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Pre-pregnancy obesity and the risk of peripartum cardiomyopathy: A systematic review and meta-analysis

The outcome of this review is to assess the association between pre-pregnancy obesity and PPCM incidence. There were a total of 5.373.581 participants were included in this study. Pre-pregnancy obesity was significantly associated with PPCM incidence compared to normal-weight subjects (OR = 1.79 (1.16,2.76); p = 0.008; I2 = 59%, Pheterogeneity = 0.04). The sub-group analysis showed that pre-pregnancy women with obesity class I (OR = 1.58 (1.20,2.07); p = 0.001; I2 = 0%, Pheterogeneity = 0.64) and class II and III (OR = 2.65 (2.04,3.45); p < 0.001; I2 = 6%, Pheterogeneity = 0.36) was significantly associated with PPCM incidence compared to normal-weight subjects.


Introduction
Peripartum cardiomyopathy (PPCM) is an idiopathic cardiomyopathy with left ventricular (LV) systolic dysfunction, occurring in the last month of pregnancy until several months after parturition. 1 Among all of the risk factors associated with PPCM, obesity is one of the several modifiable risk factors of PPCM. 2 Recently, there are four observational studies showed that pre-pregnancy obesity was significantly associated with PPCM and another observational study found no significant association. 2e6 Due to equivocal results, this meta-analysis aims to evaluate the association between prepregnancy obesity with PPCM.

Search strategy
We performed a systematic literature search in adherence to PRISMA statement guidelines in several online databases using a broad search terms for "pre-pregnancy obesity" AND "peripartum cardiomyopathy". The search was started from inception until March 19, 2022. Any duplication were removed, and the remaining articles were manually screened for eligibility based on their titles and abstracts. All relevant articles were assessed by analyzing their full-text forms. Studies that did not fulfill our inclusion criteria were removed.

Selection criteria
Articles eligibility was assessed by two independent investigators and any discrepancies were resolved by discussion. We included observational studies containing pre-pregnancy obesity group, normal weight group and incidence of PPCM. Obesity was defined according to the World Health Organization criteria. 7 Whereas, PPCM diagnosis criteria was based on European Society of Cardiology guideline. 1 Any editorial, commentaries, reviews, and case reports/case series were excluded from this study.

Data extraction
Two authors carried out data extraction independently. We used a predesigned extraction form that comprised the authors, year of publications, country, category of BMI, PPCM criteria diagnosis, and study outcomes to collect relevant data from each included study. Quality assessment was carried out using the NewcastleeOttawa Scale.

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Indian Heart Journal

Statistical analysis
All statistical analyses in this study are using Review Manager 5.4.1 software. To describe the dichotomous variables, we used the Mantel-Haenzel formula to gauge the pooled estimates and its 95% confidence interval in the form of odds ratios. A two-tailed p-value 0.05 was considered statistically significant. Heterogeneity across studies was assessed by the inconsistency index (I 2 ) test, with a I 2 value above 50% or p < 0,05, demonstrating moderate to high heterogeneity. 8 We performed sensitivity analysis by leave one out method to conduct statistical robustness and assess the heterogeneity. If high heterogeneity was noted, a random effects model was assigned. The results of sub-group analysis, comprising obesity class I, II and III were assessed to gain a broad association between obesity and PPCM.

Study selection and characteristic
The study flow is illustrated in [ Fig. 1]. At the end of the study selection, we collected five observational studies 2e6 with a total of 5.373.581 participants. Total PPCM patients were 506 (0.001%) across of 5 studies. We merged the variable of obesity class II and III because differences in dichotomization of BMI were noted across the studies. The characteristics of included studies were describe in supplementary Table S4.

Discussion
This meta-analysis showed that pre-pregnancy obesity was significantly associated with PPCM. The significance was also obtained in sub-group analysis consisting population with obesity class I, II, and III. The odds ratio was highest in obesity class II and III group, followed by obesity class I, demonstrating a possible doseeresponse relationship.
In the sensitivity analysis, heterogeneity was significantly reduced after excluding Nabbaale et al study, as the only study consisting African predominance participants, showing that race might play a role related to obesity and PPCM incidence. Kao et al.'s study showed that pre-pregnancy obesity was associated with PPCM in the Caucasian race and Hispanic race but not in the African American race. 9 Consistently, an observational study from Nigeria also found that pre-pregnancy obesity was not significantly associated with PPCM and underweight subjects was more likely to get PPCM. 10 Hence, underweight group was probably more noxious compared to obesity group in term of increase risk of PPCM incidence in african race population.
There are three possible hypotheses of pathophysiology including hemodynamic changes, apoptosis, and inflammation. In obesity, high accumulation of fat alters circulating blood volume leading to an increased stroke volume which in turn causing LV wall stress, leading to eccentric LV hypertrophy, ultimately resulting in LV dysfunction. 11 Concurrently, pregnancy increases cardiac output through increasing stroke volume, which accounts for 45% and 55% in normal singleton and twin pregnancy, respectively. 12 Stroke volume will reach its peak at the end of the second trimester and may persist up to 12 weeks postpartum. 12 This phenomenon can cause reversible LV hypertrophy, leading to transient LV dysfunction during the third trimester. 13 Eventually, all of these hemodynamic changes contribute to PPCM. 13 Similarity was found between obesity and PPCM patients, whereby the level of inflammatory cytokines and biomarker of cell apoptosis in both conditions were significantly increased compared to healthy patients. 14,15 Thereby, a high level of proinflammatory cytokines and the apoptosis process in cardiomyocytes may result in LV dysfunction and remodeling, manifesting as heart failure. 13 Despite promising results, there are several limitations in our study. Firstly, most of the studies were retrospective observational studies. Secondly, there is a moderate high heterogeneity due to race and ethnicity differences interstudy. Thirdly, BMI data from all included studies was collected from database or pre-tested study questionary which can increased the risk of bias. Fourthly, due to insufficient data in majority studies, only a few studies were included in this review.
In conclusion, this study suggested that patients with prepregnancy obesity is at higher risk of developing PPCM. To truly evaluate the impact of obesity on PPCM, prospective observational studies with heterogenous population are needed.

Funding
There is no funding in this review.

Data availability
Available on reasonable request.

Ethical approval
Not Applicable.

Informed consent
Not Applicable.

Declaration of competing interest
The authors declare that they have no conflicts of interest.