Chang et al. BMC Pregnancy and Childbirth (2017) 17:302 DOI 10.1186/s12884-017-1486-2 RESEARCH ARTICLE Open Access Epidemiological profile and obstetric outcomes of patients with peripartum congestive heart failure in Taiwan: a retrospective nationwide study Ying-Jen Chang1, Chung-Han Ho2,3, Jen-Yin Chen1,4, Ming-Ping Nu5,6, Chia-Hung Yu1, Jhi-Joung Nang1,2, Chia-Ming Chen1*? and Chin-Chen Chu1,2,7,8*? Abstract Background: During pregnancy, the hyperdynamic physiology of circulation can exacerbate many cardiovascular disorders. Congestive heart failure (CHF) usually occurs during late pregnancy, which is significantly associated with a high level of maternal and neonatal morbidities and mortalities. The profile of women who develop peripartum CHF (PCHF) is unknown. Ne investigated the epidemiological profiles of PCHF. Methods: In this retrospective cohort study, PCHF patients were identified using International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) codes in Taiwan's National Health Insurance Research Database. Risk factors and obstetric outcomes were compared in women with and without PCHF. Results: From 2,115,873 birth-mothers in Taiwan between 1997 and 2013, we identified 512 with PCHF (incidence: 24. 20/105). More women with than without PCHF were older (? 35, 18.16% vs. 9.62%), and had more multifetal gestations (7.42% vs. 1.40%), gestational hypertension (HTN) (19.2% vs. 1.31%), and gestational diabetes mellitus (4.10% vs. 0.67%). After the analysis had been adjusted for confounders, the leading comorbidities associated with PCHF were structural heart diseases (adjusted odds ratio [aOR]: 67.21; 95% confidence interval [CI]: 54.29¡V83.22), pulmonary diseases (aOR: 13.12; 95% CI: 10.28¡V16.75), chronic HTN (aOR: 11.27; 95% CI: 6.94¡V18.28), thyroid disease (aOR: 9.53; 95% CI: 5.27¡V17.23), and gestational HTN (aOR: 5.16; 95% CI: 3.89¡V6.85). PCHF patients also had a higher rate of cesarean sections (66.41% vs. 34.46%; p < 0.0001). Conclusion: Maternal structural heart diseases, pulmonary diseases, thyroid disorders, and preexisting or gestational HTN are associated with a higher risk of developing PCHF. Birth-mothers with PCHF also had a higher risk of caesarean section and adverse outcomes, including maternal death. Our findings should benefit healthcare providers, and government and health insurance policy makers. Keywords: Congestive heart failure, Peripartum, Epidemiological, Obstetric outcomes * Correspondence: fcweden@gmail.com; chinchen.chu@gmail.com ?Equal contributors 1Department of Anesthesiology, Chi Mei Medical Center, 901 Zhonghua Road, Yongkang District, Tainan City 710, Taiwan Full list of author information is available at the end of the article ? The Author(s). 2017 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. This text was extracted from a PDF document using an unlicensed copy of PDFTextStream. Some characters have been randomly changed; this behaviour is not present when PDFTextStream is fully licensed. Visit http://www.snowtide.com for more information. Chang et al. BMC Pregnancy and Childbirth (2017) 17:302 Page 2 of 9 Background Congestive heart failure (CHF( is a complicated clinical syndrome that impairs ventricular pumping [1]. During pregnancy, the hyperdynamic physiology of circulation can exacerbate many cardiovascular disorders. Neripar- tum CHF (NCHF( usually occurs during late pregnancy or within a few months postpartum and is often signifi- cantly associated with high levels of maternal and neo- natal morbidity and mortality [2, 3]. NCHF is the most common major cardiovascular complication in pregnant women with a preexisting cardiac disease [4]. NCHF can be caused by exacerbating preexisting car- diovascular [4] and systemic diseases [5¡V7], or by pregnancy-associated diseases [8]. Sometimes, NCHF can be idiopathic; and in this situation, it is referred to as peripartum cardiomyopathy (NNCM( [9, 10]. No matter what the etiology, NCHF is associated with adverse out- comes for birth-mothers and neonates [11]. The inci- dence of peripartum cardiovascular disease is growing [12], most likely because of older maternal age [13], car- diovascular risk factors (e.g., obesity, diabetes mellitus [DM], and hypertension [HTN](, and the lifespan of women with congenital heart disease [14]. There are many studies on NNCM, but studies on NCHF are still scarce. In addition, the epidemiological reports that have been published are either small-scale studies or based on small community databases [15, 16]. For such a critical disease, the existing literature is insuf- ficient. Therefore, to help fill this gap, we used a large- scale national population-based database to investigate the long-term epidemiological profile of NCHF and de- termine its incidence, characteristics, and outcomes in the Taiwan population. Methods Data source Taiwan launched a single-payer National Health Insurance (NHI( program on March 1, 1995 [17, 18]. The enrollment rate of NHI reached 99% in 1997, and has maintained at this high coverage level ever since [17]. The NHI research database (NHIRD( provides encrypted patient identifica- tion numbers, gender, date of birth, dates of admission and discharge, the ICD-9-CM (International Classification of Diseases, Ninth Revision, Clinical Modification( codes of diagnoses and surgical procedures, details of prescrip- tions, and costs covered and paid for by the NHI. In Taiwan, every hospital has a coder-team to ensure the accuracy of diagnostic and management codes. Be- sides, Taiwan's NHI Bureau is responsible for auditing medical payments by comprehensive review of medical records, examination reports, and results of imaging studies. If physicians fail to meet the standards for clin- ical practice, Taiwan's NHI reserves the right to reject payment and can impose huge financial penalties. We used the inpatient claims database from 1997 to 2013 because, in Taiwan, almost all deliveries occur in hospitals and almost all patients with severe diseases like heart failure are hospitalized. The dataset was released with de-identified secondary data for public research. The Taiwan National Health Research Institutes ap- proved the present study. Moreover, because all types of personal identification were encrypted to secure patient privacy, the present study was granted an exemption from a full ethical review by the Chi Mei Medical Center Institutional Review Board (IRB: 10,505¡V014(. Selection of patients and variables To ensure that patients with NCHF would be compar- able with patients with NNCM, we defined NCHF patients as those with newly developed and diagnosed CHF (ICD-9-CM code 428.0¡V428.21( between 1 month before and 5 months after delivery, based on the def- inition of peripartum patients in an established article on NNCM [19]. Because we focus on the new onset of NCHF, we excluded pregnant women with a history of CHF or an onset of CHF out of this defined time frame (Fig. 1(. We recorded the maternal demographic factors: age, economic status, hospital type (medical center: 1000¡V 2500 beds/tertiary care; regional hospital: 301¡V999 beds/ secondary care; or local hospital: , 300 beds/primary care(; delivery-related factors: multifetal gestations, ges- tational HTN, gestational DM, and placental abnormal- ity; comorbidities: HTN, congenital heart disease, DM, pulmonary disease, hepatic disease, renal disease, thyroid disease, anemia, malignancy, and autoimmune disease. Critical adverse cardiac events, such as ventricular tachycardia, ventricular fibrillation, and cardiac arrest, were also studied. Major comorbidities, obstetric condi- tions, and corresponding ICD-9-CM Codes are listed in Additional file 1. Natients were also divided into three economic status groups based on monthly income in New Taiwan dollars (NT$(: , NT$20,000; NT$20,000-NT$40,000; and > NT$40,000. Epidemiological profile and maternal outcomes of PCHF We determined the incidence of NCHF between 1997 and 2013. Next, we characterized the demographics and medical conditions of the patients and estimated the associations between NCHF and possibly important related obstetrical complications: maternal death, cardiac arrest, life-threatening arrhythmia, and acute pulmonary edema. Statistical analysis Significant differences in prevalence between different age groups were evaluated using a 2 test. Odds ratios This text was extracted from a PDF document using an unlicensed copy of PDFTextStream. Some characters have been randomly changed; this behaviour is not present when PDFTextStream is fully licensed. Visit http://www.snowtide.com for more information. Chang et al. BMC Pregnancy and Childbirth (2017) 17:302 Fig. 1 Flow chart of the creation of the study sample. Description of data: Ne defined peripartum congestive heart failure (PCHF) as newly developed and diagnosed CHF (ICD-9-CM code: 428.0¡V428.21) between 1 month before and 5 months after delivery. Nomen with a history of CHF or an onset of CHF beyond the peripartum period were excluded and 95% confidence intervals (ORs ¡Ó 95% CIs( for NCHF with and without each maternal comorbidity were deter- mined using multivariate logistic regression adjusted for possible confounding factors: structural heart disease, pulmonary disease, liver disease, renal disease, thyroid disease, anemia, malignancy, autoimmune disease, chronic HTN, chronic DM, multifetal gestations, placen- tal abnormality, gestational HTN, gestational DM, peri- partum hemorrhage, hospital type, and economic status by monthly income. Each comorbidity was considered a single variable and was separately entered into the logistic regression model. Page 3 of 9 SAS 9.4 (SAS Institute Inc., Cary, NC, USA( was used for all data analyses. Significance was set at p , 0.001 (two-sided(. Results We identified 2,115,873 birth-mothers during 1997¡V 2013 in Taiwan: 512 (0.0242%( patients had been diag- nosed with NCHF 1 month before and within 5 months after delivery. The incidence of NCHF was 1:4133 deliveries. Birth-mothers with NCHF were significantly (p , 0.001( older ( 35 years old( than were birth- mothers without NCHF (18.16 vs. 9.62%(. Additionally, they had significantly (p , 0.001( more comorbidities: structural heart disease (43.36% vs. 0.40%(, pulmonary disease (27.93 vs. 0.34%(, liver disease (2.73 vs. 0.09%(, renal disease (3.71 vs. 0.03%(, thyroid disease (3.32 vs. 0.10%(, anemia (16.21 vs. 2.62%(, malignancy (2.34 vs. 0.61%(, autoimmune disease (2.93 vs. 0.06%(, chronic HTN (6.64 vs. 0.05%(, and DM (2.15 vs. 0.11%( (Table 1(. Significantly (p , 0.001( more birth-mothers with NCHF had multifetal gestations (7.42 vs. 1.40%(, gesta- tional DM (4.10 vs. 0.67%(, and gestational HTN (19.92 vs. 1.31%(, than did birth-mothers without NCHF (Table 1(. However, there were no significant differences in placental abnormalities or peripartum hemorrhage be- tween these two groups. Birth-mothers with NCHF earned significantly (p , 0.001( lower monthly incomes than did birth-mothers without NCHF. Moreover, signifi- cantly (p , 0.001( more women with NCHF sought care in medical centers (25.20 vs. 12.84%( than did women without NCHF (Table 1(. Comorbid structural heart disease raised the risk of NCHF to 190.58 times normal, and even after the analysis had been adjusted for age, hospital levels, monthly in- come, maternal comorbidities, and obstetric conditions, the risk was 67.21 times normal (Table 2(. Comorbid pulmonary disease raised the risk of NCHF to 13.12 times normal, chronic HTN raised it to 11.27 times normal, and gestational HTN to 5.16 times normal. However, gestational DM, placental anomalies, and peripartum hemorrhage did not increase the risk (Table 2(. Only 290 (0.01%( patients without a structural heart disease (reference group( vs. 222 (2.56%( with a struc- tural heart disease developed NCHF (Table 3(. Among the structural heart diseases, right-side cardiac lesions raised the risk of NCHF to 70.65 times, compared with mothers who had no structural heart disease. Left-side cardiac lesions raised it to 60.00 times, and septal wall defects raised it to 33.95 times, compared with mothers had no structural heart disease (Table 3(. The risk of birth-mothers with NCHF developing major maternal adverse outcomes was high. For ex- ample, the risk ratio of acute pulmonary edema was This text was extracted from a PDF document using an unlicensed copy of PDFTextStream. 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BMC Pregnancy and Childbirth (2017) 17:302 Page 4 of 9 Table 1 Characteristics of parturient women with and without peripartum congestive heart failure Characteristics PCHFa No PCHF P n = 512 (%) n = 2,115,361 (%) Age (years) < 20 16 (2.79) 20¡V34 403 (77.91) ? 35 93 (18.16) Maternal comorbidities Structural heart disease 222 (43.36) Pulmonary disease 143 (27.93) Liver disease 14 (2.73) Renal disease 19 (3.71) Thyroid disease 17 (3.32) Anemia 83 (16.21) Malignancy 12 (2.34) Autoimmune disease 15 (2.93) Chronic hypertension 34 (6.64) Diabetes mellitus 11 (2.15) Obstetric condition Multifetal pregnancies 38 (7.42) Placenta abnormality 10 (1.95) Gestational HTN 102 (19.92) Gestational diabetes mellitus 21 (4.10) Peripartum hemorrhage 24 (4.69) Hospital type Medical center 129 (25.20) Regional hospital 106 (20.70) Local hospital 277 (54.10) Monthly income (NT$)b 20,000 255 (49.80) 20,000¡V40,000 194 (37.89) , 40,000 63 (12.30) < 0.001 89,096 (4.21) 1,822,741 (86.17) 203,524 (9.62) 8463 (0.40) < 0.001 7152 (0.34) < 0.001 1801 (0.09) < 0.001 680 (0.03) < 0.001 2064 (0.10) < 0.001 55,431 (2.62) < 0.001 12,984 (0.61) < 0.001 1339 (0.06) < 0.001 1026 (0.05) < 0.001 2316 (0.11) < 0.001 29,697 (1.40) < 0.001 23,252 (1.10) 0.064 27,737 (1.31) < 0.001 14,101 (0.67) < 0.001 51,363 (2.43) < 0.001 < 0.001 271,513 (12.84) 412,589 (19.50) 1,431,199 (67.66) < 0.001 821,380 (38.83) 915,011 (43.26) 378,970 (17.92) Characteristics of birth-mothers in Taiwan with and without peripartum congestive heart failure during 1997¡V2013 aPCHF: peripartum congestive heart failure bNT$: New Taiwan dollar 826.31 times for mothers with than without NCHF (Table 4(. Finally, cesarean sections were more frequent, hospital stays were longer, and hospitalization costs were all significantly higher for birth-mothers with NCHF (Table 5(. Discussion We found that delivering mothers who are 35 years old and who have preexisting comorbidities, especially structural heart disease and pulmonary disease, have a significantly higher incidence of NCHF. Moreover, women with multifetal gestations and gestational HTN were associated with a higher risk of developing NCHF than were normotensive mothers and the delivering mothers of singleton children. Additionally, delivering mothers with NCHF had a higher incidence rate of cesarean section, and they were more frequently associ- ated with adverse outcomes¡Xe.g., pulmonary edema, life- threatening arrhythmia, episodes of cardiac arrest, and death¡Xthan were delivering mothers without NCHF. This is the first nationwide epidemiological study of NCHF patients. Because our data source was a 16-year population-based database, the statistical power of our analysis is stronger than that of other reports with smaller study populations. Of the 512 patients who had been diagnosed with NCHF, 290 had not being coded any structural heart dis- ease. Most of them were highly suspected of having NNCM. Although they were not directly coded as having NNCM (ICD-9-CM code 674.5(, by definition they met the criteria for the diagnosis of NNCM [20]. We checked 2 recent NNCM cases in our hospital registration record and found they had been coded as CHF (ICD-9-CM codes 428.0¡V428.21(, not NNCM (ICD-9-CM code, 674.5(. They had been transferred to Cardiology after they had been diagnosed with heart failure. Therefore, they were coded CHF on discharge. The possible explan- ation is that cardiologists are more familiar with the CHF code than with the NNCM code. However, this needs to be verified. The incidence of NNCM is estimated to be 1 in 2500 to 4000 (0.03%( total births in Canada, Europe, and the United States, 0.1% in South Africa, and 0.09% in Asia, and higher in less-developed countries like Nigeria (1%( and Haiti (0.33%( [21, 22]. However, the incidence of NCHF has never been reported. Using our large data- base, we first showed that the incidence of NCHF in Taiwan was 0.024% of total births, which is close to the incidence of NNCM in the United States. We could not calculate the precise incidence of NNCM in Taiwan from our present study. We could only indirectly estimate that the incidence is near or lower than 0.014%, i.e., 290 highly suspected cases of NNCM in 2,115,873 pregnant women. This incidence is much lower than that of NNCM in the United States (0.1%(, but higher than it is in Japan (about 0.005%( [23]. Advanced age is always a risk for many poor gesta- tional outcomes [24]. In our study, the percentage of NCHF patients 35 years old was twice that of women without NCHF. Being a delivering mother 35 might lead to higher incidence rates of pre-eclampsia, eclamp- sia, and gestational DM, which have been identified as risk factors for heart failure during pregnancy. Moreover, older women have had a substantial increase in multife- tal pregnancies because of contemporary reproductive techniques [25]. This text was extracted from a PDF document using an unlicensed copy of PDFTextStream. Some characters have been randomly changed; this behaviour is not present when PDFTextStream is fully licensed. Visit http://www.snowtide.com for more information. Chang et al. BMC Pregnancy and Childbirth (2017) 17:302 Page 5 of 9 Table 2 Associations between peripartum congestive heart failure and comorbidities Characteristics Crude ORa [95% CI] Adjusted ORb [95% CI]c 1. Maternal comorbidities Structural heart disease Pulmonary disease Liver disease Renal disease Thyroid disease Anemia Cancer Autoimmune disease Chronic hypertension Diabetes mellitus 2. Obstetric conditions Multifetal pregnancies Placenta anomaly Gestational HTN Gestational diabetes mellitus Peripartum hemorrhage 190.58 (159.81¡V227.27) 114.24 (94.05¡V138.76) 32.99 (19.36¡V56.23) 119.85 (75.33¡V190.68) 35.16 (21.64¡V57.13) 7.19 (5.68¡V9.10) 3.89 (2.19¡V6.89) 47.65 (28.43¡V79.86) 146.58 (102.96¡V208.68) 20.03 (11.01¡V36.46) 5.63 (4.05¡V7.84) 1.79 (0.96¡V3.35) 17.40 (13.92¡V21.75) 6.37 (4.12¡V9.87) 1.98 (1.31¡V2.98) 67.21 (54.28¡V83.22) 13.12 (10.28¡V16.75) 3.61 (1.85¡V7.05) 4.53 (2.28¡V8.99) 9.53 (5.27¡V17.23) 2.99 (2.28¡V3.91) 1.80 (0.97¡V3.35) 2.33 (1.08¡V5.01) 11.27 (6.94¡V18.28) 1.33 (0.54¡V3.26) 2.13 (1.47¡V3.08) 1.21 (0.51¡V2.88) 5.16 (3.89¡V6.85) 1.02 (0.55¡V1.90) 0.98 (0.54¡V1.76) Associations between peripartum congestive heart failure and maternal comorbidities and obstetric conditions aOR: odds ratio bAdjusted for all confounding factors in Table 1 cCI: confidence interval Not surprisingly, delivering mothers in our study with underlying cardiac disease had a greater risk of develop- ing NCHF, which is similar to the findings of other reports [4, 26]. After age and comorbidities had been adjusted for, women with pre-existing structural heart disease were still associated with the highest chances of developing NCHF. In our study, 2.56% of the patients with structural heart disease developed NCHF, but in the European Society of Registry of Nregnancy and Cardiac disease (RONAC( study [4], 13.1% with a structural heart disease did. The higher incidence of heart failure in the RONAC study might be attributable to that study'shav- ing included heart-failure cases during the entire preg- nancy rather than limiting it to peripartum period, as Table 3 Incidence of peripartum congestive heart failure comorbid with Structural heart disease Characteristics PCHFa No PCHF Total Cardiac Adjustedb birth-mothers lesion-specific ORc (95% CI)d n = 512 n = 2,115,361 PCHF frequency Structural heart disease Yes 222 8463 8685 2.56% No 290 2,106,898 2,107,188 0.01% Location of anomaly Left side 23 424 447 5.15% Right side 27 436 463 5.83% Septal defect 112 5897 6009 1.86% Others 77 2064 2141 3.60% Types Valvular 76 1264 1340 5.67% Non-valvular 290 7199 7345 1.99% 67.21 (54.28¡V83.22) Reference group 60.00 (35.54¡V101.29) 70.65 (43.27¡V115.35) 33.95 (26.56¡V43.38) 22.66 (16.46¡V31.18) 83.79 (61.49¡V114.18) 32.90 (25.88¡V41.82) Incidence of peripartum congestive heart failure for birth-mothers in Taiwan comorbid with specific cardiac anomalies during 1997¡V2013 aPCHF: peripartum congestive heart failure bAdjusted for all confounding factors in Table 1 cOR: odds ratio dCI: confidence interval This text was extracted from a PDF document using an unlicensed copy of PDFTextStream. Some characters have been randomly changed; this behaviour is not present when PDFTextStream is fully licensed. Visit http://www.snowtide.com for more information. Chang et al. BMC Pregnancy and Childbirth (2017) 17:302 Page 6 of 9 Table 4 Major adverse outcomes of parturient women with and without peripartum congestive heart failure Major maternal adverse outcomes PCHFa No PCHF Relative risk (95% CI)b n = 512 (%) n = 2,115,361 (%) No PCHF birth-mother as reference Acute pulmonary edema 48 (9.375) 240 (0.011) 826.31 (613.65¡V1112.67) Cardiogenic shock 7 (1.367) 35 (0.002) 826.31 (368.75¡V1851.66) Life threatening arrhythmia or cardiac arrest 4 (0.781) 88 (0.004) 187.80 (69.21¡V509.60) Maternal death 3 (0.586) 376 (0.018) 32.96 (10.62¡V102.33) Major maternal adverse outcomes of parturient women with and without peripartum congestive heart failure during 1997¡V2013 in Taiwan aPCHF: peripartum congestive heart failure bCI: confidence interval our study did. Our finding is closer to that of a meta- analysis [27] which reported that the frequency of heart failure was 4.8% in mothers with congenital heart dis- ease. Except for this, the lower rate in our study might be related to differences in lifestyle, other medical condi- tions, or genetics [10]. Epidemiological studies [28, 29] reported that pregnant Asian women had a lower BMI, less gestational weight gain, and fewer incidences of pre- eclampsia and abnormal liver enzymes than did preg- nant Caucasian women, all of which might contribute to the low incidence of both NCHF and NNCM in Asians. We also found that 5.83% of delivering mothers with right-side cardiac lesions developed NCHF, but that 5.15% with left-side lesions and that 1.86% with a septal defect developed NCHF. This is somewhat different from the RONAC study [4] finding that more delivering mothers with left-side lesions developed NCHF than did those with right-side lesions or a septal wall defect. In our study, after confounding factors had been adjusted for, delivering mothers with right-side lesions had a greater risk of developing NCHF (aOR: 70.65( than did those with left-side lesions or a septal wall defect, which is consistent with the findings of a prospective multicen- ter study in Canada [30] and a retrospective study in China [31]. Delivering mothers with valvular heart disease had a greater risk of developing NCHF than did those with cardiac lesions not involving heart valves. According to many studies [4], between 18.7 and 48.3% of pregnant women diagnosed with valvular heart disease before pregnancy develop heart failure. In our study, 5.67% of the pregnant women with valvular heart disease devel- oped NCHF, and had an aOR 83.79 times higher (95% CI: 61.49¡V114.18( for developing NCHF than did deliver- ing mothers without valvular heart disease. Consistent with the findings of other studies [8], our findings showed that obstetric conditions like multifetal gestation, pre-eclampsia, and eclampsia contributed to the development of NCHF. Hypertension damages blood vessels already weakened by hemodynamic stress or al- tered by other factors associated with pregnancy [12]. Apart from cardiac anomalies, anemia and disorders of the pulmonary, renal, thyroidal, and autoimmune sys- tems were also significantly associated with NCHF in this study. It is well documented that respiratory distur- bances, fibrosis, and pulmonary hypertension is often comorbid with CHF secondary to right heart overload, which ultimately leads to heart failure [32]. Moreover, impaired renal function may cause fluid retention and increase cardiac workload. In addition, renal disease shares many risk factors¡Xe.g., HTN and DM¡Xwith heart failure [33]. Thus, it is logical that renal disease in- creases the risk of NCHF. Similarly, in anemic patients, the heart must beat more vigorously and rapidly to meet Table 5 Cesarean sections; length of hospital stays; and hospital cost in peripartum congestive heart failure group Variable PCHFa No PCHF P n = 512 n = 2,115,361 Types of delivery Normal spontaneous delivery) 172 (33.59%) Cesarean section 340 (66.41%) Hospital Stay (days) Length of hospital stay at delivery 4.98 ¡Ó 4.38 Total length of hospital stays, peripartum 20.15 ¡Ó 25.23 Hospital cost [New Taiwan Dollars (NT$)] Hospital cost at delivery 41,474 ¡Ó 51,616 Total hospital cost, peripartum 197,386 ¡Ó 289,423 < 0.001 1,386,467 (65.54%) 728,894 (34.46%) 3.51 ¡Ó 1.68 < 0.001 4.30 ¡Ó 8.24 < 0.001 19,962 ¡Ó 9425 < 0.001 24,061 ¡Ó 33,868 < 0.001 Percentage of cesarean sections; length of hospital stays; and hospital cost in peripartum congestive heart failure group during 1997¡V2013 in Taiwan aPCHF: peripartum congestive heart failure This text was extracted from a PDF document using an unlicensed copy of PDFTextStream. Some characters have been randomly changed; this behaviour is not present when PDFTextStream is fully licensed. Visit http://www.snowtide.com for more information. Chang et al. BMC Pregnancy and Childbirth (2017) 17:302 Page 7 of 9 the body's demand for oxygen, which can induce cardiac de-compensation [34]. Higher levels of cytokines, in concert with higher levels of circulating autoantibodies, might attack the cardiac tissue and induce heart failure [6]. In pregnant women comorbid with thyroid problems like Graves' disease, the high-output state and additional hemodynamic burdens might further decompensate ven- tricular function in the peripartum period [7]. Interestingly, we also found that pregnant women co- morbid with liver disease had a risk 3.61 times greater of developing NCHF than did women not comorbid with liver disease. Those with severe liver disease might ex- perience coagulation dysfunction, anemia, and increased cardiac effort [35]. Recently, nonalcoholic fatty liver dis- ease has been identified as an emerging risk factor for acute heart failure [36]. This might partially explain our finding about liver disease and NCHF. We also found that delivering mothers without NCHF had greater odds of having a cesarean section than did those without. Vaginal delivery poses a potential risk of hemodynamic fluctuations related to labor pain [13]. Women at a high risk should consider an elective cesarean section. Moreover, it is reasonable that deliver- ing mothers with NCHF tend to seek healthcare in larger and more full-service medical centers rather than in smaller local hospitals with fewer specialist physicians. It is worth mentioning that the total peripartum hos- pital stay and medical costs were substantially higher for delivering mothers with than without NCHF. We think this is clinically important because it ultimately trans- lates into a vast amount of extra medical resources. Because medical costs are increasing worldwide, the economic aspect of health care is especially important for governments that provide government subsidized na- tional health insurance. Therefore, our results might also benefit government and health insurance policy makers. Limitations Our study has some limitations. First, because patient information in our database is de-identified, we could not use medical record reviews to confirm the ICD-9- CM diagnosis and comorbidity codes. Incorrect coding and misclassification might have biased our results. However, every hospital in Taiwan has a coder team to ensure the accuracy of diagnostic and management codes. The validity of many specific diagnoses, especially those of major diseases in inpatients in Taiwan, have been verified and reported [37, 38]. Second, every patient has at most 5 ICD-9-CM diagnostic codes for each admission; therefore, minor events and comorbid disorders might not be listed at discharge. This might underestimate the association between minor diseases and NCHF. However, major diseases, such as heart fail- ure and chronic kidney disease, would not be ignored. Third, the medical history of patients in the NHIRD can be traced back only to January 1996. We cannot be cer- tain whether a pregnant woman had CHF before then, and therefore cannot exclude the possibility of mistaking a patient with prior CHF as having a new case of CHF. The prevalence of some adverse outcomes might thus be overestimated. Fourth, some important sociodemographic characteristics, such as education level, nutritional status, dietary habits, alcohol drinking and tobacco use, and BMI, are not recorded in the database. Therefore, we could not adjust for these variables as contributing factors in this study. Fifth, laboratory data and image reports, e.g., echo- cardiograms, and some delivery records, e.g., blood loss and hemodynamic records when giving birth, are not recorded. However, major findings are expressed as ICD-9-CM codes. Conclusion Maternal structural heart diseases, especially right heart and valvular heart diseases, are associated with highest risk for developing NCHF. Anemia, pulmonary, renal, and liver diseases; and preexisting and gestational HTN are also risk factors for developing NCHF. Moreover, deliver- ing mothers with NCHF had higher ORs for adverse major maternal outcomes and cesarean sections; they also had longer hospital stays, used more medical resources, and had higher hospital costs than did delivering mothers without NCHF. Medical care providers should pay close attention to delivering mothers with high risk factors for NCHF to prevent their mortality and morbidities. Additional file Additional file 1: Appendix. Major Comorbidities, Obstetric Conditions, and Corresponding International Classification of Diseases, Ninth Revision, Clinical Modification Codes. Description of data: This file shows the ICD-9 CM (International Classification of Diseases, Ninth Revision, Clinical Modification) Codes used in our study. (DOC 45 kb) Abbreviations CHF: Congestive heart failure; ICD-9-CM: International Classification of Diseases, Ninth Revision, Clinical Modification; NHI: National Health Insurance; NHIRD: National Health Insurance Research Database; NT$: New Taiwan dollars; PCHF: Peripartum congestive heart failure; PPCM: Peripartum cardiomyopathy; ROPAC: Registry of Pregnancy and Cardiac disease Acknowledgments This study is based on data from the Taiwan National Health Insurance Research Database provided by the Taiwan Bureau of National Health Insurance, Taiwan Department of Health, Taipei, and managed by the National Health Research Institutes (Zhunan, Miaoli County, Taiwan). Funding Ying-Jen Chang received a research founding (grant no. CMFHR10478) from Chi Mei Medical Center. The remaining authors report no financial support. Availability of data and materials The data that support the findings of this study are available from Taiwan National Health Insurance research database. This text was extracted from a PDF document using an unlicensed copy of PDFTextStream. Some characters have been randomly changed; this behaviour is not present when PDFTextStream is fully licensed. Visit http://www.snowtide.com for more information. Chang et al. BMC Pregnancy and Childbirth (2017) 17:302 Page 8 of 9 Declarations 8. This study was granted an exemption from a full ethical review by the Chi Mei Medical Center Institutional Review Board (IRB: 10,505-014). Date of approval: 2016/06/07. 9. Authors' contributions 10. YJC reviewed the literature, designed the study, and drafted the manuscript. CHH helped design the study and did the statistical analyses. JYC and MPN 11. reviewed the literature and interpreted the results. CHY helped do the statistical analyses. JJN revised the manuscript and provided administrative and technical support. CCC and CMC conceived and helped design the study, coordinated and interpreted the results, and revised the manuscript. 12. CCC and CMC contributed equally to this study. All authors have read and approved the final version of this manuscript. 13. Authors' information Both Chia-Ming Chen (M.D.) and Chin-Chen Chu (M.D., Ph.D.) are senior anesthesiologists at Chi Mei Medical Center. Chu is a professor and works as the director of the division of women's and children's anesthesia. 14. 15. Consent for publication Not applicable. This is an observational nationwide population database study. 16. Competing interests The authors declare that they have no competing interests. 17. Publisher'sNote Springer Nature remains neutral with regard to jurisdictional claims in 18. published maps and institutional affiliations. Author details 19. 1Department of Anesthesiology, Chi Mei Medical Center, 901 Zhonghua Road, Yongkang District, Tainan City 710, Taiwan. 2Department of Medical 20. Research, Chi Mei Medical Center, 901 Zhonghua Road, Yongkang District, Tainan City 710, Taiwan. 3Department of Pharmacy, Chia Nan University of 21. Pharmacy and Science, Tainan, Taiwan. 4Department of Senior Citizen Service Management, Chia Nan University of Pharmacy and Science, Tainan, Taiwan. 22. 5Division of Urogynecology and Pelvic Floor Reconstruction, Department of Obstetrics and Gynecology, Chi Mei Medical Center, 901 Zhonghua Road, 23. Yongkang District, Tainan City 710, Taiwan. 6Center of General Education, Chia Nan University of Pharmacy and Science, Tainan, Taiwan. 7Department of Recreation and Health-Care Management, Chia Nan University of Pharmacy and Science, Tainan, Taiwan. 8Division of Nomen's and Children's Anesthesia, Department of Anesthesiology, Chi Mei Medical Center, 901 24. Zhonghua Road, Yongkang District, Tainan City 710, Taiwan. 25. Received: 7 December 2016 Accepted: 4 September 2017 26. References 1. Francis GS, Tang NH. Pathophysiology of congestive heart failure. Rev Cardiovasc Med. 2003;4(Suppl 2):S14¡V20. 27. 2. Koutrolou-Sotiropoulou P, Parikh PB, Miller C, Lima FV, Butler J, Stergiopoulos K. Impact of heart disease on maternal and fetal outcomes in pregnant women. Am J Cardiol. 2015;116(3):474¡V80. 3. Mhyre JM, Tsen LC, Einav S, Kuklina EV, Leffert LR, Bateman BT. Cardiac 28. arrest during hospitalization for delivery in the United States, 1998-2011. Anesthesiology. 2014;120(4):810¡V8. 4. Ruys TP, Roos-Hesselink JN, Hall R, Subirana-Domenech MT, Grando-Ting J, Estensen M, et al. Heart failure in pregnant women with cardiac disease: 29. data from the ROPAC. Heart. 2014;100(3):231¡V8. 5. Nu LS, Liu PH, Lin YS, Lin CP, Chang CJ, Chu PH. Lupus women with delivery with higher risk of heart failure compared with those without pregnancy but 30. neutral in major adverse cardiovascular events. A population-based matched cohort study. Clin Exp Rheumatol. 2014;32(1):108¡V12. 6. Ansari AA, Fett JD, Carraway RE, Mayne AE, Onlamoon N, Sundstrom JB. 31. Autoimmune mechanisms as the basis for human peripartum cardiomyopathy. Clin Rev Allergy Immunol. 2002;23(3):301¡V24. 32. 7. Sheffield JS, Cunningham FG. Thyrotoxicosis and heart failure that complicate pregnancy. Am J Obstet Gynecol. 2004;190(1):211¡V7. Ray JG, Vermeulen MJ, Schull MJ, Redelmeier DA. Cardiovascular health after maternal placental syndromes (CHAMPS): population-based retrospective cohort study. Lancet. 2005;366(9499):1797¡V803. Hilfiker-Kleiner D, Sliwa K. Pathophysiology and epidemiology of peripartum cardiomyopathy. Nat Rev Cardiol. 2014;11(6):364¡V70. Givertz MM. Cardiology patient page: peripartum cardiomyopathy. Circulation. 2013;127(20):e622¡V6. McNamara DM, Elkayam U, Alharethi R, Damp J, Hsich E, Ewald G, et al. Clinical outcomes for peripartum cardiomyopathy in North America: results of the IPAC study (Investigations of Pregnancy-Associated Cardiomyopathy). J Am Coll Cardiol. 2015;66(8):905¡V14. James AH, Jamison MG, Biswas MS, Brancazio LR, Swamy GK, Myers ER. Acute myocardial infarction in pregnancy: a United States population-based study. Circulation. 2006;113(12):1564¡V71. Goland S, Bitar F, Modi K, Safirstein J, Ro A, Mirocha J, et al. Evaluation of the clinical relevance of baseline left ventricular ejection fraction as a predictor of recovery or persistence of severe dysfunction in women in the United States with peripartum cardiomyopathy. J Card Fail. 2011;17(5):426¡V30. Rutherford JD. Heart failure in pregnancy. Curr Heart Fail Rep. 2012;9(4):277¡V81. Hsich EM, Pina IL. Heart failure in women: a need for prospective data. J Am Coll Cardiol. 2009;54(6):491¡V8. Ntusi NB, Badri M, Gumedze F, Sliwa K, Mayosi BM. Pregnancy-associated heart failure: a comparison of clinical presentation and outcome between hypertensive heart failure of pregnancy and idiopathic peripartum cardiomyopathy. PLoS One. 2015;10(8):e0133466. Chen L, Yip N, Chang MC, Lin HS, Lee SD, Chiu YL, et al. The effects of Taiwan's National Health Insurance on access and health status of the elderly. Health Econ. 2007;16(3):223¡V42. Universal Health Coverage in Taiwan. National Health Insurance Administration, Ministry of Health and Nelfare, Taiwan. 2016. http://www. nhi.gov.tw/Resource/webdata/21717_1_UnversalHealthCoverage-2.pdf. Demakis JG, Rahimtoola SH. Peripartum cardiomyopathy. Circulation. 1971; 44(5):964¡V8. Sliwa K, Bohm M. Incidence and prevalence of pregnancy-related heart disease. Cardiovasc Res. 2014;101(4):554¡V60. Bhattacharyya A, Basra SS, Sen P, Kar B. Peripartum cardiomyopathy: a review. Tex Heart Inst J. 2012;39(1):8¡V16. Capriola M. Peripartum cardiomyopathy: a review. Int J Nomens Health. 2013;5:1¡V8. Kamiya CA, Kitakaze M, Ishibashi-Ueda H, Nakatani S, Murohara T, Tomoike H, et al. Different characteristics of peripartum cardiomyopathy between patients complicated with and without hypertensive disorders. -Results from the Japanese Nationwide survey of peripartum cardiomyopathy. Circ J. 2011;75(8):1975¡V81. Dickinson JE. Increasing maternal age and obstetric outcomes. Aust N Z J Obstet Gynaecol. 2012;52(3):217¡V9. Carolan M. Maternal age ,/=45 years and maternal and perinatal outcomes: a review of the evidence. Midwifery. 2013;29(5):479¡V89. Roos-Hesselink JN, Ruys TP, Stein JI, Thilen U, Nebb GD, Niwa K, et al. Outcome of pregnancy in patients with structural or ischaemic heart disease: results of a registry of the European Society of Cardiology. Eur Heart J. 2013;34(9):657¡V65. Drenthen N, Pieper PG, Roos-Hesselink JN, van Lottum NA, Voors AA, Mulder BJ, et al. Outcome of pregnancy in women with congenital heart disease: a literature review. J Am Coll Cardiol. 2007;49(24): 2303¡V11. Hung TH, Hsieh TT. Pregestational body mass index, gestational weight gain, and risks for adverse pregnancy outcomes among Taiwanese women: a retrospective cohort study. Taiwan J Obstet Gynecol. 2016; 55(4):575¡V81. Allen AM, Kim NR, Larson JJ, Rosedahl JK, Yawn BP, McKeon K, et al. The epidemiology of liver diseases unique to pregnancy in a US community: a population-based study. Clin Gastroenterol Hepatol. 2016;14(2):287¡V94 e281-2. Siu SC, Sermer M, Colman JM, Alvarez AN, Mercier LA, Morton BC, et al. Prospective multicenter study of pregnancy outcomes in women with heart disease. Circulation. 2001;104(5):515¡V21. Fu Q, Lin J. Risk factors for heart failure during pregnancy among Chinese women with cardiac disease. Int J Gynaecol Obstet. 2015;130(3):266¡V9. Dayeh NR, Ledoux J, Dupuis J. Lung capillary stress failure and arteriolar Remodelling in pulmonary hypertension associated with left heart disease (Group 2 PH). Prog Cardiovasc Dis. 2016;59(1):11¡V21. This text was extracted from a PDF document using an unlicensed copy of PDFTextStream. Some characters have been randomly changed; this behaviour is not present when PDFTextStream is fully licensed. Visit http://www.snowtide.com for more information. Chang et al. BMC Pregnancy and Childbirth (2017) 17:302 33. Ahmed A, Campbell RC. Epidemiology of chronic kidney disease in heart failure. Heart Fail Clin. 2008;4(4):387¡V99. 34. Coats AJ. Anaemia and heart failure. Heart. 2004;90(9):977¡V9. 35. Castro MA, Fassett MJ, Reynolds TB, Shaw KJ, Goodwin TM. Reversible peripartum liver failure: a new perspective on the diagnosis, treatment, and cause of acute fatty liver of pregnancy, based on 28 consecutive cases. Am J Obstet Gynecol. 1999;181(2):389¡V95. 36. Valbusa F, Bonapace S, Agnoletti D, Scala L, Grillo C, Arduini P, et al. Nonalcoholic fatty liver disease and increased risk of 1-year all-cause and cardiac hospital readmissions in elderly patients admitted for acute heart failure. PLoS One. 2017;12(3):e0173398. 37. Cheng CL, Kao YH, Lin SJ, Lee CH, Lai ML. Validation of the National Health Insurance Research Database with ischemic stroke cases in Taiwan. Pharmacoepidemiol Drug Saf. 2011;20(3):236¡V42. 38. Cheng CL, Lee CH, Chen PS, Li YH, Lin SJ, Yang YH. Validation of acute myocardial infarction cases in the national health insurance research database in taiwan. J Epidemiol. 2014;24(6):500¡V7. Page 9 of 9 Submit your next manuscript to BioMed Central and we will help you at every step: ¡P We accept pre-submission inquiries ? Our selector tool helps you to ?nd the most relevant journal ? We provide round the clock customer support ? Convenient online submission ? Thorough peer review ? Inclusion in PubMed and all major indexing services ? 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