Caesarean delivery and subsequent pregnancy interval: a systematic review and meta-analysis

Research article
Open access
Published: 27 August 2013

Sinéad M O’Neill¹,
Patricia M Kearney²,
Louise C Kenny³,
Tine B Henriksen⁴,
Jennifer E Lutomski¹,
Richard A Greene¹ &
…
Ali S Khashan³

BMC Pregnancy and Childbirth volume 13, Article number: 165 (2013) Cite this article

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Abstract

Background

Caesarean delivery has increased worldwide, however, the effects on fertility are largely unknown. This systematic review aims to compare subsequent sub-fertility (time to next pregnancy or birth) among women with a Caesarean delivery to women with a vaginal delivery.

Methods

Systematic review of the literature including seven databases: CINAHL; the Cochrane Library; Embase; Medline; PubMed; SCOPUS and Web of Knowledge (1945 - October 2012), using detailed search-strategies and reference list cross-checking. Cohort, case–control and cross-sectional studies were included. Two assessors reviewed titles, abstracts, and full articles using standardised data abstraction forms and assessed study quality.

Results

11 articles were eligible for inclusion in the systematic review, of these five articles which adjusted for confounders were combined in a meta-analysis, totalling 750,407 women using fixed-effect models. Previous Caesarean delivery was associated with an increased risk of sub-fertility [pooled odds ratio (OR) 0.90; 95% CI 0.86, 0.93]. Subgroup analyses by parity [primiparous women: OR 0.91; 95% CI 0.87, 0.96; not limited to primiparous women: OR 0.81; 95% CI 0.73, 0.90]; by publication date (pre-2000: OR 0.80, 95% CI 0.68, 0.94; post-2000: OR 0.90, 95% CI 0.86, 0.94); by length of follow-up (<10 years: OR 0.81, 95% CI 0.73, 0.90; >10 years: OR 0.91, 95% CI 0.87, 0.96); by indication for mode of delivery (specified: 0.92, 95% CI 0.88, 0.97; not specified: OR 0.81, 95% CI 0.73, 0.90); by cohort size (<35,000: OR 0.79, 95% CI 0.67, 0.92; >35,000: OR 0.90, 95% CI 0.87, 0.95), by definition of sub-fertility used divided into (birth interval [BI]: OR 0.89, 95% CI 0.84, 0.94; inter-pregnancy interval [IPI]: OR 0.91, 95% CI 0.85, 0.97; and categorical measures: OR 0.81, 95% CI 0.73, 0.90); continuous measures: OR 0.91, 95% CI 0.87, 0.96) were performed. Results of the six studies not included in the meta-analysis (which did not adjust for confounders) are presented individually.

Conclusions

The meta-analysis shows an increased waiting time to next pregnancy and risk of sub-fertility among women with a previous Caesarean delivery. However, included studies are limited by poor epidemiological methods such as variations in the definition of time to next pregnancy, lack of confounding adjustment, or details of the indication for Caesarean delivery. Further research of a more robust methodological quality to better explore any underlying causes of sub-fertility and maternal intent to delay childbearing is warranted.

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Background

Over the past three decades, rates of Caesarean delivery have increased dramatically worldwide [1, 2]. In the United Kingdom (UK) for example, 2% of all births were delivered via Caesarean section in 1953, 18% in 1997 and 21% in 2001 [3]. In 2010, the Caesarean delivery rate was 24.8% in the UK [4]. Statistics from 2010–2011 for Australia and the United States of America (USA) show almost one in every three pregnant women has a Caesarean delivery [5, 6].

A number of possible biological mechanisms for an association between Caesarean delivery and sub-fertility have been postulated including infection at the site of the wound, scar adhesion and placental bed disruption [7]. The waiting time to next pregnancy or birth is reported to be a robust surrogate marker of sub-fertility in the literature [8]. A number of studies to date have assessed the long-term consequences of Caesarean delivery on subsequent fertility [7, 9, 10] including two reviews [11, 12]. To date, few studies have found that women with a Caesarean delivery are less likely to have a subsequent pregnancy and have a longer pregnancy interval compared to women with a vaginal delivery, even after adjustment for parity [9, 11, 13–15]. In addition, one study examined a sub-group of women with pre-eclampsia and it was reported that women who delivered by Caesarean were 20% less likely to have another pregnancy [16]. Other studies have claimed a Caesarean delivery does not affect future fertility [17, 18].

A recent systematic review and meta-analysis investigating the rate of continuation to a subsequent pregnancy reported that women with a previous Caesarean delivery are 9% less likely to have a subsequent pregnancy and 11% less likely to have a subsequent birth [12]. This systematic review however did not meta-analyse subsequent pregnancy interval, which is arguably a more robust marker of sub-fertility. However, it must be noted that women who have a Caesarean delivery may differ in many respects, for example, in height, age, body mass index (BMI) and obstetric history. Thus, any association between mode of delivery and subsequent sub-fertility may be confounded by a variety of medical, obstetrical, social and socioeconomic confounding factors [19–23]. Furthermore, residual confounding such as the indication for Caesarean delivery may explain part or all of the association between Caesarean delivery and sub-fertility [18].

There are an estimated 70 million couples worldwide who are infertile and the long-term clinical outcomes associated with sub-fertility are uncertain [24]. With one in every six couples reported to be seeking fertility treatment [25] any potential association between mode of delivery and subsequent sub-fertility could have major social, clinical and public health implications.

Therefore, the purpose of this systematic review and meta-analysis is to update, compile and critically review the existing evidence on the effects of a Caesarean delivery on the waiting time to subsequent pregnancy or birth and to provide a quantitative estimate of the overall relationship between mode of delivery and subsequent sub-fertility.

Methods

Primary objective

The main objective of this systematic review and meta-analysis is to collect and interpret the published literature on the association between a Caesarean delivery and subsequent sub-fertility (time to next pregnancy or birth) and to calculate a pooled estimate of the odds of sub-fertility following a Caesarean delivery.

Primary outcome

The outcome of interest is subsequent sub-fertility, defined as pregnancy interval (the waiting time to next pregnancy or birth). Pregnancy interval has been classified according to the standard definitions used in the literature to date for the purpose of this systematic review and meta-analysis as follows:

1.
Inter-pregnancy interval (IPI), defined as the time passed since the termination of the previous pregnancy and the conception of the next pregnancy, or
2.
Birth interval (BI) defined as the time elapsed from the date of delivery of the previous child to the date of delivery of the subsequent child.

The outcome will be a dichotomous measure of the time to next pregnancy within the follow-up time period reported in each study. Where a study reports estimates of two separate intervals as a measure of sub-fertility (i.e. a period of >1 year or a period of >3 years trying to conceive), the longer time interval will be used in the meta-analysis. Furthermore, where a study provides stratified estimates and sub-group analyses, only the overall estimate of sub-fertility will be included in the meta-analysis.

Search strategy

The protocol for this systematic review and meta-analysis was registered on PROSPERO, the international prospective register of systematic reviews (unique identification number: CRD42012003166) and is available in full on the National Institute for Health Research (NIHR) website [26]. This systematic review and meta-analysis was conducted in accordance with the preferred reporting items for systematic reviews and meta-analyses statement (PRISMA) [27], which is a detailed checklist of items specifically designed for this purpose. We performed a comprehensive search of the published literature using a combination of medical subject headings (MeSH) or key word terms for Caesarean delivery and sub-fertility (time to next pregnancy including IPI or BI). We searched the following databases for potentially eligible studies: CINAHL (1981 to October 17^th 2012), the Cochrane Library (1993 to October 17^th 2012), Embase (1974 to October 17^th 2012), Medline (1966 to October 17^th 2012), PubMed (1966 to October 17^th 2012), SCOPUS (1960 to October 17^th 2012) and Web of Knowledge (1945 to October 17^th 2012). Terms for Caesarean delivery included Caesarean section, Caesarean delivery, abdominal delivery, C-section, mode of delivery, and post Caesarean delivery. Terms for pregnancy interval included birth interval, birth spacing, pregnancy interval, first birth interval, inter-delivery interval, pregnancy gap and pregnancy spacing (Additional file 1). We enhanced our electronic search by cross-checking the reference lists of all relevant studies. We included studies which examined the association between mode of delivery and sub-fertility defined as time to next pregnancy or birth. No date or language restrictions were imposed. Eligibility criteria for inclusion in the systematic review included:

1.
Data were from an original study (i.e. no review articles, editorials or commentaries).
2.
Study design: cohort, cross-sectional or case–control studies, in which mode of delivery and the subsequent IPI or BI were reported.
3.
Outcome definitions: studies which defined sub-fertility using the standard pregnancy interval definitions (IPI or BI) were considered appropriate for inclusion in the systematic review and meta-analysis.

Eligibility criteria for inclusion in the meta-analysis (in addition to the above criteria) included:

4.
Reporting of an adjusted effect estimate (relative risk [RR], odds ratio [OR], or hazard ratio [HR]) or sufficient data in order to calculate these estimates of the relationship between Caesarean delivery and subsequent sub-fertility.

Study selection and data abstraction

Titles and abstracts of studies retrieved from the search strategy were reviewed independently applying the appropriate inclusion and exclusion criteria by the researchers. The full text article was obtained for all potentially eligible studies for further appraisal. Using a standardised data abstraction form, two assessors (SMON, ASK) individually entered the following data from each study: first author’s name, year, study design, location of the study (country), study period and follow-up, data source (i.e. hospital database, nationwide registers, patient records), total sample size, measure of pregnancy interval used (IPI or BI, and whether it was measured as a continuous or categorical outcome), statistical tests used, the indication for Caesarean delivery (breech, elective, emergency), the population sampled (i.e. primiparous, multiparous women), the exclusion criteria and the main results and conclusions of each study. Discrepancies in data abstraction between assessors were resolved through consensus.

Statistical analysis

Primary analysis

The primary analysis estimated the relationship between prior Caesarean delivery and subsequent sub-fertility (pregnancy interval between the index and subsequent pregnancy) compared to women with a prior vaginal delivery. The generic inverse variance method with a fixed-effect model was used to calculate pooled estimates across the studies. A funnel plot was produced to estimate the likelihood of publication bias using the pooled OR and standard error (SE). Only studies which reported adjusting for a minimum of three confounders including maternal age were included in the meta-analysis. Studies which reported crude estimates are presented individually in a separate table.

Subgroup analyses

Firstly, we estimated separate ORs by parity (primiparous versus not limited to primiparous women), to assess the degree of confounding by number of previous deliveries. Secondly, we estimated the pooled OR by publication date (pre-2000, post 2000). Thirdly, we performed an analysis by length of follow-up (<10 years, >10 years). Next we performed a separate analysis based on whether an indication for mode of delivery was available or not (yes, not specified). Next we carried out an analysis by cohort size (<35,000, >35,000) and finally by definition of sub-fertility used: (a) BI versus IPI and (b) categorical measures (e.g. <1 year, >3 years) vs. continuous measures

Analyses were performed using Review Manager version 5.1 software [28].

Heterogeneity assessment

Heterogeneity between the included studies was assessed by examining the differences in study characteristics including study setting (high-income developed country versus low-income developing country), study design (case–control, cohort or cross-sectional), sampling frame (population-based or single/select institutions), and definition of the outcome measure used. In the meta-analysis, we used the I² statistic to ascertain statistical heterogeneity, following the Cochrane Handbook for Systematic Reviews threshold recommendations [29]. An I² statistic value between 0% and 40% suggests heterogeneity may not be important; 30% to 60% represents moderate heterogeneity; 50% to 90% represents substantial heterogeneity; and 75% to 100% represents considerably significant heterogeneity. The magnitude and direction of the effects (Chi-squared test P-value, 95% confidence interval for I²) determine the importance of the I² statistic according to the handbook.

Quality assessment

The methodological quality was assessed using a quality assessment tool based on six different types of bias common in observational studies (selection, exposure, outcome, analytic, attrition and confounding) for each study included in the review. This bias classification tool has been described in detail elsewhere [30]. Study bias was recorded as minimal, low, moderate or high according to the perceived degree of bias present for each of the six types of bias. For example, for confounding factor bias a study would be classified as minimal in bias if it adjusted for at least three key confounders including maternal age. An overall likelihood of bias was then estimated based on the total amount of bias perceived to be present.

Ethical approval was not required for this systematic review and meta-analysis as it did not include any experimental research on humans or personal information which would otherwise require informed consent.

Results

Database search results

The database searches produced 13,658 citations, of which the titles and abstracts of 10,241 were screened after removal of 3,417 duplicates. Of these, 12 were considered potentially relevant and the full text was obtained (Figure 1). From here, four were excluded with the main reasons being lack of data on the exposure (mode of delivery) or the outcome of interest (sub-fertility defined as time to next pregnancy/birth) and one study [31] used the same data source as another eligible study [16] and so in order to avoid duplication of data was removed. After hand-searching the reference lists of eligible studies, a further three studies were obtained yielding a total of 11 studies which met the inclusion criteria of the systematic review.

Characteristics of studies included in the review

The characteristics of the included studies are presented in Table 1. Five studies defined time to next pregnancy using IPI [7, 10, 18, 32, 33], five studies used BI [16, 34–37] and one study reported both [17]. Six studies [16–18, 32, 33, 36] reported time to next pregnancy on a continuous scale (e.g. median IPI or BI in days), whilst five studies [7, 10, 34, 35, 37] categorised time to next pregnancy (e.g. >3 years trying to conceive or conceiving within five years). Four studies were published in the 1980’s [33, 35–37], one study in the 1990’s [34] and six from the year 2000 on [7, 10, 16–18, 32]. Study populations ranged in size from 547 to 596,341 women [16, 32] and were conducted in countries including the Netherlands [32], Scotland [18], Norway [16], England [7, 17], Brazil [34], Sweden [37] and the USA [33, 35, 36]. One study included 22 sub-Saharan African countries [10]. Length of follow-up ranged from a minimum of one year [36] to a maximum of 34 years [16].

Table 1 Characteristics of studies included in the systematic review

Full size table

Three studies used national registers [16, 18, 37], three used smaller databases (i.e. a single hospital obstetric database) [17, 32, 33], four studies used interview or questionnaire survey data [7, 10, 34, 36], and one study used patient medical records [35]. Eight studies included primiparous women only (i.e. those women with only one previous pregnancy) [16–18, 32, 33, 35–37] and three were not limited to primiparous women [7, 10, 34]. Studies included 10 cohort [7, 10, 16–18, 32–34, 36, 37], and one case–control [35]. Indication for mode of delivery was reported in four studies [16–18, 32]. Exclusion criteria, confounder adjustment and matching techniques varied between studies and only one study was conducted in a low-income region (Sub-Saharan Africa) [10].

Primary outcome analysis

Five studies adjusted for confounders and are included in the meta-analysis with data on 750,407 women available. A fixed-effect model is reported as heterogeneity between the studies was considered low to moderate (I² = 30%, P = <0.0001). The pooled adjusted OR of sub-fertility is 0.90 (95% CI 0.86, 0.93) (Figure 2). Inspection of the funnel plot (Figure 3) showed that one study [7] may attribute some degree of publication bias, although, there are other possible explanations.