Inclusion of studies
We identified seven studies providing information on pregnancy outcomes in women treated for cervical intraepithelial neoplasia that we subsequently excluded as they presented no data on a non-treated control group.w16-w22 One further study investigating laser treatment (laser conisation and laser ablation) was excluded as the authors did not provide outcome data for the excisional or the ablative treatment separately.w23
We identified 15 studies that fulfilled the eligibility criteria and provided data on perinatal mortality.w1 w2 w4-w6 w8 w10 w11 w13-w15 w24-w28
The number of studies that evaluated the other severe pregnancy outcomes was smaller: 11 studies reported on preterm delivery before 34 weeks of gestationw13 w4 w7 w11-w15 w25 w29 w30
and five studies on birth weight <2000 g.w8 w9 w13 w15 w25
Two studies involved only women treated for carcinoma in situ,w25 w30
while the rest included varying degrees of cervical intraepithelial neoplasia. For two of those reports, the original papers did not provide data on procedure specific outcomes, which were obtained directly from the authors.w13 w14
For the study by Jakobsson et al procedure specific outcomes were available only for the period 1997-2004.w14
We found eight new studies that were not included in the meta-analysis of Kyrgiou et al16
: six newer reportsw10-w15
and two older references identified by more comprehensive literature retrieval.w25 w28
Reports were written in English, except one that was in Norwegian.w25
Table 1 describes the characteristics of included studies ranked by year of publication. Women were treated by cold knife conisation in nine studies,w1-w3 w11-w14 w24 w25 large loop excision of the transformation zone in eight studies,w4-w7 w10 w11 w13 w14 and laser conisation in four studies.w8 w27-w29 In three studies, women were treated with excision biopsies without further clarification of the specific treatment.w14 w15 w30 Pregnancy outcomes after ablative treatment were less often described: two reports after cryotherapy,w11 w14 four after laser ablation,w8 w9 w13 w14 and only one after diathermy.w13
Table 1 Characteristics of included studies
Most included studies concerned retrospective cohorts; only one included a prospective cohort.w11 w25 In five studies, the control group comprised all women without a history of treatment included in national, regional, or service based birth registries.w12-w14 w30 Three studies compared pregnancy outcomes in the same group of women before and after treatment.w2 w25 w29 The other studies selected a control population after matching each treated woman with one to four untreated ones for several potential confounding factors such as age, parity, period of birth, smoking status, socioeconomic status, and obstetric antecedents (table 1).
Figure 1 shows the variation in relative risk for perinatal mortality associated with excision of cervical intraepithelial neoplasia. This forest plot contains subgroup meta-analyses by treatment procedure. Because of significant heterogeneity between procedures (P=0.031), we have not shown an overall pooled relative risk.
Fig 1 Meta-analysis of relative risk of perinatal mortality associated with excisional treatment for cervical intraepithelial neoplasia. *0.5 added to each cell of 2×2 contingency table because no cases were found in one of comparison groups. (more ...)
The risk of perinatal mortality was significantly increased in women treated with cold knife conisation (relative risk 2.87, 95% confidence interval 1.42 to 5.81). The Norwegian study showed an outlying high relative risk of 11.35 (2.68 to 48.10).w25 Omission of this study still yielded a pooled relative risk that was significantly different from unity (2.08, 1.04 to 4.13).
The risk associated with laser conisation was heterogeneous (I2=67%, P=0.082) and therefore not pooled. One study in which mini-conisation was used showed no increase (0.67, 0.11 to 3.96)w27 and another showed a substantial increase but did not reach significance (8.00, 0.91 to 70.14).w8
Four of seven studies showed a non-significantly increased risk of perinatal mortality in women treated with large loop excision of the transformation zone,w4-w6 w10 whereas in three the relative risk was near to or not significantly lower than unity.w11 w13 w14 This yielded a pooled relative risk of 1.17 (0.74 to 1.87).
Women whose cervical intraepithelial neoplasia was treated by excision without specification of the procedure showed a significantly increased risk of perinatal mortality.
Although the risk associated with ablative treatment was not increased (fig 2), there was a tendency for increased perinatal mortality in women treated with diathermy (relative risk 1.54, 0.84 to 2.82).
Fig 2 Meta-analysis of relative risk of perinatal mortality associated with ablative treatment for cervical intraepithelial neoplasia. *0.5 added to each cell of 2×2 contingency table because no cases found in one comparison group, allowing computation (more ...)
Severe and extreme preterm delivery
Severe preterm delivery (gestation <32/34 weeks) was significantly more common after cold knife conisation (pooled relative risk 2.78, 1.72 to 4.51) (table 2).
Table 2 Meta-analysis of studies comparing outcome of severe preterm delivery (<32/34 weeks) according to treatment for cervical intraepithelial neoplasia
In a small French study, one case of preterm delivery at less then 32 weeks was observed in 53 women who became pregnant after treatment with laser conisation, whereas none was observed in pregnancies before treatment.w29
Treatment with large loop excision of the transformation zone was not associated with an increased risk of severe preterm delivery (relative risk 1.20, 0.50 to 2.89) and showed heterogeneous results regarding extreme preterm delivery (table 3).
Table 3 Meta-analysis of studies comparing outcome of extreme preterm delivery (<28/30 weeks) according to treatment for cervical intraepithelial neoplasia
In two studies that used cold knife conisation or another excisional procedure without distinction by procedure, relative risks for severew15 w30 and extreme preterm deliveryw15 were significantly increased. El-Bastawissi et al used cold knife conisation or large loop excision and observed a relative risk for preterm delivery at <34 weeks of 2.13 (1.54 to 2.95),w30 which was intermediate to the pooled relative risks for cold knife conisation (2.78) and large loop excision (1.20). In the other study the relative risks for preterm delivery were 4.17 (1.72 to 10.10) at <32 weeks (table 2) and 13.00 (1.70 to 99.12) <28 weeks (table 3).w15
Laser ablation or cryotherapy was not associated with higher rates of severe or extreme preterm delivery: relative risks generally were lower but not significantly lower than unity. In one study laser ablation was associated with a significantly lower probability of severe and extreme preterm delivery with relative risks of 0.29 (0.15 to 0.58) and 0.27 (0.09 to 0.82), respectively.w14
In one study diathermy resulted in significantly increased rates of both severe (relative risk 2.54, 1.65 to 3.89) and extreme (relative risk 2.15, 1.11 to 4.18) preterm delivery.w13
Severe and extreme low birth weight
Tables 4, 5, and 6 show the effects on birth weight. Three studies that evaluated cold knife conisation, laser conisation, or excision with laser conisation/large loop excision showed a significantly increased risk for birth weights <1500 gw8 w13 w15 (table 5). In two Norwegian studies cold knife conisation and excisional treatment (with laser conisation/large loop excision) were associated with extreme low birth weight (<1000 g, table 6).w15 w25
Table 4 Meta-analysis of studies comparing outcome of severe low birth weight (<2000 g) according to treatment for cervical intraepithelial neoplasia
Table 5 Meta-analysis of studies comparing outcome of severe low birth weight (<1500 g) according to treatment for cervical intraepithelial neoplasia
Table 6 Meta-analysis of studies comparing outcome of severe low birth weight (<1000 g) according to treatment for cervical intraepithelial neoplasia
Laser ablation was not associated with increased risks for very low birth weight (table 6), while a significantly higher rate of birth weights of <2000 g (table 4) and <1500 g (table 5) was observed in women treated with diathermy.w13
Robustness of pooled relative risks
Treatment of cervical intraepithelial neoplasia with large loop excision resulted in a non-significantly increased risk of perinatal mortality (1.17, 0.74 to 1.87) (fig 1). Three of the seven studies, however, showed no counts in one of the comparison groups,w4 w6 w13 necessitating the use of a continuity correction (κ=0.5). Table 7 shows the results of alternative models for combining relative risks and different continuity corrections. All models and continuity corrections resulted in similar pooled estimates, underlying the robustness of the meta-analysis. Similar pooled relative risks for perinatal mortality were also obtained for the other excisional methods (data available from authors).
Table 7Relative risk (95% confidence interval) for perinatal mortality in women treated with large loop excision of transformation zone for cervical cancer precursors versus women not treated. Results obtained with different models and methods for (more ...)
Too few studies evaluating other outcomes were available to test the robustness of the pooled estimates.
Obstetric harm after treatment
We pooled the absolute frequency of adverse obstetric outcomes after treatment (pT) and in the cumulated control populations (pC) and derived the number needed to treat to observe obstetric harm in one treated woman (NNTH) (table 8). We excluded the study of Lund et alw25 because of outlying relative risks that we considered were not representative for the other studies.
Table 8 Meta-analysis of adverse obstetric outcomes in treated women (by procedure) and in non-treated control populations, with pooled frequency of obstetric events and number needed to treat to observe harm (NNTH)
We estimated that previous treatment with cold knife conisation, laser conisation, or diathermy would result in about one perinatal death in every 70 pregnancies. After large loop excision of the transformation zone, however, we estimate only two perinatal deaths in 1000 pregnancies. Severe and extreme preterm delivery and low birth weight were common (NNTH often <60) after cold knife conisation and diathermy but rare after large loop excision (NNTH (delivery <32-34 weeks, birth weight <2000 g) >100 or NNTH (birth weight <1500 g) >500).