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Increased Risk of Preterm Birth among Women with Mitral Valve Prolapse: A Nationwide, Population-Based Study
Increased Risk of Preterm Birth among Women with Mitral Valve Prolapse: A Nationwide, Population-Based Study CHAO-HUNG CHEN, MD, MPH, MING-CHAO HUANG, MD, HUNG-CHANG LIU, MD, CHANG-JER HUANG, MD, HERNG-CHING LIN, PHD, AND YU RU KOU, PHD
PURPOSE: Using nationwide population-based databases, we aimed to assess the association between mitral valve prolapse (MVP) and adverse pregnancy outcomes. METHODS: The Taiwan Birth Registry and the National Health Insurance Research Dataset were used for analysis. Of all pregnant women in Taiwan who had singleton births in 2005, we identified a total of 3104 mothers diagnosed with MVP during ambulatory or emergency care visits, together with 12,245 mothers unaffected by MPV. Multivariate logistic regression was performed. RESULTS: Multivariate logistic regressions showed that, compared with unaffected mothers, the adjusted odds ratios of preterm birth and cesarean section for mothers with MVP were 1.27 (95% confidence interval [CI], 1.10–1.48) and 1.34 (95% CI, 1.20–1.50), respectively. In further stratification based on the timing of the MVP diagnosis, the highest risks of preterm birth were observed for mothers diagnosed with MVP during (but not before) pregnancy (odds ratio [OR], 1.54; p Z .001). No significant difference was observed between women with and without MVP for other outcomes such as low birthweight, intrapartum complications, low Apgar scores, and congenital malformations. CONCLUSIONS: Our study found a significant risk of preterm delivery among women with MVP. A multidisciplinary team approach to providing obstetric care, with the mission of monitoring signs of cardiac complications and preterm birth, is imperative. Ann Epidemiol 2011;21:391–398. Ó 2011 Elsevier Inc. All rights reserved. KEY WORDS:
Mitral Valve Prolapse, Pregnancy Outcomes, Preterm Birth.
INTRODUCTION Mitral valve prolapse (MVP) is the most frequently observed valvular heart abnormality in young women of childbearing age (1, 2). Although MVP is usually an isolated abnormality, this illness may contribute to a certain degree of mitral regurgitation or may be accompanied by some complications (mitral insufficiency and arrhythmias) (3, 4). MVP is common during gestation, affecting approximately 8.3% of pregnant women (3). There have been few studies evaluating the association between MVP and birth outcomes. Findings usually suggest that MVP does not interfere with regular pregnancy (1, 2, 5, 6). For example, Tang et al (6) reviewed obstetrical performance and outcomes among 37 pregnant mothers with MVP between 1979 and
From the Department & Institute of Physiology (C.-H.C., Y.R.K.), National Yang-Ming University; Department of Thoracic Surgery (C.-H.C., H.-C. Liu, C.-J.H.), Mackay Memorial Hospital; Mackay Medicine, Nursing, and Management College (C.-H.C.); Department of Obstetrics and Gynecology (M.-C.H.), Mackay Memorial Hospital; and School of Health Care Administration (H.-C. Lin), Taipei Medical University, Taipei, Taiwan. Address correspondence to: Yu Ru Kou, PhD, Department & Institute of Physiology, National Yang-Ming University, No.155, Sec.2, Linong Street, Taipei, 112 Taiwan. Tel.: 886-2- 2826-7086; Fax: 886-2- 28264049. E-mail: [email protected]. Received January 20, 2011; accepted February 2, 2011. Ó 2011 Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010
1982. Neither cardiac complications nor maternal mortality was reported among these women. Jana et al. (1) examined outcomes of 34 pregnancies in 15 mothers with MVP. Compared with the institute’s reference neonatal growth curve, the mean weight of 2.8 kg among neonates born to mothers with MVP was appropriate for the mean gestation of 38.5 weeks. However, there have also been a few case reports regarding more serious complications such as stroke (7), thromboembolic ischemia (8), and bacterial endocarditis (9) associated with MVP in pregnancy. Because limited findings have generally indicated that most women with MVP tolerate pregnancy and childbirth well and develop no notable cardiac complications, MVP and pregnancy have not been well studied. Previous studies generally had restricted or selective data with a small number of cases and inadequate consideration of confounders (e.g., maternal morbidity (10, 11) and paternal age (12)). The timing of the MVP diagnosis may affect consequent clinical intervention and management (13, 14), but this aspect has not been explored clearly in the existing literature. The generalizability of previous studies is further constrained by the nonrepresentative nature of the data. Because diverse physiologic changes occurring in pregnancy have a profound impact on pregnant women, further study may be necessary for more effective management of mothers with MVP in the course of pregnancy and labor. 1047-2797/$ - see front matter doi:10.1016/j.annepidem.2011.02.004
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Selected Abbreviations and Acronyms LBW Z low birthweight MVP Z mitral valve prolapse NHIRD Z National Health Insurance Research Dataset NHI Z National Health Insurance
Thus, this study aimed to assess the association between MVP and pregnancy outcomes using a nationwide, population-based dataset. The risk of low birthweight (LBW), preterm delivery, cesarean delivery, intrapartum complications, low Apgar score, and congenital malformations were evaluated for women with MVP compared with unaffected women, and for women diagnosed with MVP before or during pregnancy. We hypothesized that women with MVP might experience more adverse pregnancy outcomes, with worse results among those diagnosed during gestation (because of the more proximal and immediate effects from their valvular problems).
METHODS Database Two nationwide, population-based datasets were used in this study. One was the Taiwan National Health Insurance Research Dataset (NHIRD), published by Taiwan’s National Health Research Institute. Taiwan initiated its National Health Insurance (NHI) program in 1995, with over 22 million citizens (O98% of the Taiwanese population) currently enrolled. The NHIRD includes all inpatient medical claims and payments for people covered under the program, together with registries of contracted medical institutions and board-certified physicians. The second dataset was the Taiwan Birth Registry. The birth registry data are accurate and comprehensive because registering births is mandatory in Taiwan. In this dataset, information including birthdates for both infants and their parents, parity, parental education levels, as well as infant gender, birthweight, and gestational week at birth. The validity of the Taiwan Birth Registry has been previously confirmed (15). The two datasets were linked with assistance from the Bureau of the NHI, which encrypted all personal identifiers before releasing the information. Because deidentified secondary data are available to the public for academic purposes, this study was exempt from full review by the internal review board. Study Sample Of all pregnant women who had singleton births in 2005, a total of 3104 mothers were identified as having at least two consensus diagnoses of MVP (ICD-9-CM code 4240)
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during ambulatory or emergency care visits, either within the 2 years preceding the index pregnancy or during gestation. Two diagnoses were required to ensure diagnostic validity, which is usually a concern in a claims dataset. In further stratifying this study group, 2449 mothers were diagnosed with MVP before pregnancy, and 655 mothers received a diagnosis of MVP during the pregnancy (but not within 2 years before the index gestation). The comparison group was extracted from the remaining women who had singleton births in 2005. A total of 12,245 mothers (approximately four for every mother with MVP) were randomly selected to frequency match the study group in terms of maternal age (!20, 20–24, 25–29, 30–34, and >35 years). Thus, the study group was initially classified by age, with the percentages determined for the resulting strata. Then the comparison strata were generated to have the same percentages as the corresponding strata of the study group. All in all, 15,349 women were recruited into our study.
Variables of Interest The dependent variables of interest in this study were dichotomized as LBW (!2500 vs. >2500 g), preterm delivery (!37 vs. >37 weeks), cesarean delivery (yes vs. no), any intrapartum complication (e.g., fetal distress, placenta previa, abruptio placentae, premature rupture of membrane, meconium stain, all coded as yes or no), low Apgar score (!7 vs. >7), and any congenital malformation (e.g., cleft lip and palate, imperforate anus, misshapen ear, ventricular septal defect, congenital intestinal atresia, hypospadias, polydactyly, Down syndrome; all coded as yes or no). The main independent variable was whether or not a woman had been diagnosed with MVP before or during the index pregnancy. The timing of the MVP diagnosis, either within the 2 years before or during the pregnancy, was further distinguished. Other factors found in the literature to be related to adverse birth outcomes were also considered, including family monthly income (four groups coded as !NT$15,000, NT$15,000–30,000, NT$30,001–50,000, >NT$50,001 [US$1.00 Z NT$ 32.00 in 2005]), infant gender, parity (1, 2, or >3), maternal education level (five groups coded as elementary school or lower, junior high school, senior high school, college or above, and unknown). We also considered maternal comorbidity within 2 years of the pregnancydthat is, whether the expectant mother had been diagnosed as having diabetes, hypertension, rheumatoid arthritis, systemic lupus erythematosus, renal disease, coronary heart disease, hyperlipidemia, anemia, or any major mental disorder within 2 years before the index pregnancy. Finally, paternal age, independent of maternal effects, has been associated with adverse
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pregnancy outcomes (12). Paternal age was also considered as a potential confounder in the analysis. Statistical Analysis The chi-square test of significance was used to identify differences in the infant characteristics in terms of gender, family monthly income, paternal age, and maternal characteristics of age, education level, parity, and comorbid illnesses by women’s MVP status. Because of the use of frequency matching and a rather large sample size, logistic regression was an appropriate method for analysis (16, 17). Multivariate logistic regression analyses were used to calculate the adjusted odds ratios of each dependent variable of pregnancy outcomes for women with MVP either before or during pregnancy compared with non-MVP mothers. Further, women with MVP were then stratified by the timing of their MVP diagnosis. The risks of adverse pregnancy outcomes were assessed using multivariate logistic regression models by the timing of MVP diagnosis (i.e., received a diagnosis of MVP either before or during the index pregnancy) in comparison with women without MVP, after adjusting for the potential confounders. Both maternal and paternal age were considered as continuous variables in the models to avoid potential residual confounding effects. All statistical analyses were performed using STATA version 7.0 software (StataCorp, College Station, TX). All tests of significance were two-tailed, with the level of significance set at p ! .05.
RESULTS Table 1 displays and compares women with and without MVP in relation to infant, maternal, and paternal characteristics. We found that maternal education level (p ! .001), family monthly income (p ! .001), and parity (p ! .001) differed significantly across the MVP and comparison groups. Compared with those without MVP, mothers diagnosed with MVP before or during pregnancy were significantly more likely to also have certain other comorbid diagnoses. In terms of adverse pregnancy outcomes, we found that mothers with MVP were significantly more likely to have neonates with LBW (6.2% vs. 5.2%; p Z .03), preterm birth (8.6% vs. 6.5%; p ! .001), and cesarean delivery (20.7% vs. 14.9%; p ! .001), compared with non-MVP women. However, the distributions of outcomes including intrapartum complications, low Apgar scores, and congenital malformation did not differ significantly between women with and without MVP. In Table 2, we estimated the risk of various adverse pregnancy outcomes among mothers with and without MVP. Variables that were not significant in the bivariate and multivariate logistic regression analyses were excluded
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from the final prediction equations. The results of the multivariate logistic regressions showed that compared with unaffected mothers, the OR of preterm birth for mothers with MVP was 1.27 (95% CI, 1.10–1.48) after adjusting for family monthly income and maternal characteristics of age, education level, parity, hypertension, rheumatoid arthritis, systemic lupus erythematosus, renal disease, coronary heart disease, hyperlipidemia, anemia, and any major mental disorder, and paternal age. The odds of cesarean section were 1.34 times greater (95% CI, 1.20–1.50) for women with MVP, compared with those without MVP, after adjusting for family monthly income and the maternal characteristics listed previously. However, no significant difference was found between MVP groups in terms of LBW, intrapartum complications, low Apgar scores, and congenital malformations, after potential confounders were considered. In Table 3, the timing of the MVP diagnosis was further stratified. After adjusting for family monthly income, maternal characteristics and paternal age, the risk of having preterm infants was significantly higher for mothers diagnosed with MVP before pregnancy (OR, 1.20; 95% CI, 1.02–1.42) compared with those who were not. After adjusting for listed covariates, the risk of preterm birth further increased significantly (OR, 1.54; 95% CI, 1.18–2.01) for women who were diagnosed with MVP during (but not before) pregnancy, compared with women without MVP (p ! .001for trend). Mothers with MVP, no matter whether the diagnosis was made before or during pregnancy, were all significantly more likely to have cesarean delivery, compared with unaffected mothers. No difference was observed for other outcomes, including intrapartum complications, low Apgar scores, and congenital malformations, among the three groups stratified by the timing and status of MVP (data not shown in table). In general, women with adverse pregnancy outcomes were more likely to have lower education levels, lower family monthly incomes, and have comorbid hypertension and hyperlipidemia (all p ! .05). DISCUSSION This is the first nationwide, population-based report on the association between MVP and adverse pregnancy outcomes. Our results indicated that women with an MVP diagnosis were significantly at a 1.27- and 1.34-fold increased risk of having preterm births and cesarean deliveries, respectively, after adjusting for monthly family income and maternal and/or paternal characteristics. In further stratifying the timing of the MVP diagnosis, the odds of preterm delivery for mothers with MVP diagnosed before pregnancy were 1.20 times those of unaffected women. Significantly higher risks were even observed for mothers who were diagnosed with MVP during (but not before) pregnancy (OR, 1.54; p ! .001 for trend).
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TABLE 1. Comparisons of women with and without mitral valve prolapse in relation to infant, maternal and paternal characteristics in Taiwan, 2005 (n Z 15,349) Mothers with MVP prolapse before or during pregnancy (n Z 3104) Variable Infant characteristics Gender Male Female Maternal characteristics Age (years) <19 20–24 25–29 30–34 >35 Age (year), mean (SD) Education level Elementary school or lower Junior high school Senior high school College or above Unknown Family monthly income (NT$) !15,000 15,000–30,000 30,001–50,000 O50,000 Parity 1 2 >3 Diabetes Yes No Hypertension Yes No Rheumatoid arthritis Yes No Systemic lupus erythematosus Yes No Renal disease Yes No Coronary heart disease Yes No Hyperlipidemia Yes No Anemia Yes No Any major mental disorder Yes No
Mothers without MVP (n Z 12,245)
Total No.
%
Total No.
%
1632 1472
52.6 47.4
6358 5887
51.9 48.1
43 380 1086 1049 546
1.4 12.2 35.0 33.8 17.6 29.8 (4.8)
175 1495 4280 4140 2155
1.4 12.2 35.0 33.8 17.6 29.8 (4.9)
30 313 1303 1454 4
1.0 10.1 42.0 46.8 0.1
90 902 4837 6402 14
0.7 7.4 39.5 52.3 0.1
1123 1340 512 129
36.2 43.2 16.5 4.2
4015 5147 2415 668
32.8 42.0 19.7 5.5
1344 1220 540
43.3 39.3 17.4
6109 4657 1479
49.9 38.0 12.1
89 3015
2.9 97.1
329 11,916
2.7 97.3
36 3068
1.2 98.8
82 12,163
0.7 99.3
24 3080
0.8 99.2
46 12,199
0.4 99.6
14 3090
0.5 99.5
25 12,220
0.2 99.8
37 3067
1.2 98.8
68 12,177
0.6 99.4
47 3057
1.5 98.5
56 12,189
0.5 99.5
97 3007
3.1 96.9
192 12,053
1.6 98.4
87 3017
2.8 97.2
206 12,039
1.7 98.3
183 2921
5.9 94.1
356 11,889
2.9 97.1
p-value .515
O.999
.913 !.001
!.001
!.001
.581
.005
.003
.015
!.001 !.001 !.001 !.001 !.001
(Continued)
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TABLE 1. (Continued) Mothers with MVP prolapse before or during pregnancy (n Z 3104) Variable Paternal characteristics Age (years) <19 20–24 25–29 30–34 35–39 >40 Age (year), mean (SD) Pregnancy outcomes Low birthweight Yes No Birth weight, mean (SD) Preterm birth Yes No Gestational age, mean (SD) Cesarean section Yes No Any intrapartum complications Yes No Apgar score !7 at 5 minutes Yes No Any congenital malformation Yes No
Total No.
%
3 129 689 1058 721 504
0.1 4.2 22.2 34.1 23.2 16.2 36.6 (16.0)
Mothers without MVP (n Z 12,245) Total No.
%
p-value .356
19 519 2716 4375 2787 1829
0.2 4.2 22.2 35.7 22.8 14.9 37.1 (16.7)
.097 .03
192 2912
6.2 93.8 3106.6 (439.6)
639 11,606
8.6 91.4 38.2 (1.6)
795 11,450
642 2462
20.7 79.3
1830 10,415
14.9 85.1
518 2586
16.7 83.3
1940 10,305
15.8 84.2
11 3093
0.4 99.6
49 12,196
0.4 99.6
21 3083
0.7 99.3
74 12,171
0.6 99.4
266 2838
5.2 94.8 3124.7 (429.9) 6.5 93.5 38.5 (1.5)
.04 !.001 !.001 !.001
.252
.715
.647
Previous literature generally indicated that women with MVP tolerated pregnancy and delivery fairly well, with favorable perinatal outcomes. MVP was not found to be a significant risk factor for developing cardiac complications (2, 5, 6, 18). Incidences of antepartum and intrapartum complications, signs of fetal distress, and use of analgesia for mothers with MVP did not differ significantly from noncardiac patients (5, 19). Although the labor induction rate was twice as high, nonetheless, 24 out of 28 women with MVP had vaginal deliveries (19). The mean birthweight and gestation at delivery of children born to mothers with MVP were generally appropriate (1, 19). However, Jana et al. (1) further reported 3 out of 34 such neonates were delivered preterm. Most infants were born without congenital abnormalities (1, 6) and maternal mortality was not observed (6). Our studies extend previous findings by investigating neonatal Apgar scores and by more comprehensively evaluating the outcomes of LBW, preterm delivery, and cesarean section. Generally, our results agree with previous studies in noting no increased risk of LBW, intrapartum complications,
low Apgar score, or congenital malformations among children born to mothers with MVP. Nevertheless, women with MVP experienced a significantly increased risk of cesarean section. Although MVP diagnosis alone is generally not a sufficient indicator for cesarean section, cesarean delivery may be implemented in cases where complications are occurring or to avoid the sudden rise and drop in systemic vascular action during maternal pushing (20). Furthermore, our results are unique in demonstrating increased risk of preterm birth among mothers with MVP. The findings were particularly evident when further stratifying the timing of the MVP diagnosis, a pattern suggesting more adverse effects in terms of preterm delivery for those diagnosed with MVP during, rather than before pregnancy. In reviewing previous literature, the link between MVP and preterm delivery has not been clearly indicated or adequately explained. As novel evidence, we speculate that discordant muscle traction, or lower muscle tone, might explain this association. During pregnancy, to keep the developing fetus within the uterus, myometrial contractions need to be restrained, with the cervix remaining closed and
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TABLE 2. Crude and adjusted odds ratios (OR) of low birthweight, preterm birth, cesarean section, any complication in labor, low Apgar score, and any congenital malformation among women with and without mitral valve prolapse (MVP), 2005 (n Z 15,349)
Variable Low birthweight Crude OR, 95% CI Adjusted OR,a 95% CI Preterm birth Crude OR, 95% CI Adjusted OR,a 95% CI Cesarean section Crude OR, 95% CI Adjusted OR,b 95% CI Any intrapartum complications Crude OR, 95% CI Adjusted OR,b 95% CI Apgar score !7 at 5 minutes Crude OR, 95% CI Adjusted OR,b 95% CI Any congenital malformation Crude OR, 95% CI Adjusted OR,b 95% CI
Mothers with MVP before or during pregnancy (n Z 3104)
Mothers without MVP (n Z 12,245)
1.20 (1.01–1.42)* 1.15 (0.97–1.37)
1.0 1.0
1.35 (1.16–1.56)*** 1.27 (1.10–1.48)***
1.0 1.0
1.48 (1.34–1.64)*** 1.34 (1.20–1.50)***
1.0 1.0
1.06 (0.96–1.18) 1.10 (0.99–1.23)
1.0 1.0
0.89 (0.41–1.73) 0.86 (0.44–1.66)
1.0 1.0
1.12 (0.65–1.84) 1.10 (0.67–1.79)
1.0 1.0
*p ! .05; **p ! .01; ***p ! .001. a Adjusted ORs were calculated by multivariate logistic regressions which were adjusted for family monthly income and maternal characteristics of age (continuous), education level, parity, hypertension, rheumatoid arthritis, systemic lupus erythematosus, renal disease, coronary heart disease, hyperlipidemia, anemia, and any major mental disorder and paternal age (continuous). b Adjusted ORs were calculated by multivariate logistic regressions which were adjusted for family monthly income and maternal characteristics of age (continuous), education level, parity, hypertension, rheumatoid arthritis, systemic lupus erythematosus, renal disease, coronary heart disease, hyperlipidemia, anemia, and any major mental disorder.
firm. However, preterm labor may occur in situations of excessive uterine stretch and may be related to cervical weakness (21). Cervical weakness may contribute to compromised maternal defenses against rising infection and lead to stretching of the cervical myometrium and fetal membranes, activating ‘‘labor-associated’’ genes. Meanwhile, stretch-induced labor may occur because of increased expression of ‘‘labor-associated proteins’’ (21, 22). Similar to the discordant muscle tension in the uterus and cervix during preterm deliveries, excessive papillary muscle traction, possibly owing to muscle weakness, also plays a chief role in superior displacement of the mitral leaflets in patients with MVP (23–25). The greater prevalence of adverse outcomes related to MVP diagnosis during rather than before pregnancy further suggests discordant muscle traction, especially during pregnancy, might synchronously affect both cardiac papillary and uterine cervical muscles. The risk of preterm delivery is consequently amplified. It is worth noting that significantly greater proportions of mothers with MVP before or during pregnancy were
diagnosed with other diseases, such as hypertension, renal disease, coronary heart disease, anemia, compared with women without MVP. It is possible that women with MVP were more likely to have doctor’s appointments and, therefore, for additional diseases to be found. Existing literature has also reported the occurrence of comorbid illnesses among women with MVP (26, 27). In our study, maternal comorbidity was considered and adjusted for in the regression analyses so that the association between MVP and pregnancy outcomes could be better evaluated. To the best of our knowledge, our study is the most comprehensive, nationwide, population-based study ever conducted to evaluate the association between MVP and pregnancy outcomes. Linking two nationwide datasets leaves little room for selection and nonresponse bias, and the large sample size provides ample statistical power for estimation. Our study also leads the way toward examining an array of pregnancy outcomes in relation to the timing of the maternal MVP diagnosis. However, three limitations of this study merit attention. First, the validity of diagnoses in claims datasets is usually a concern. In Taiwan, a diagnosis of MVP involves clinical examination and conformation to two-dimensional echocardiography criteria. Generally, the displacement of the mitral valve leaflets into the left atrium by at least 2 mm, with or without leaflet thickening, is required for an MVP diagnosis (28). Although the possibility of overdiagnosis is often considered in claims datasets, the NHI discourages upcoding by routinely performing sample cross-checks of each medical institution’s claims with its medical charts. Punitive procedures are applied for coding infractions. It is generally accepted that the NHI’s checks and balances promote appropriate coding. Second, the NHIRD database only represents patients who sought treatment for MVP. We therefore might have missed women whose MVP, either before or during gestation, is not disruptive and causes no substantial symptoms. In such cases, treatment might not be sought for the condition at all (4). Furthermore, women whose MVP was diagnosed outside the 2-year window of the index pregnancy could be treated as non-MVP and recruited into the comparison cohort. These women may have minor or much alleviated symptoms and thus no clinic visits during this period. Finally, some important variables such as the severity of MVP, maternal cigarette smoking, body mass index, nutrition, and alcohol consumption, which are likely to be related to pregnancy outcomes, were not available in our claims dataset. There are substantial implications of this study. Although the outcomes of pregnancies for mothers diagnosed with MVP are generally favorable, our results provide a compelling reason to carefully monitor and evaluate pregnant women with MVP to prevent potential preterm delivery, particularly women who are newly diagnosed
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TABLE 3. Adjusted odds ratios (OR) of low birthweight, preterm birth, and cesarean section among women without and with mitral valve prolapse (MVP) diagnosed before or during pregnancy, 2005 (n Z 15,349) Mothers with MVP diagnosed before pregnancy (n Z 2449) Variable Low birthweight Yes Crude OR, 95% CI Adjusted ORa, 95% CI Preterm birth Yes Crude OR, 95% CI Adjusted ORa, 95% CI Cesarean section Yes Crude OR, 95% CI Adjusted OR,b 95% CI
No.
%
Mothers with MVP diagnosed during pregnancy (n Z 655) No.
% 6.1
Mothers without MVP (n Z 12,245) No.
152 6.2 1.20 (1.00–1.44)* 1.15 (0.96–1.39)
40 1.18 (0.85–1.64) 1.15 (0.83–1.61)
200 8.2 1.28 (1.09–1.51)** 1.20 (1.02–1.42)*
66 10.1 1.61 (1.24–2.10)*** 1.54 (1.18–2.01)**
795
504 20.6 1.47 (1.32–1.65)*** 1.37 (1.21–1.54)***
138 21.1 1.52 (1.25–1.84)*** 1.26 (1.02–1.56)*
1,830
%
639
5.2 1.0 1.0 6.5 1.0 1.0 14.9 1.0 1.0
*p ! .05; **p ! .01; ***p ! .001. a Adjusted ORs were calculated by multivariate logistic regressions which were adjusted for family monthly income and maternal characteristics of age (continuous), education level, parity, hypertension, rheumatoid arthritis, systemic lupus erythematosus, renal disease, coronary heart disease, hyperlipidemia, anemia, and any major mental disorder and paternal age (continuous). b Adjusted ORs were calculated by multivariate logistic regressions which were adjusted for family monthly income and maternal characteristics of age (continuous), education level, parity, hypertension, rheumatoid arthritis, systemic lupus erythematosus, renal disease, coronary heart disease, hyperlipidemia, anemia, and any major mental disorder.
with MVP during pregnancy. Currently, pregnant women with a history of MVP in Taiwan are followed through obstetric ultrasound, usually without prescription of medication. Careful observation and proper management of complications (e.g., cardiac arrhythmias) if there are any, along with timely detection of signs of preterm birth are needed during such pregnancies. During labor, although epidural anesthesia may be safely employed, the use of antibiotic prophylaxis remains controversial (29). In sum, preconception evaluation and counseling, awareness of this common cardiac lesion, intensive cardiovascular examination, careful monitoring during prenatal care, and cooperation between the patient, the obstetrician, the cardiologist, and the supporting medical team are essential steps to optimize both maternal and fetal health. Our study highlights a significant potential risk of preterm delivery of women with MVP, for whom favorable pregnancy outcomes have usually been assumed. Women who are newly diagnosed with MVP during pregnancy may be facing a greater threat. A multidisciplinary team approach to providing obstetric care, with the mission of monitoring and timely management of signs of cardiac complications and preterm birth is imperative. Future studies are needed to replicate the results and identify the mechanisms, which are still indistinct, connecting MVP to preterm delivery.
This study is based in part on data from the National Health Insurance Research Database provided by the Bureau of National Health Insurance, Department of Health and managed by National Health Research Institutes of Taiwan. The interpretation and conclusions contained herein
do not represent those of Bureau of National Health Insurance, Department of Health or National Health Research Institutes.
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14. Martinez-Diaz JL. Valvular heart disease in pregnancy: a review of the literature. Bol Asoc Med P R. 2008;100:55–59. 15. Lin CM, Lee PC, Teng SW, Lu TH, Mao IF, Li CY. Validation of the Taiwan Birth Registry using obstetric records. J Formos Med Assoc. 2004;103:297–301. 16. Cheung YB. Analysis of matched case-control data. J Clin Epidemiol. 2003;56:814. 17. Clayton D, Hills M. Statistical models in epidemiology. New York: Oxford University Press; 1993. 18. Kral J, Spacil J, Hradec J, Cech E. [Pregnancy and labor in women with mitral valve prolapse]. Cas Lek Cesk. 1990;129:1029–1032. 19. Chia YT, Yeoh SC, Lim MC, Viegas OA, Ratnam SS. Pregnancy outcome and mitral valve prolapse. Asia Oceania J Obstet Gynaecol. 1994;20:383– 388. 20. Stout KK, Otto CM. Pregnancy in women with valvular heart disease. Heart. 2007;93:552–558. 21. Mohan AR, Loudon JA, Bennett PR. Molecular and biochemical mechanisms of preterm labour. Semin Fetal Neonatal Med. 2004;9:437–444. 22. Ou CW, Orsino A, Lye SJ. Expression of connexin-43 and connexin-26 in the rat myometrium during pregnancy and labor is differentially regulated by mechanical and hormonal signals. Endocrinology. 1997;138:5398–5407.
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23. Boudoulas H, Wooley CF. Floppy mitral valve/mitral valve prolapse/ mitral valvular regurgitation: effects on the circulation. J Cardiol. 2001;37(Suppl 1):15–20. 24. Lee TM, Su SF, Huang TY, Chen MF, Liau CS, Lee YT. Excessive papillary muscle traction and dilated mitral annulus in mitral valve prolapse without mitral regurgitation. Am J Cardiol. 1996;78:482–485. 25. Sanfilippo AJ, Harrigan P, Popovic AD, Weyman AE, Levine RA. Papillary muscle traction in mitral valve prolapse: quantitation by twodimensional echocardiography. J Am Coll Cardiol. 1992;19:564–571. 26. Lin SS, Lauer MS, Asher CR, Cosgrove DM, Blackstone E, Thomas JD, et al. Prediction of coronary artery disease in patients undergoing operations for mitral valve degeneration. J Thorac Cardiovasc Surg. 2001;121:894–901. 27. Singh SK, Kumar V, Dubey NK, Jain M, Anand R. Mitral valve prolapse with pulmonary haemosiderosis and severe anaemia: cause or association? J Indian Med Assoc. 2001;99:515–516. 28. Freed LA, Levy D, Levine RA, Larson MG, Evans JC, Fuller DL, et al. Prevalence and clinical outcome of mitral-valve prolapse. N Engl J Med. 1999;341:1–7. 29. Teerlink JR, Foster E. Valvular heart disease in pregnancy. A contemporary perspective. Cardiol Clin. 1998;16:573–598.
PURPOSE: Using nationwide population-based databases, we aimed to assess the association between mitral valve prolapse (MVP) and adverse pregnancy outcomes. METHODS: The Taiwan Birth Registry and the National Health Insurance Research Dataset were used for analysis. Of all pregnant women in Taiwan who had singleton births in 2005, we identified a total of 3104 mothers diagnosed with MVP during ambulatory or emergency care visits, together with 12,245 mothers unaffected by MPV. Multivariate logistic regression was performed. RESULTS: Multivariate logistic regressions showed that, compared with unaffected mothers, the adjusted odds ratios of preterm birth and cesarean section for mothers with MVP were 1.27 (95% confidence interval [CI], 1.10–1.48) and 1.34 (95% CI, 1.20–1.50), respectively. In further stratification based on the timing of the MVP diagnosis, the highest risks of preterm birth were observed for mothers diagnosed with MVP during (but not before) pregnancy (odds ratio [OR], 1.54; p Z .001). No significant difference was observed between women with and without MVP for other outcomes such as low birthweight, intrapartum complications, low Apgar scores, and congenital malformations. CONCLUSIONS: Our study found a significant risk of preterm delivery among women with MVP. A multidisciplinary team approach to providing obstetric care, with the mission of monitoring signs of cardiac complications and preterm birth, is imperative. Ann Epidemiol 2011;21:391–398. Ó 2011 Elsevier Inc. All rights reserved. KEY WORDS:
Mitral Valve Prolapse, Pregnancy Outcomes, Preterm Birth.
INTRODUCTION Mitral valve prolapse (MVP) is the most frequently observed valvular heart abnormality in young women of childbearing age (1, 2). Although MVP is usually an isolated abnormality, this illness may contribute to a certain degree of mitral regurgitation or may be accompanied by some complications (mitral insufficiency and arrhythmias) (3, 4). MVP is common during gestation, affecting approximately 8.3% of pregnant women (3). There have been few studies evaluating the association between MVP and birth outcomes. Findings usually suggest that MVP does not interfere with regular pregnancy (1, 2, 5, 6). For example, Tang et al (6) reviewed obstetrical performance and outcomes among 37 pregnant mothers with MVP between 1979 and
From the Department & Institute of Physiology (C.-H.C., Y.R.K.), National Yang-Ming University; Department of Thoracic Surgery (C.-H.C., H.-C. Liu, C.-J.H.), Mackay Memorial Hospital; Mackay Medicine, Nursing, and Management College (C.-H.C.); Department of Obstetrics and Gynecology (M.-C.H.), Mackay Memorial Hospital; and School of Health Care Administration (H.-C. Lin), Taipei Medical University, Taipei, Taiwan. Address correspondence to: Yu Ru Kou, PhD, Department & Institute of Physiology, National Yang-Ming University, No.155, Sec.2, Linong Street, Taipei, 112 Taiwan. Tel.: 886-2- 2826-7086; Fax: 886-2- 28264049. E-mail: [email protected]. Received January 20, 2011; accepted February 2, 2011. Ó 2011 Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010
1982. Neither cardiac complications nor maternal mortality was reported among these women. Jana et al. (1) examined outcomes of 34 pregnancies in 15 mothers with MVP. Compared with the institute’s reference neonatal growth curve, the mean weight of 2.8 kg among neonates born to mothers with MVP was appropriate for the mean gestation of 38.5 weeks. However, there have also been a few case reports regarding more serious complications such as stroke (7), thromboembolic ischemia (8), and bacterial endocarditis (9) associated with MVP in pregnancy. Because limited findings have generally indicated that most women with MVP tolerate pregnancy and childbirth well and develop no notable cardiac complications, MVP and pregnancy have not been well studied. Previous studies generally had restricted or selective data with a small number of cases and inadequate consideration of confounders (e.g., maternal morbidity (10, 11) and paternal age (12)). The timing of the MVP diagnosis may affect consequent clinical intervention and management (13, 14), but this aspect has not been explored clearly in the existing literature. The generalizability of previous studies is further constrained by the nonrepresentative nature of the data. Because diverse physiologic changes occurring in pregnancy have a profound impact on pregnant women, further study may be necessary for more effective management of mothers with MVP in the course of pregnancy and labor. 1047-2797/$ - see front matter doi:10.1016/j.annepidem.2011.02.004
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Selected Abbreviations and Acronyms LBW Z low birthweight MVP Z mitral valve prolapse NHIRD Z National Health Insurance Research Dataset NHI Z National Health Insurance
Thus, this study aimed to assess the association between MVP and pregnancy outcomes using a nationwide, population-based dataset. The risk of low birthweight (LBW), preterm delivery, cesarean delivery, intrapartum complications, low Apgar score, and congenital malformations were evaluated for women with MVP compared with unaffected women, and for women diagnosed with MVP before or during pregnancy. We hypothesized that women with MVP might experience more adverse pregnancy outcomes, with worse results among those diagnosed during gestation (because of the more proximal and immediate effects from their valvular problems).
METHODS Database Two nationwide, population-based datasets were used in this study. One was the Taiwan National Health Insurance Research Dataset (NHIRD), published by Taiwan’s National Health Research Institute. Taiwan initiated its National Health Insurance (NHI) program in 1995, with over 22 million citizens (O98% of the Taiwanese population) currently enrolled. The NHIRD includes all inpatient medical claims and payments for people covered under the program, together with registries of contracted medical institutions and board-certified physicians. The second dataset was the Taiwan Birth Registry. The birth registry data are accurate and comprehensive because registering births is mandatory in Taiwan. In this dataset, information including birthdates for both infants and their parents, parity, parental education levels, as well as infant gender, birthweight, and gestational week at birth. The validity of the Taiwan Birth Registry has been previously confirmed (15). The two datasets were linked with assistance from the Bureau of the NHI, which encrypted all personal identifiers before releasing the information. Because deidentified secondary data are available to the public for academic purposes, this study was exempt from full review by the internal review board. Study Sample Of all pregnant women who had singleton births in 2005, a total of 3104 mothers were identified as having at least two consensus diagnoses of MVP (ICD-9-CM code 4240)
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during ambulatory or emergency care visits, either within the 2 years preceding the index pregnancy or during gestation. Two diagnoses were required to ensure diagnostic validity, which is usually a concern in a claims dataset. In further stratifying this study group, 2449 mothers were diagnosed with MVP before pregnancy, and 655 mothers received a diagnosis of MVP during the pregnancy (but not within 2 years before the index gestation). The comparison group was extracted from the remaining women who had singleton births in 2005. A total of 12,245 mothers (approximately four for every mother with MVP) were randomly selected to frequency match the study group in terms of maternal age (!20, 20–24, 25–29, 30–34, and >35 years). Thus, the study group was initially classified by age, with the percentages determined for the resulting strata. Then the comparison strata were generated to have the same percentages as the corresponding strata of the study group. All in all, 15,349 women were recruited into our study.
Variables of Interest The dependent variables of interest in this study were dichotomized as LBW (!2500 vs. >2500 g), preterm delivery (!37 vs. >37 weeks), cesarean delivery (yes vs. no), any intrapartum complication (e.g., fetal distress, placenta previa, abruptio placentae, premature rupture of membrane, meconium stain, all coded as yes or no), low Apgar score (!7 vs. >7), and any congenital malformation (e.g., cleft lip and palate, imperforate anus, misshapen ear, ventricular septal defect, congenital intestinal atresia, hypospadias, polydactyly, Down syndrome; all coded as yes or no). The main independent variable was whether or not a woman had been diagnosed with MVP before or during the index pregnancy. The timing of the MVP diagnosis, either within the 2 years before or during the pregnancy, was further distinguished. Other factors found in the literature to be related to adverse birth outcomes were also considered, including family monthly income (four groups coded as !NT$15,000, NT$15,000–30,000, NT$30,001–50,000, >NT$50,001 [US$1.00 Z NT$ 32.00 in 2005]), infant gender, parity (1, 2, or >3), maternal education level (five groups coded as elementary school or lower, junior high school, senior high school, college or above, and unknown). We also considered maternal comorbidity within 2 years of the pregnancydthat is, whether the expectant mother had been diagnosed as having diabetes, hypertension, rheumatoid arthritis, systemic lupus erythematosus, renal disease, coronary heart disease, hyperlipidemia, anemia, or any major mental disorder within 2 years before the index pregnancy. Finally, paternal age, independent of maternal effects, has been associated with adverse
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pregnancy outcomes (12). Paternal age was also considered as a potential confounder in the analysis. Statistical Analysis The chi-square test of significance was used to identify differences in the infant characteristics in terms of gender, family monthly income, paternal age, and maternal characteristics of age, education level, parity, and comorbid illnesses by women’s MVP status. Because of the use of frequency matching and a rather large sample size, logistic regression was an appropriate method for analysis (16, 17). Multivariate logistic regression analyses were used to calculate the adjusted odds ratios of each dependent variable of pregnancy outcomes for women with MVP either before or during pregnancy compared with non-MVP mothers. Further, women with MVP were then stratified by the timing of their MVP diagnosis. The risks of adverse pregnancy outcomes were assessed using multivariate logistic regression models by the timing of MVP diagnosis (i.e., received a diagnosis of MVP either before or during the index pregnancy) in comparison with women without MVP, after adjusting for the potential confounders. Both maternal and paternal age were considered as continuous variables in the models to avoid potential residual confounding effects. All statistical analyses were performed using STATA version 7.0 software (StataCorp, College Station, TX). All tests of significance were two-tailed, with the level of significance set at p ! .05.
RESULTS Table 1 displays and compares women with and without MVP in relation to infant, maternal, and paternal characteristics. We found that maternal education level (p ! .001), family monthly income (p ! .001), and parity (p ! .001) differed significantly across the MVP and comparison groups. Compared with those without MVP, mothers diagnosed with MVP before or during pregnancy were significantly more likely to also have certain other comorbid diagnoses. In terms of adverse pregnancy outcomes, we found that mothers with MVP were significantly more likely to have neonates with LBW (6.2% vs. 5.2%; p Z .03), preterm birth (8.6% vs. 6.5%; p ! .001), and cesarean delivery (20.7% vs. 14.9%; p ! .001), compared with non-MVP women. However, the distributions of outcomes including intrapartum complications, low Apgar scores, and congenital malformation did not differ significantly between women with and without MVP. In Table 2, we estimated the risk of various adverse pregnancy outcomes among mothers with and without MVP. Variables that were not significant in the bivariate and multivariate logistic regression analyses were excluded
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from the final prediction equations. The results of the multivariate logistic regressions showed that compared with unaffected mothers, the OR of preterm birth for mothers with MVP was 1.27 (95% CI, 1.10–1.48) after adjusting for family monthly income and maternal characteristics of age, education level, parity, hypertension, rheumatoid arthritis, systemic lupus erythematosus, renal disease, coronary heart disease, hyperlipidemia, anemia, and any major mental disorder, and paternal age. The odds of cesarean section were 1.34 times greater (95% CI, 1.20–1.50) for women with MVP, compared with those without MVP, after adjusting for family monthly income and the maternal characteristics listed previously. However, no significant difference was found between MVP groups in terms of LBW, intrapartum complications, low Apgar scores, and congenital malformations, after potential confounders were considered. In Table 3, the timing of the MVP diagnosis was further stratified. After adjusting for family monthly income, maternal characteristics and paternal age, the risk of having preterm infants was significantly higher for mothers diagnosed with MVP before pregnancy (OR, 1.20; 95% CI, 1.02–1.42) compared with those who were not. After adjusting for listed covariates, the risk of preterm birth further increased significantly (OR, 1.54; 95% CI, 1.18–2.01) for women who were diagnosed with MVP during (but not before) pregnancy, compared with women without MVP (p ! .001for trend). Mothers with MVP, no matter whether the diagnosis was made before or during pregnancy, were all significantly more likely to have cesarean delivery, compared with unaffected mothers. No difference was observed for other outcomes, including intrapartum complications, low Apgar scores, and congenital malformations, among the three groups stratified by the timing and status of MVP (data not shown in table). In general, women with adverse pregnancy outcomes were more likely to have lower education levels, lower family monthly incomes, and have comorbid hypertension and hyperlipidemia (all p ! .05). DISCUSSION This is the first nationwide, population-based report on the association between MVP and adverse pregnancy outcomes. Our results indicated that women with an MVP diagnosis were significantly at a 1.27- and 1.34-fold increased risk of having preterm births and cesarean deliveries, respectively, after adjusting for monthly family income and maternal and/or paternal characteristics. In further stratifying the timing of the MVP diagnosis, the odds of preterm delivery for mothers with MVP diagnosed before pregnancy were 1.20 times those of unaffected women. Significantly higher risks were even observed for mothers who were diagnosed with MVP during (but not before) pregnancy (OR, 1.54; p ! .001 for trend).
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TABLE 1. Comparisons of women with and without mitral valve prolapse in relation to infant, maternal and paternal characteristics in Taiwan, 2005 (n Z 15,349) Mothers with MVP prolapse before or during pregnancy (n Z 3104) Variable Infant characteristics Gender Male Female Maternal characteristics Age (years) <19 20–24 25–29 30–34 >35 Age (year), mean (SD) Education level Elementary school or lower Junior high school Senior high school College or above Unknown Family monthly income (NT$) !15,000 15,000–30,000 30,001–50,000 O50,000 Parity 1 2 >3 Diabetes Yes No Hypertension Yes No Rheumatoid arthritis Yes No Systemic lupus erythematosus Yes No Renal disease Yes No Coronary heart disease Yes No Hyperlipidemia Yes No Anemia Yes No Any major mental disorder Yes No
Mothers without MVP (n Z 12,245)
Total No.
%
Total No.
%
1632 1472
52.6 47.4
6358 5887
51.9 48.1
43 380 1086 1049 546
1.4 12.2 35.0 33.8 17.6 29.8 (4.8)
175 1495 4280 4140 2155
1.4 12.2 35.0 33.8 17.6 29.8 (4.9)
30 313 1303 1454 4
1.0 10.1 42.0 46.8 0.1
90 902 4837 6402 14
0.7 7.4 39.5 52.3 0.1
1123 1340 512 129
36.2 43.2 16.5 4.2
4015 5147 2415 668
32.8 42.0 19.7 5.5
1344 1220 540
43.3 39.3 17.4
6109 4657 1479
49.9 38.0 12.1
89 3015
2.9 97.1
329 11,916
2.7 97.3
36 3068
1.2 98.8
82 12,163
0.7 99.3
24 3080
0.8 99.2
46 12,199
0.4 99.6
14 3090
0.5 99.5
25 12,220
0.2 99.8
37 3067
1.2 98.8
68 12,177
0.6 99.4
47 3057
1.5 98.5
56 12,189
0.5 99.5
97 3007
3.1 96.9
192 12,053
1.6 98.4
87 3017
2.8 97.2
206 12,039
1.7 98.3
183 2921
5.9 94.1
356 11,889
2.9 97.1
p-value .515
O.999
.913 !.001
!.001
!.001
.581
.005
.003
.015
!.001 !.001 !.001 !.001 !.001
(Continued)
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TABLE 1. (Continued) Mothers with MVP prolapse before or during pregnancy (n Z 3104) Variable Paternal characteristics Age (years) <19 20–24 25–29 30–34 35–39 >40 Age (year), mean (SD) Pregnancy outcomes Low birthweight Yes No Birth weight, mean (SD) Preterm birth Yes No Gestational age, mean (SD) Cesarean section Yes No Any intrapartum complications Yes No Apgar score !7 at 5 minutes Yes No Any congenital malformation Yes No
Total No.
%
3 129 689 1058 721 504
0.1 4.2 22.2 34.1 23.2 16.2 36.6 (16.0)
Mothers without MVP (n Z 12,245) Total No.
%
p-value .356
19 519 2716 4375 2787 1829
0.2 4.2 22.2 35.7 22.8 14.9 37.1 (16.7)
.097 .03
192 2912
6.2 93.8 3106.6 (439.6)
639 11,606
8.6 91.4 38.2 (1.6)
795 11,450
642 2462
20.7 79.3
1830 10,415
14.9 85.1
518 2586
16.7 83.3
1940 10,305
15.8 84.2
11 3093
0.4 99.6
49 12,196
0.4 99.6
21 3083
0.7 99.3
74 12,171
0.6 99.4
266 2838
5.2 94.8 3124.7 (429.9) 6.5 93.5 38.5 (1.5)
.04 !.001 !.001 !.001
.252
.715
.647
Previous literature generally indicated that women with MVP tolerated pregnancy and delivery fairly well, with favorable perinatal outcomes. MVP was not found to be a significant risk factor for developing cardiac complications (2, 5, 6, 18). Incidences of antepartum and intrapartum complications, signs of fetal distress, and use of analgesia for mothers with MVP did not differ significantly from noncardiac patients (5, 19). Although the labor induction rate was twice as high, nonetheless, 24 out of 28 women with MVP had vaginal deliveries (19). The mean birthweight and gestation at delivery of children born to mothers with MVP were generally appropriate (1, 19). However, Jana et al. (1) further reported 3 out of 34 such neonates were delivered preterm. Most infants were born without congenital abnormalities (1, 6) and maternal mortality was not observed (6). Our studies extend previous findings by investigating neonatal Apgar scores and by more comprehensively evaluating the outcomes of LBW, preterm delivery, and cesarean section. Generally, our results agree with previous studies in noting no increased risk of LBW, intrapartum complications,
low Apgar score, or congenital malformations among children born to mothers with MVP. Nevertheless, women with MVP experienced a significantly increased risk of cesarean section. Although MVP diagnosis alone is generally not a sufficient indicator for cesarean section, cesarean delivery may be implemented in cases where complications are occurring or to avoid the sudden rise and drop in systemic vascular action during maternal pushing (20). Furthermore, our results are unique in demonstrating increased risk of preterm birth among mothers with MVP. The findings were particularly evident when further stratifying the timing of the MVP diagnosis, a pattern suggesting more adverse effects in terms of preterm delivery for those diagnosed with MVP during, rather than before pregnancy. In reviewing previous literature, the link between MVP and preterm delivery has not been clearly indicated or adequately explained. As novel evidence, we speculate that discordant muscle traction, or lower muscle tone, might explain this association. During pregnancy, to keep the developing fetus within the uterus, myometrial contractions need to be restrained, with the cervix remaining closed and
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TABLE 2. Crude and adjusted odds ratios (OR) of low birthweight, preterm birth, cesarean section, any complication in labor, low Apgar score, and any congenital malformation among women with and without mitral valve prolapse (MVP), 2005 (n Z 15,349)
Variable Low birthweight Crude OR, 95% CI Adjusted OR,a 95% CI Preterm birth Crude OR, 95% CI Adjusted OR,a 95% CI Cesarean section Crude OR, 95% CI Adjusted OR,b 95% CI Any intrapartum complications Crude OR, 95% CI Adjusted OR,b 95% CI Apgar score !7 at 5 minutes Crude OR, 95% CI Adjusted OR,b 95% CI Any congenital malformation Crude OR, 95% CI Adjusted OR,b 95% CI
Mothers with MVP before or during pregnancy (n Z 3104)
Mothers without MVP (n Z 12,245)
1.20 (1.01–1.42)* 1.15 (0.97–1.37)
1.0 1.0
1.35 (1.16–1.56)*** 1.27 (1.10–1.48)***
1.0 1.0
1.48 (1.34–1.64)*** 1.34 (1.20–1.50)***
1.0 1.0
1.06 (0.96–1.18) 1.10 (0.99–1.23)
1.0 1.0
0.89 (0.41–1.73) 0.86 (0.44–1.66)
1.0 1.0
1.12 (0.65–1.84) 1.10 (0.67–1.79)
1.0 1.0
*p ! .05; **p ! .01; ***p ! .001. a Adjusted ORs were calculated by multivariate logistic regressions which were adjusted for family monthly income and maternal characteristics of age (continuous), education level, parity, hypertension, rheumatoid arthritis, systemic lupus erythematosus, renal disease, coronary heart disease, hyperlipidemia, anemia, and any major mental disorder and paternal age (continuous). b Adjusted ORs were calculated by multivariate logistic regressions which were adjusted for family monthly income and maternal characteristics of age (continuous), education level, parity, hypertension, rheumatoid arthritis, systemic lupus erythematosus, renal disease, coronary heart disease, hyperlipidemia, anemia, and any major mental disorder.
firm. However, preterm labor may occur in situations of excessive uterine stretch and may be related to cervical weakness (21). Cervical weakness may contribute to compromised maternal defenses against rising infection and lead to stretching of the cervical myometrium and fetal membranes, activating ‘‘labor-associated’’ genes. Meanwhile, stretch-induced labor may occur because of increased expression of ‘‘labor-associated proteins’’ (21, 22). Similar to the discordant muscle tension in the uterus and cervix during preterm deliveries, excessive papillary muscle traction, possibly owing to muscle weakness, also plays a chief role in superior displacement of the mitral leaflets in patients with MVP (23–25). The greater prevalence of adverse outcomes related to MVP diagnosis during rather than before pregnancy further suggests discordant muscle traction, especially during pregnancy, might synchronously affect both cardiac papillary and uterine cervical muscles. The risk of preterm delivery is consequently amplified. It is worth noting that significantly greater proportions of mothers with MVP before or during pregnancy were
diagnosed with other diseases, such as hypertension, renal disease, coronary heart disease, anemia, compared with women without MVP. It is possible that women with MVP were more likely to have doctor’s appointments and, therefore, for additional diseases to be found. Existing literature has also reported the occurrence of comorbid illnesses among women with MVP (26, 27). In our study, maternal comorbidity was considered and adjusted for in the regression analyses so that the association between MVP and pregnancy outcomes could be better evaluated. To the best of our knowledge, our study is the most comprehensive, nationwide, population-based study ever conducted to evaluate the association between MVP and pregnancy outcomes. Linking two nationwide datasets leaves little room for selection and nonresponse bias, and the large sample size provides ample statistical power for estimation. Our study also leads the way toward examining an array of pregnancy outcomes in relation to the timing of the maternal MVP diagnosis. However, three limitations of this study merit attention. First, the validity of diagnoses in claims datasets is usually a concern. In Taiwan, a diagnosis of MVP involves clinical examination and conformation to two-dimensional echocardiography criteria. Generally, the displacement of the mitral valve leaflets into the left atrium by at least 2 mm, with or without leaflet thickening, is required for an MVP diagnosis (28). Although the possibility of overdiagnosis is often considered in claims datasets, the NHI discourages upcoding by routinely performing sample cross-checks of each medical institution’s claims with its medical charts. Punitive procedures are applied for coding infractions. It is generally accepted that the NHI’s checks and balances promote appropriate coding. Second, the NHIRD database only represents patients who sought treatment for MVP. We therefore might have missed women whose MVP, either before or during gestation, is not disruptive and causes no substantial symptoms. In such cases, treatment might not be sought for the condition at all (4). Furthermore, women whose MVP was diagnosed outside the 2-year window of the index pregnancy could be treated as non-MVP and recruited into the comparison cohort. These women may have minor or much alleviated symptoms and thus no clinic visits during this period. Finally, some important variables such as the severity of MVP, maternal cigarette smoking, body mass index, nutrition, and alcohol consumption, which are likely to be related to pregnancy outcomes, were not available in our claims dataset. There are substantial implications of this study. Although the outcomes of pregnancies for mothers diagnosed with MVP are generally favorable, our results provide a compelling reason to carefully monitor and evaluate pregnant women with MVP to prevent potential preterm delivery, particularly women who are newly diagnosed
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TABLE 3. Adjusted odds ratios (OR) of low birthweight, preterm birth, and cesarean section among women without and with mitral valve prolapse (MVP) diagnosed before or during pregnancy, 2005 (n Z 15,349) Mothers with MVP diagnosed before pregnancy (n Z 2449) Variable Low birthweight Yes Crude OR, 95% CI Adjusted ORa, 95% CI Preterm birth Yes Crude OR, 95% CI Adjusted ORa, 95% CI Cesarean section Yes Crude OR, 95% CI Adjusted OR,b 95% CI
No.
%
Mothers with MVP diagnosed during pregnancy (n Z 655) No.
% 6.1
Mothers without MVP (n Z 12,245) No.
152 6.2 1.20 (1.00–1.44)* 1.15 (0.96–1.39)
40 1.18 (0.85–1.64) 1.15 (0.83–1.61)
200 8.2 1.28 (1.09–1.51)** 1.20 (1.02–1.42)*
66 10.1 1.61 (1.24–2.10)*** 1.54 (1.18–2.01)**
795
504 20.6 1.47 (1.32–1.65)*** 1.37 (1.21–1.54)***
138 21.1 1.52 (1.25–1.84)*** 1.26 (1.02–1.56)*
1,830
%
639
5.2 1.0 1.0 6.5 1.0 1.0 14.9 1.0 1.0
*p ! .05; **p ! .01; ***p ! .001. a Adjusted ORs were calculated by multivariate logistic regressions which were adjusted for family monthly income and maternal characteristics of age (continuous), education level, parity, hypertension, rheumatoid arthritis, systemic lupus erythematosus, renal disease, coronary heart disease, hyperlipidemia, anemia, and any major mental disorder and paternal age (continuous). b Adjusted ORs were calculated by multivariate logistic regressions which were adjusted for family monthly income and maternal characteristics of age (continuous), education level, parity, hypertension, rheumatoid arthritis, systemic lupus erythematosus, renal disease, coronary heart disease, hyperlipidemia, anemia, and any major mental disorder.
with MVP during pregnancy. Currently, pregnant women with a history of MVP in Taiwan are followed through obstetric ultrasound, usually without prescription of medication. Careful observation and proper management of complications (e.g., cardiac arrhythmias) if there are any, along with timely detection of signs of preterm birth are needed during such pregnancies. During labor, although epidural anesthesia may be safely employed, the use of antibiotic prophylaxis remains controversial (29). In sum, preconception evaluation and counseling, awareness of this common cardiac lesion, intensive cardiovascular examination, careful monitoring during prenatal care, and cooperation between the patient, the obstetrician, the cardiologist, and the supporting medical team are essential steps to optimize both maternal and fetal health. Our study highlights a significant potential risk of preterm delivery of women with MVP, for whom favorable pregnancy outcomes have usually been assumed. Women who are newly diagnosed with MVP during pregnancy may be facing a greater threat. A multidisciplinary team approach to providing obstetric care, with the mission of monitoring and timely management of signs of cardiac complications and preterm birth is imperative. Future studies are needed to replicate the results and identify the mechanisms, which are still indistinct, connecting MVP to preterm delivery.
This study is based in part on data from the National Health Insurance Research Database provided by the Bureau of National Health Insurance, Department of Health and managed by National Health Research Institutes of Taiwan. The interpretation and conclusions contained herein
do not represent those of Bureau of National Health Insurance, Department of Health or National Health Research Institutes.
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