Caesarean section in pregnancies conceived by assisted reproductive technology: a systematic review and meta-analysis

Background Caesarean section rates are higher among pregnancies conceived by assisted reproductive technology (ART) compared to spontaneous conceptions (SC), implying an increase in neonatal and maternal morbidity. We aimed to compare caesarean section rates in ART pregnancies versus SC, overall, by indication (elective versus emergent), and by type of ART treatment (in-vitro fertilization (IVF), intracytoplasmic sperm injection (ICSI), fresh embryo transfer, frozen embryo transfer) in a systematic review and meta-analysis. Methods We searched Medline, EMBASE and CINAHL databases using the OVID Platform from 1993 to 2019, and the search was completed in January 2020. The eligibility criteria were cohort studies with singleton conceptions after in-vitro fertilization and/or intracytoplasmic sperm injection using autologous oocytes versus spontaneous conceptions. The study quality was assessed using the Newcastle Ottawa Scale and GRADE approach. Meta-analyses were performed using odds ratios (OR) with a 95% confidence interval (CI) using random effect models in RevMan 5.3, and I-squared (I2) test > 75% was considered as high heterogeneity. Results One thousand seven hundred fifty studies were identified from the search of which 34 met the inclusion criteria. Compared to spontaneous conceptions, IVF/ICSI pregnancies were associated with a 1.90-fold increase of odds of caesarean section (95% CI 1.76, 2.06). When stratified by indication, IVF/ICSI pregnancies were associated with a 1.91-fold increase of odds of elective caesarean section (95% CI 1.37, 2.67) and 1.38-fold increase of odds of emergent caesarean section (95% CI 1.09, 1.75). The heterogeneity of the studies was high and the GRADE assessment moderate to low, which can be explained by the observational design of the included studies. Conclusions The odds of delivering by caesarean section are greater for ART singleton pregnancies compared to spontaneous conceptions. Preconception and pregnancy care plans should focus on minimizing the risks that may lead to emergency caesarean sections and finding strategies to understand and decrease the rate of elective caesarean sections. Supplementary Information The online version contains supplementary material available at 10.1186/s12884-021-03711-x.


Background
Infertility, defined as the inability to conceive after 12 or more months of regular unprotected intercourse, affects 12-15% of couples [1,2]. Between 1 and 5% of children in industrialized countries are born following assisted reproductive technologies (ART) [3]. ART has been associated with higher caesarean section rates compared to women who conceive spontaneously [4].
The overall rate of caesarean sections continues to increase at a rapid rate. The ideal caesarean section rate is 10-15% according to the World Health Organization (WHO) [5], which states that population level rates higher than 10% are not associated with reductions in maternal and neonatal mortality [5]. Globally, the rate of caesarean section has increased from 12.1% in 2000 to 21.1% in 2015 [6].
Previous studies have compared caesarean sections between fresh and frozen embryo transfer in ART pregnancies [7], in oocyte donation pregnancies [8], and in multiple pregnancies conceived by IVF [9,10]. Two systematic reviews and meta-analyses published in 2004 estimated an increased risk of caesarean delivery among the IVF/ICSI population [11,12], followed by a third meta-analysis published in 2012 which confirmed those findings [4]. However, the identification of associated treatment factors has not been addressed in previous meta-analyses. This can help to establish care plans for women undergoing ART to improve pregnancy deliveries and to reduce possible harm in unnecessary caesarean sections in these pregnancies.
The objective of the present study is to conduct a systematic review and meta-analysis to assess the risk of caesarean section in IVF/ICSI singleton pregnancies compared to spontaneous conceptions, overall and by indication (elective versus emergent), and by type of ART treatment (IVF, ICSI, fresh embryo transfer, and frozen embryo transfer).

Search strategy and information sources
We conducted a literature search from 1993 to 2019 on MEDLINE, EMBASE and the cumulative index to nursing and allied health literature (CINAHL) database using the OVID Platform. The search was completed in January 2020. MeSH terms and the indexing of terms were used. The keywords used in database searches were; in vitro fertilization/or intracytoplasmic sperm injection/, fertilization in vitro, in vitro fertilization*.mp., reproductive techniques assisted, caesarean section/ or repeat caesarean section/, cesarean section*mp., ceasarean section*.mp., caesarean section*.mp., c-section*.mp., caesarean delivery, caesarean section, elective. Keywords with the notation "*mp" indicate the plural form of that term was searched, and the term was also searched as a keyword (See supplementary materials, Additional file 1). Additionally, search criteria included studies after 1990 limited to only English and French literature and grey literature. References of past systematic reviews were also searched for relevant articles to include in the review. The PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-analyses) Statement [13] was followed in preparation of this manuscript. PROSPERO register (CRD42020165075).

Study selection and eligibility criteria
Two team members independently performed the title and abstract screening and conducted full text screening (NAL, FTSE). Conflicts were resolved by consensus or by a third team member (MPV). Criteria to identify eligible publications for the current review were established using the PICOS (Population-Intervention-Comparators-Outcomes-Study design) framework. The inclusion criteria were singleton pregnancies conceived using ART (IVF and/or ICSI) with autologous oocytes compared to spontaneously conceived singleton pregnancies. The exclusion criteria were pregnancies conceived using intrauterine insemination (IUI), exclusive ovulation induction, or IVF/ICSI using donor gametes (oocyte, embryo or sperm), gestational surrogacy and twins or higher order multiples pregnancies.

Exposure and outcome measures
The main exposure was IVF and/or ICSI combined. Additional analyses were conducted by type of fertilization (IVF or ICSI), and type of embryo transfer (fresh or frozen). The outcomes of interest were caesarean section, overall and by indication (e.g. elective and emergent caesarean section). We used the Lucas et al. classification of urgency of caesarean section [14], grouped as emergent (grade I: emergent and grade II: urgent) and elective (grade III: scheduled and grade IV: elective). Most literature classifies caesarean section as elective or emergent, where an elective caesarean section is one performed for nonclinical reasons and an emergent caesarean section is one performed due to an immediate threat to the life of the woman or fetus [14].

Assessment of heterogeneity
The similarity between the included studies (mainly regarding study design and clinical characteristics) was assessed to ensure pooling was appropriate. The I 2 statistic was used to analyze heterogeneity. High heterogeneity is indicated by a percentage greater than 75%.

Risk of bias and quality assessment
Risk of bias and quality assessment of included studies was performed independently by two authors (NAL, FTSE). Conflicts were resolved by consensus or by a third team member (MPV). Study quality was assessed by two reviewers using the Newcastle-Ottawa Scale (NAL, FTSE). This system involves eight scored items, each included study was evaluated in these categories and received a total score ranging from 0 to 9 points. A score of 8 or 9 indicates a high-quality study, a score of 6 to 7 indicates a moderate quality study, and < 5 low quality study [15]. Publication bias was assessed by Funnel Plot graphics using RevMan 5.3 software if the pooled analysis included more than 10 studies (Additional file 2) [16]. In addition, a senior investigator (FTSE) applied the GRADE (Grading of Recommendations Assessment, Development, and Evaluation) approach to rate the quality of the evidence using GRADE Profiler (GRADEpro), version 3.6 [17].

Statistical analysis
Data extracted from included studies was composed into 2 × 2 tables to conduct a meta-analysis using RevMan 5.3 software. Studies with similar outcomes were pooled together and the tables were used to calculate crude odds ratios. For the outcome of caesarean section, measures of association were reported as odds ratios with a 95% confidence interval. Data was analyzed using the random effect model which assumes heterogeneity and the significance of the pool odds ratio was analyzed using the Mantel-Haenszel statistical method. When conducting the meta-analysis, the number of individuals undergoing caesarean section for five studies [18][19][20][21][22] needed to be estimated based on percentages provided as no explicit number was stated in the study.
This systematic review and meta-analysis did not involve consumer and community participation.
Three studies were matched cohorts [23,26,35], and two unmatched cohorts [40,50]. The quality of studies was moderate to high with NOS scores ranging from 7 to 9 ( Table 1). The GRADE quality assessment was low (Additional file 4).
Three studies were matched cohorts [23,26,35], and two unmatched cohorts [40,50]. The quality of studies was moderate to high with NOS scores ranging from 7 to 9 ( Table 1). The GRADE quality assessment was low (Additional file 4).

Main findings
Our study indicates that IVF/ICSI pregnancies are associated with higher odds of caesarean section compared to spontaneous conceptions. The odds were also greater for elective caesarean sections compared to spontaneous conceptions than for emergent caesarean sections. This trend was also apparent, in IVF or ICSI, and fresh or frozen embryo transfer, compared to spontaneous conception. Our study presents updated rates of caesarean section between ART and spontaneous pregnancies, with 16 studies conducted after 2012. In addition, we considered type of treatment (IVF, ICSI, fresh, and frozen embryo transfer) as independent factors. A strength of the study is the type of included studies. While the quality scores ranged from low to high with scores from 4 to 9, 25 studies (75%) were considered high quality studies. Furthermore, majority of the included studies, with the exception of two studies, considered potential confounders in the analysis. According to the GRADE approach, the quality of the caesarean section effect estimate, overall, by indication (emergent, elective), IVF, or ICSI was moderate, while it was low for Fresh or Frozen embryo transfer. The high heterogeneity (I 2 > 75%) and low GRADE scores in some of the subgroup analyses can be explained by variations in the definition of the outcomes and/or indication of emergent or elective caesarean section, and inclusion and exclusion criteria including maternal age, type of ART, and infertility diagnosis among others. Differences in the study populations can also account for the high heterogeneity. Our review included studies from different income countries. The rates of caesarean section differ among these countries, with high-income countries, showing increased rates during the past three decades [54]. The type of health care system (public, private) is also associated with caesarean section rates, with private health systems cited as the most important structural factor in increased caesarean delivery [55,56]. These same factors are associated with access to ART, with documented widespread disparities in access to ART between countries, and between private and public health care systems [57]. In addition, our analysis included only observational studies and not randomized clinical trials (to our knowledge inexistent in this context) which may negatively influence the quality of the evidence. However, the large sample size of our pooled analysis and long observation periods overcome these limitations.

Comparison with existing literature
These results are consistent with the findings of three past systematic reviews and meta-analyses which examined obstetric and perinatal outcomes among the IVF/ ICSI population compared to spontaneous conceptions [4,11,12]. Pandey et al. (2012) reported that the relative risk of having a caesarean section was 1.56 (95% CI 1.51-1.60) in IVF/ICSI conceptions compared to spontaneous conceptions [4]. They also reported a statistically increased risk of caesarean section in singleton frozen embryo transfer pregnancies compared with singletons from spontaneous conception with a relative risk ratio of 1.76 (95% CI 1.65-1.87) [4]. However, they did not evaluate and present findings on the caesarean section rates based on fertilization mode (IVF or ICSI), or other fresh embryo transfer. Helmerhorst et al. (2004) reported that rates of caesarean section were significantly higher after ART compared to spontaneous conception, with a relative risk ratio of 1.54 (95% CI 1.44-1.66) in singleton matched births [12]. The findings of these two systematic reviews support the results in this study which exhibited that there is an increased risk for caesarean section in singleton IVF/ICSI populations and frozen embryo transfer populations compared to spontaneous conception groups.

Interpretation
Pregnancies following ART have a higher risk of adverse maternal and neonatal outcomes, which can explain the higher rate of emergent caesarean sections compared to spontaneous conceptions [58,59]. However, provider or patient factors associated with a higher rate of elective caesarean section in ART pregnancies need to be further investigated.

Conclusions and implications
The probability of singleton pregnancies ending in delivery by caesarean section is higher in women who conceive using ART compared to spontaneous conceptions. As access to ART has increased worldwide, there is a need to determine why caesarean sections are more common following ART than in spontaneous conceptions, and how these rates can be decreased. While the rate of caesarean section is one important health quality measure, maternal satisfaction and choice, as well as local resources and guidelines are other considerations in choosing mode of delivery. These factors were not considered in the present review. Future quantitative and qualitative studies need to address both provider and patient beliefs and preferences to offer further insight on the drivers of these findings. Preconception and pregnancy care plans following ART should focus on minimizing the risks that may lead to emergency caesarean sections. Furthermore, effective knowledge translation interventions are needed at different levels (organizational, providers, and patients) to decrease elective caesarean sections in pregnancies conceived by ART [60].