of cervical dysplasia have led to a 10-fold decrease in the incidence and mortality of cervical cancer. Conization, which consists of the more or less extensive resection of the transformation zone according to the procedure used, is the treatment of choice for high-grade cervical lesions, and can be performed with a cold knife, laser or electrosurgical loop. Severe dysplasia affects mostly women between the ages of 25 and 29 [8]. Since the 1980s, the number of younger girls being treated and the age of first pregnancy have both increased, highlighting the interest in studying the relationship between cervical surgery and obstetric outcome. Leiman, in 1980, was the

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first to demonstrate the correlation between the mean height of the excised cone and the rate of premature births [9] and other works later confirmed these data [10,11]. The present study examines the influence of conization on several obstetric and neonatal parameters, comparing a group of patients who underwent surgery to a paired control group. 2. Materials and methods This retrospective case–control study was performed using data from the electronic databases of the Gynecopathologic and Obstetrics Departments of Erasme University Hospital, and was approved by the Hospital Ethics Committee. The population of patients who underwent conization between January 1999 and 2008 was cross-checked with the database of the Maternity Department to select patients who delivered in Erasme Hospital after undergoing operations on the uterine cervix (with cold knife, laser or loop). The pathologist measured the cone dimensions before fixation, and the volume of the cone was calculated using the following mathematical formula: V = (1/3)pr2h (r = transverse diameter/2, h = height). Each patient who underwent conization was paired with two control patients who did not undergo conization based on their age at the time of delivery, history of gestation, parity, cigarette smoking and human immunodeficiency virus status. Each patient

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was paired with the first preceding and following patients fulfilling the criteria mentioned above. For each pregnancy, the following obstetric data were studied: duration of gestation from the first day of the last menstrual period, delivery before the end of 37 weeks, prenatal hospitalization (for any reason prior to admission for delivery), preterm labor requiring tocolytic treatment, premature rupture of membranes (PROM), and contamination by group B Streptococcus Beta, four weeks before delivery. The characteristics of onset of labor and mode of delivery were recorded. The neonatal variables studied were weight (g), size (cm), and cranial circumference (cm) at birth, gender of the newborn, Apgar score one minute and five minutes after birth, umbilical artery blood pH, and eventual hospitalization (and duration of hospitalization) in the neonatal intensive care unit (NICU). The correlation between data related to conization (time spent between conization and last menstrual period, technique used, diameter and height of the cone, pathologic result of the excised cone) and obstetric data was studied. Statistical analyzes were performed with the Statistix 9 software. The comparison between the mean values of continuous variables was performed with Student’s t-test (mean  standard deviation) or Wilcoxon rank-sum test (median value and P25–P75), depending on whether or not the distribution was normal. Variables composed of two groups or more were analyzed with the Kruskal– Wallis test. A difference was considered significant if p < 0.05.

Table 1 Population characteristics. Demographic characteristics Study group n = 106

Weight at start pregnancy (kg) Weight at end pregnancy (kg) Age at delivery (years)

Control group n = 212

p-Value

x¯

SD

x¯

SD

65.98 78.78 31.6

15.89 16.37 4.79

65.60 77.85 31.6

13.31 12.87 4.79

0.7 0.9 0.9

Demographic characteristics Study group n = 106

Women who smoke Risk factors

Control group n = 212

p-Value

N

%

N

%

37 11

34.9 10.6

74 29

34.9 13.7

1.0 0.4

Obstetric characteristics Study group n = 106

PROM Spontaneous pretem labor Chorioamnionitis Preterm < 37 weeks Preterm < 34 weeks MIC hospitalization GBS+

Control group n = 212

p-Value

N

%

N

%

10 10 3 19 7 18 17

9.4 9.4 2.8 17.9 6.6 17.0 20.2

4 5 2 13 0 8 34

1.9 2.4 0.9 6.1 0.0 3.8 16.6

0.002 0.005 0.204 0.001 <0.001 <0.001 0.461

Obstetric characteristics Study group n = 106

Mean gestational age

Control group n = 212

p-Value

x¯

SD

x¯

SD

38.23

2.52

39.16

1.57

0.002

Delivery characteristics Study group n = 106

Induced labor Caesarean Vacuum assisted

Control group n = 212

p-Value

N

%

N

%

26 14 17

24.5 13.2 16.0

56 40 39

26.4 18.9 18.5

Risk factors: arterial hypertension, diabetes, preterm births, IUGR, cervical insufficiency, hydramnios, urinary tract infection.

0.718 0.206 0.604

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Table 3 Conization data (n = 88).

3. Results Between January 2000 and December 2010, a total of 106 deliveries of women who underwent surgical conization were recorded in our hospital. This included 88 patients who were operated on between January 1999 and December 2010. In this group of patients, 72 women delivered once, 14 delivered twice and two delivered thrice after surgery. The mean age at the time of conization was 29. The characteristics of the study population are presented in Table 1. Forty patients (46%) underwent a loop procedure, 14 (16%) had a cold-knife procedure and 33 (37.9%) had a CO2 laser procedure (one missing data). The pathologic analysis revealed 10 cases (11.8%) of low-grade cervical intraepithelial neoplasia (CIN1), 23 cases (27.0%) of CIN2 and 52 (61.2%) cases of CIN3 (Table 2). The median time between conization and pregnancy was 24 months (1–102). The mean cone height was 1.4 cm (4.9 mm), and the mean exocervical diameter (maximal transverse diameter) was 9.3 mm (4.8 mm). The median excised cone volume was 1104.5 mm3 (Table 3). The mean height of the surgical specimens excised tended to increase with the severity of the lesion, but no correlation was found between the mean height and the excision technique used. Table 1 summarizes the maternal data of the two populations. No significant difference was observed between these populations according to the pairing criteria chosen (age at delivery, cigarette smoking, gestation and parity). No weight difference before and after pregnancy was detected between the study and control populations. Gestational age at delivery (Table 4) was significantly lower in the study population (38.23  2.52 weeks) than in the control population (39.16  1.57 weeks, p = 0.002). The risk factors for premature birth studied were arterial hypertension, diabetes, history of preterm labor, history of failure to thrive, cervical weakness, polyhydramnios and urinary infection. A similar proportion of patients had one risk factor for premature birth in both groups [11/106 (10.6%) vs. 29/212 (13.7%), p = 0.40]. The patients who underwent conization presented a significantly higher risk of PROM [10/106 (9.4%) vs. 4/212 (1.9%), p = 0.002]. Their risk of spontaneous preterm labor [10/106 (9.4%) vs. 5/212 (2.4%), p = 0.005] and prenatal hospitalization [18/106 (17%) vs. 8/212 (3.8%), p < 0.001] was also significantly increased. The indications for hospitalization in operated patients were: PROM (seven cases, mean gestational age 30.7 weeks) preterm labor (nine cases, mean gestational age 30.9 weeks) and second trimester bleeding (two cases). In the control group, the indications for prenatal hospitalization were PROM (one patient, 30 weeks), preterm labor (five cases, mean gestational age 30.6 weeks), pulmonary infection (one case), and failure to thrive (one case). No correlation was found between the characteristics of the conization (technique used or size of the specimen), and the obstetric variables analyzed in this study. Indeed, considering loop, Table 2 Mean height of the surgical specimen according to the histological diagnosis and the surgical technique (n = 88). N Histological diagnosis CIN 1 10 CIN 2 23 CIN 3 52 Missing data 3 Surgical technique Loop 40 Cold knife 14 Laser 33 Missing data 1

%

Mean height (mm)

SD

p-Value

11.8 27 61.2

9.34 11.65 13.34

4.06 5.97 4.38

0.038

46 16.1 37.9

11.64 13.71 12.63

4.79 5.6 4.89

0.56

Mean age Height of cone (mm) Mean ectocervical diameter (mm)

Time between conization and pregnancy Specimen volume (mm3)

N

x¯

SD

88 86 86

29.0 12.4 19.3

4.5 4.9 4.8

N

Median

P25–P75

88 86

24 1104.5

7–42 714.5–1665

cold-knife and laser techniques, the incidences of delivery before 37 weeks of gestation were 14.9%, 20% and 20.9%, respectively, and 6.4%, 6.7% and 7% when deliveries before 34 weeks were considered (p = 0.75 at 37 weeks and 0.99 at 34 weeks). Nineteen out of 106 (17.9%) premature deliveries were observed in the study group [six (5.7%) before 34 weeks], which is significantly more than the control group (13/212, 6.1%, p = 0.001), where there was no delivery before 34 weeks. The mode of delivery (spontaneous vaginal delivery, assisted vaginal delivery or cesarean section) was similar in the two groups (Table 4). Neonates of mothers who had undergone surgery were significantly smaller (49.1  2.6 cm vs. 50.0  2.2 cm; p = 0.01) and weighed less (3147  611 g vs. 3347  497 g; p = 0.01) than those of the control group. Twenty newborns (22.6% vs. 10.4%; p = 0.03) from the first group were admitted to the NICU, and their hospitalization stay was significantly longer [11 days (2–24) vs. two days (1–5); p = 0.01]. Nevertheless, the Apgar scores (at one and five minutes) and umbilical artery blood pH were similar in both groups (Table 4). No significant correlation was found between the size of the excised cone, the time between surgery and delivery, and the histological type, and obstetric and neonatal outcome in these populations. 4. Comments A total of 8500 cervical conizations are performed every year in Belgium. The results presented above indicate that there is an impact of cervical conization and increasing time until first pregnancy on neonatal and obstetric outcome. Kyrgiou et al. have already shown that all cervical resection techniques are associated with obstetric complications [12]. Prematurity is a leading cause of perinatal morbidity and mortality and has an important financial impact. Therefore, it is critical to prevent it and develop new tools to detect cervical dysfunction. In this study, the mean length of pregnancy was one week shorter in patients who underwent surgery than in those of the control group (38.2 weeks vs. 39.2 weeks; p < 0.05). The relative risk (RR) for premature delivery (before the end of 37 weeks) was 3.34 (95% CI: 1.58–7.06). These results are in agreement with lesspowered meta-analysis, which reported an RR of 7.0 for delivery before 37 weeks (95% CI: 1.8–28, p = 0.002) [12,13], but contradict the study by Sadler et al., who reported an RR for premature delivery of 1.1 (0.8–1.5) after conization [14]. It should be noted, however, that the latter study did not consider cold-knife conization, while it considered both ablation and excision techniques. Indeed, Arbyn et al. [11] showed that a significant increase in the risk of preterm birth (before 34–37 weeks) was observed with cold-knife conization only (RR:2.78, 95% CI: 1.72– 4.71), and ablation procedures have not been associated with an increased risk of premature delivery. Premature deliveries are the result of premature onset of labor or PROM. Both complications were detected in our series, and the latter was also reported by authors studying the consequences of

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Table 4 Neonatal data. Surgery group (n = 106)

Birth weight (g) Size (cm)

Control group (n = 212)

x¯

SD

x¯

SD

3146.9 49.1

611.3 2.6

3347.3 50.0

496.9 2.2

Surgery group (n = 106)

Umbilical artery pH 1 min Apgar score 5 min Apgar score Neonatal admission (days)

Control group (n = 212) P25–P75

Median

P25–P75

7.3 9 10 11 (N = 20)

7.27–7.45 9–10 9–10 2–24

7.3 9 10 2 (N = 22)

7.25–7.35 9–10 9–10 1–5

Control group (n = 212)

0.22 0.37 0.95 0.01 p-Value

N

%

N

%

20 57 13

22.6 54.3 12.3

22 112 7

10.4 52.6 3.3

loop excision (2.69, 95% CI: 1.62–4.46) [11], by Samson et al. (OR 4.10, 95% CI: 1.48–4.09) [15] and by Sadler et al. (laser and loop, in 2004) [14]. Structural modification of the cervix and partial destruction of the endocervical glands might be associated with a change in the quantity and biochemical composition of the mucus. Indeed, its components change along the canal, providing a mechanical and biochemical barrier against ascending infections responsible for PROM [16]. An increase in cytokines and chemokines can be induced by the presence of microorganisms present in the choriodecidual space, and has been demonstrated in patients with PROM or preterm labor associated with endouterine infection [17]. The rate of anovaginal colonization by group B Streptococcus Beta being similar in both groups, the higher rate of PROM and preterm labor observed could result from a higher sensitivity. This retrospective study indicates that the risk of obstetric complications is higher in patients who underwent cervical conization. Nevertheless, the direct implication of surgery or associated pre-existing risk factors is difficult to ascertain, because several risk factors for cervical dysplasia are also risk factors for premature onset of labor [18]. Indeed, Bruinsma et al. [19] showed that the risk of premature delivery was greater in a group of nontreated patients with cervical dysplasia than in the general population. A similar observation was made by Shanbhag et al. after pairing for age, smoking habits and socioeconomic status [20]. The impact of pre-existing factors was also studied by comparing deliveries before and after conization in the same patients. The results are contradictory, as Andia et al. [21] reported a similar rate of premature deliveries, whereas Albrechtsen et al. [22] observed a statistically significant increase in risk. In our population, the size of the surgical specimen excised increased with the underlying severity of the pathology. This is probably due to the adjustment of the resection to the dimensions of the dysplasia, as observed by colposcopy. No correlation was found between the characteristics of the conization (technique used or size of the specimen) and the obstetric item analyzed. More powered studies lead to different results. Indeed, Sadler et al. [14] showed that the risk of PROM was higher (RR: 3.0) when the height of the specimen was more than 17 mm. Moreover, Leiman and Kyrgiou [9,12,23] observed a significant increase in the risk of premature delivery, over 10 mm. The mean birth weight of infants born of mothers who had undergone surgery was lower than the weight of infants born of mothers from the general population. Furthermore, these infants

0.01 0.01 p-Value

Median

Surgery group (n = 106)

Duration of neonatal admission (days) Gender (M) Birth weight < 2500 g

p-Value

0.03 0.75 0.002

were more frequently admitted to the NICU and for a longer period of time. This observation has also been described by other authors [11–13], although Kyrgiou et al. did not detect an increase in neonatal hospitalization. Given the increased neonatal morbidity associated with conization and the high rate of spontaneous regression of lowgrade dysplasia in young patients, physicians should wait before performing cervical surgery [24], and widespread anti-HPV vaccination should be promoted to avoid unnecessary surgery. Today, there is no specific recommendation for the follow-up of patients after conization. Ultrasound measurement of the cervical length is usually considered as a good predictive marker of prematurity [25]. Prophylactic cervical cerclage does not appear to reduce the risk of prematurity and can even be deleterious on its own [26]. The impact of the regular assessment of cervical length and vaginal flora and the impact of the preventive administration of corticoids on the risk of prematurity should also be evaluated for optimal prenatal care. In conclusion, the present study reports a significant increase in the risk of premature delivery, PROM and premature onset of labor during pregnancies after cervical conization. The results indicate that newborns of these women are significantly younger and weigh less at delivery, and they more commonly stay for a longer period of time in the NICU. Due to the increasing time delay to first pregnancy in Western countries, it is critical to avoid cervical surgery as much as possible. Anti-HPV vaccination and proactive surveillance of low-grade or moderate dysplasia, instead of immediate surgery, should be encouraged in young patients. Acknowledgement This work was partly supported by a grant of the belgian Televie. References [1] Franceschi S, Herrero R, Clifford GM, et al. Variations in the age-specific curves of human papillomavirus prevalence in women worldwide. Int J Cancer 2006;119(11):2677–84. [2] Lowy DR, Solomon D, Hildesheim A, Schiller JT, Schiffman M. Human papillomavirus infection and the primary and secondary prevention of cervical cancer. Cancer 2008;113(7 Suppl.):1980–93. [3] Bosch FX, Lorincz A, Munoz N, Meijer CJ, Shah KV. The causal relation between human papillomavirus and cervical cancer. J Clin Pathol 2002;55(4): 244–65. [4] McCredie MR, Sharples KJ, Paul C, et al. Natural history of cervical neoplasia and risk of invasive cancer in women with cervical intraepithelial neoplasia 3: a retrospective cohort study. Lancet Oncol 2008;9(5):425–34.

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