Risk Factors Associated with Pregnancy Induced Hypertension in the Hohoe Municipality of Ghana
- 1. Department of Epidemiology and Biostatistics, School of Public Health, University of Health and Allied Sciences, Ho, Ghana
- 2. Department of Population and Behavioral Sciences, School of Public Health, University of Health and Allied Sciences, Ho, Ghana
- 3. School of Biological Sciences, University of Cape Cast, Cape Coast, Central Region, Ghana
Abstract
Background: Pregnancy-induced hypertension develops as a result of pregnancy and generally regresses after delivery. This study determined the risk factors associated with Pregnancy-induced hypertension among pregnant women attending antenatal care clinic at the Hohoe Municipal hospital.
Methods: An unmatched case-control study involving 108 cases and 108 controls were recruited from the Antenatal care clinic. Face-to-face interviews using a pre-tested semi-structure questionnaire was used to collect information from the pregnant women. Information on blood pressure and other clinical measurements was extracted from the maternal health record book. Chi square test and Logistic regression were used to determine the association and strength of association between risk factors and Pregnancy-induced hypertension. A p-value <0.05 was declared significant.
Results: Advanced maternal age of 35-39 years, consumption of trans fatty food, a family history of hypertension and history of previous pre-term delivery were found to be significantly associated with Pregnancy-induced hypertension (AOR 3.53, p=0.048), (AOR= 4.43, p< 0.001), (AOR= 3.42, p=0.012) and (AOR= 5.14, p=0.017) respectively.
Conclusion: Maternal age, high consumption of trans fatty food, a family history of hypertension and history of previous pre-term delivery were factors found to be associated with of pregnancy-induced hypertension. Health educational programmes on causes of Pregnancy-induced hypertension need to be intensified.
Keywords
Risk Factors, Hohoe Municipality, Ghana, Pregnancy-Induced Hypertension
Citation
Jones L, Takramah W, Axame WK, Owusu R, Parbey PA, Tarkang E, Takase M, Adjuik M, Kweku M (2017) Risk Factors Associated with Pregnancy Induced Hypertension in the Hohoe Municipality of Ghana. J Prev Med Healthc 1(3): 1011
Abbreviations
HDP: Hypertensive Disorders of Pregnancy; BP: Blood Pressure; PIH: Pregnancy Induced Hypertension; HIV: Human Immunodeficiency Virus; WHO: World Health Organization; UNICEF: United Nations International Children’s Emergency Fund; SSA: Sub-Saharan Africa; BMI: Body Mass Index; GHS: Ghana Health Service; GSS: Ghana Statistical Service; MOH: Ministry of Health; IUGR: Intra-Uterine Growth Restriction; SIDS: Sudden Infant Death Syndrome; ANC: Antenatal Clinic; GH: Gestational Hypertension; PE: Preeclampsia; UNESCO: United Nations Educational Scientific and Cultural Organization; LDL: Low-density lipoptrotein; ACOG: American Congress of Obstetricians and Gynaecologists; HMH: Hohoe Municipal Hospital; MoH: Ministry of Health; GHS: Ghana Health Service; ERC: Ethics Review Committee; JHS: Junior High School; SHS: Senior High School; ISSHP: International Society for the Study of Hypertension in Pregnancy
INTRODUCTION
Pregnancy-induced hypertension (PIH) is defined as the elevation of the blood pressure to ≥140/90 mm Hg with or without proteinuria, which emerges after 20 weeks of gestation and normally resolves by 12 weeks postpartum [1,2]. It increases the likelihood of progression into preeclampsia or adverse pregnancy outcome such as premature delivery [3].
Preeclampsia and eclampsia happen to be the commonest complication of pregnancy in Sub-Saharan Africa (SSA) with over 50% pregnant women being affected [4]. According to the World Health Organization (WHO), of all the hypertensive disorders of pregnancy, preeclampsia was also found to have an adverse impact on maternal and neonatal health with no definite treatment except for the termination of pregnancy/ expulsion of the foetus [5]. Of the 99% maternal deaths occurring in developing countries, especially Africa, PIH was found to be a major cause of maternal mortality [5,6]. Preeclampsia affects 2-8% of all pregnancies worldwide causing about one-third of maternal deaths with over 6 million perinatal deaths and 8 million preterm births [7-10].
Despite the recognition of preeclampsia in ancient times, it was not found to be significant until the late 1800s when an association between hypertension, edema, proteinuria, and eclampsia was established [11]. The pathogenesis was not fully understood but was thought to be associated with placental disturbance in the early periods of pregnancy, with subsequent inflammation and progressive damage [5].
Complications arising from PIH could affect both the mother and the baby. Complications affecting the mother include renal failure, liver failure and neurological sequelae [12], while potential complications to the fetus include preterm birth, respiratory distress syndrome, and fetal growth restriction [13].
Although the cause of PIH remains unknown, some risk factors such as nulliparity, a history of preeclampsia, diabetes mellitus, renal disease, obesity, severe anemia, malaria and HIV have been reported to be associated with this complication [14- 20]. Advance in maternal age was also found to be a risk factor of PIH [21,22]. Women between the ages of 13 and 16 were found to be at risk of PIH likewise women age 35 or more [14,23].
A two-stage model which was developed to explain the mechanisms of PIH revealed that abnormal implantation, reduced placental perfusion and subsequent vascular remodeling interacts with maternal constituents (genetic, behavioral, or environmental) leading to the maternal syndrome [24,25]. In Ghana, PIH is identified as one of the commonest cause of pregnancy complications with 7.0% incidence rate of preeclampsia [26]. In the Hohoe Municipality, there is no available data on PIH. This study was set out to determine risk factors associated with PIH among pregnant women attending antenatal care (ANC) at the Hohoe Municipal Hospital (HMH).
MATERIALS AND METHODS
Study area
The study was carried out at the Hohoe Municipal Hospital (HMH) in the Hohoe Municipality which is one of the 25 administrative districts/Municipalities in the Volta Region. The Municipality shares boundaries with the Republic of Togo to the east, Jasikan district to the north, Kpando district to the west, and Afadjato-South district to the south. The municipality has one hundred and two communities with a projected population of 167,687 from the 2010 National Population and Housing Census. The municipality has been divided into seven sub-Municipalities namely; Akpafu/Santokofi, Alavanyo, Agumatsa, Lolobi, Gbi-Rural, Likpe and Hohoe sub-Municipality. There 21 health facilities including a hospital, 14 health centers and 7 CHPS compounds. The HMH has a 178-bed capacity, serving as the referral point for the clinics within and outside the Municipality. Focused ANC services are provided on daily basis at the hospital.
Study population
The study population was pregnant women aged between 17- 45 years attending Antenatal Clinic (ANC) at the Hohoe Municipal hospital (HMH) in February 2017. Pregnant women with hypertension within the gestational age of ≥ 20-42 weeks with or without proteinuria were included as cases and those without hypertension with gestational age ≥ 20 weeks and consented to participate were included as controls. Pregnant women whose gestational age were less than 20 weeks and were seriously ill requiring hospital admission or did not consent to participate were excluded from the study. Also, pregnant women less than 17 years and more than 45 years were also excluded from the study.
Study Design
The study was an unmatched case-control study involving pregnant women with gestation 20 weeks and above. Those with PIH were recruited as cases and those without PIH as controls. Information was collected using face-to-face interviews with a pre-tested semi-structured questionnaire. Information collected included background characteristics, socio-economic and lifestyle of the pregnant women.
Information was specifically collected on the consumption of industrial trans fatty foods (artificial fats) such as biscuits, pies, cakes, doughnut and crackers. Information on clinical measurements such as blood pressure (BP), blood glucose and haemoglobin level was extracted from the maternal health record book.
Sample Size Determination
Sample size was determined by using OpenEpi, Version 3, open source calculator--SSCC with the assumption that, n = sample size for cases, 80% power, for 0.05 significance level and equal number of cases and controls (The Odds ratio of control must be less than or equal to 1, assume OR =0.35 and Pcaseexp = 24.9%, n = 108. Therefore, the minimum number of participants was 216 (108 cases, 108 controls).
Sampling
Participants (cases) were recruited based on blood pressure readings extracted from their maternal health record book for their previous and current visit. These blood pressure readings were recorded at the ANC while the participants were still pregnant. A sampling frame was then obtained from the anternatal care register for all pregnant women who attended clinic the same day and did not have any indication of PIH. Simple random sampling by ballot was then used to select a control for each case from the sampling frame obtained.
Data Collection Procedure Data was collected by midwives who were recruited from the hospital and trained. Face to face interviews using the pre-tested questionnaire was used to collect information on demographic characteristics, family history of hypertension and diabetes, dietary habit and history of pre-term deliveries. Data on Blood pressure, haemoglobin levels and blood glucose were extracted from the maternal health record book.
Definitions
Gestational hypertension as defined by WHO as having systolic blood pressure ≥140 mm Hg and/or diastolic blood pressure ≥90 mm Hg, measured on two occasions at least four hours apart, after 20 weeks of gestation in a previously normotensive woman.
These criteria plus the presence of proteinuria (defined as two or more dipstick readings of ≥2+, one catheter sample reading of ≥1+, or a 24-hour urine collection containing at least 300 mg of protein) were used to identify women with PIH which is in accordance with the criteria of the International Society for the Study of Hypertension in Pregnancy (ISSHP) and American Congress of Obstetricians and Gynaecologists (ACOG).
Maternal educational level was categorized according to the UNESCO International Standard Classification of Educational level into one of five level; No education (0 years), Primary education (1-5 years), Lower secondary education (7-9 years or ‘JHS’ in Ghana), Upper secondary education (10-12 years or ‘SHS’ in Ghana), and Post-secondary/ Tertiary education (more than 12 years).
Trans fatty food as defined by [27] is a type of fat that is created when hydrogen is added to the chemical structure of a fat, typically vegetable oil to prevent it from going bad. This fat increases the low-density lipoprotein (LDL) cholesterol in the blood. Naturally occurring trans fatty foods are cheese, milk, cream, lamb, pork and beef. Industrial trans fatty foods (artificial fats) are baked foods like biscuits, pies, cakes, doughnut and crackers.
Data Analysis
Data collected were checked for consistency, coded and entered using Epi Data 3.1 software. Data were cleaned and transferred to STATA version 14.1 for analysis. The frequency distributions in the maternal socio-demographic, medical and obstetric histories were compared between cases and controls. Means of continuous variables (age of women) were determined using t-test. Chi-square test to determine association between dependent (PIH) and independent variables (level of education, marital status, smoking, alcohol intake etc.) between cases and controls. Univariate and multivariate logistic regression analysis were used to determine the strength of the association between dependent and independent variables. The effect was considered significant if the p-value was less than 0.05.
Ethical Issues
Ethical approval was obtained from the Ministry of Health/ Ghana Health Service (MoH/GHS) Ethics Review Committee (ERC) with approval number (GHS-ERC: 14/03/2017). Before commencement of the study, permission was sought from the HMH. A written informed consent was obtained from each recruited participant. It was explained to them that the study would not cause any physical pain or harm to them. They were also informed that, their information would be used for the purposes of research only and that, published findings would not reveal their identity. Participants were also informed that, the study was voluntary, and they were at liberty to withdraw from the study and were assured that, should they decide not to participate, it would not affect their future access to hospital services in any way. In this study, all eligible participants who were approached were willing and consented to participate.
RESULTS
Demographic characteristics of respondents
A total of 216 pregnant women (respondents) were recruited for the study, with 108 cases and 108 controls. The overall mean age was 28.5±11.9 years. The mean age of the cases and controls were 29.72±6.5 years and 27.22±5.6 years respectively.
With respect to education, 14.4% had no formal education, of which 16.7% were cases and 13 12.0% were controls. A little less than half (46.3%) attained Junior High School (JHS) level of education with 42.6% cases and 50.0% controls. Respondents who had attained Senior High School (SHS) level education were 12.5%, comprising 14.8% cases and 10.2% controls. Respondents who attained tertiary level education were 9.7%, out of which 7.4% were cases with the remaining 12.0% being controls.
Out of the 216 respondents, 29.6% were traders of which 29.6% were cases and 29.6% were controls. Farmers formed (23.2%of the total number of respondents, of which 29.6% were cases and 16.7% controls. Respondents who were artisans were 14.8%, out of which 13.0% were cases and 16.7% controls. Those who were civil servants were 13.0% for both cases and controls. A substantial proportion of the respondents 19.4% were, however, unemployed with 14.8% cases and 24.0% controls.
A significant proportion of the respondents 64.4% were married, of which 27.8% were cases and 56.5% were controls (Table 1).
Table 1: Demographic characteristics of the respondents
Characteristic | Cases [N=108] n (%) |
Controls [N=108] n (%) |
Total [N=216] n (%) |
Mean age (SD) (years) |
29.7 (6.5) | 27.2 (5.6) | 28.5(11.9) |
Age (years) | |||
Below 25 | 28 (25.9) | 39 (36.1) | 67 (31.0) |
25-29 | 26 (24.1) | 31 (28.7) | 57 (26.4) |
30-34 | 23 (21.3) | 25 (23.2) | 48 (22.2) |
35-39 | 25 (23.2) | 10 (9.3) | 35 (16.2) |
40-45 | 6 (5.6) | 3 (2.8) | 9 (4.2) |
Education | |||
Never | 18(16.7) | 13 (12.0) | 31 (14.4) |
Primary | 20 (18.5) | 17 (15.7) | 37 (17.1) |
JHS | 46 (42.6) | 54 (50.0) | 100 (46.3) |
SHS | 16 (14.8) | 11 (10.2) | 27 (12.5) |
Tertiary | 8 (7.4) | 13 (12.0) | 21 (9.7) |
Occupation | |||
Unemployed | 16(14.8) | 26 (24.1) | 42 (19.4) |
Farming | 32 (29.6) | 18 (16.7) | 50 (23.2) |
Trader | 32 (29.6) | 32 (29.6) | 64 (29.6) |
Artisan | 14 (13.0) | 18(16.7) | 32(14.8) |
Civil Servant | 14 (13.0) | 14 (13.0) | 28 (13.0) |
Marital Status | |||
Single | 30 (27.8) | 47 (43.5) | 75 (35.7) |
Married | 78 (72.2) | 47 (43.5) | 139 (64.4) |
Association between demographic factors and pregnancy induced hypertension
Table 2 shows that, there was a significant association between maternal age, marital status and PIH (χ2 =9.76, p=0.045) and (χ2 =8.89, p=0.012) respectively. It was found that a family history of hypertension and a family history of diabetes independently had a significant association with PIH (χ2 =25.99, p<0.001) and (χ2 =16.47, p<0.001) respectively. Association between a family history of PIH and PIH was also significant (χ2 =5.06, p=0.024). Those who reported that fat was a major part of their diets were significantly associated with PIH (χ2 =25.97, p<0.001). History of previous preterm delivery was significantly associated with PIH (χ2 = 6.41, p= 0.041).
Table 2: Association between risk factors and odds of PIH
Characteristic | Cases N=[108] n (%) | Controls N=[108] n (%) |
Total [N=216] n (%) | Chi-square ( χ2 ) (p-value) |
COR (95% CI) p-value | AOR (95% CI) p-value |
Age(years) | 9.76 (0.045) | |||||
Below 25 | 28 (25.93) | 39 (36.11) | 67 (31.02) | |||
25-29 | 26 (24.07) | 31 (28.70) | 57 (26.39) | 1.17 (0.57, 2.38) 0.669 | 1.04(0.43, 2.51) 0.938 | |
30-34 | 23 (21.30) | 25 (23.15) | 48 (22.22) | 1.28 (0.61, 2.70) 0.515 | 1.36(0.51, 3.67) 0.537 | |
35-39 | 25 (23.15) | 10 (9.26) | 35 (16.20) | 3.48 (1.45, 8.39) 0.005 | 3.24(0.96, 10.94) 0.058 | |
40-45 | 6 (5.56) | 3 (2.78) | 9 (4.17) | 2.79 (0.64,12.10) 0.172 | 2.10(0.35, 12.75) 0.416 | |
Parity | 2.94 (0.401) | |||||
No child | 27 (25.00) | 33(30.56) | 60(27.78) | |||
1-3 | 68(62.96) | 67(62.04) | 135(62.50) | 1.24 (0.67, 2.28) 0.489 | ||
4-6 | 12 (11.11) | 6(5.56) | 18(8.33) | 2.44 (0.8, 7.37) 0.113 | ||
7+ | 1(0.93) | 2 (1.85) | 3(1.39) | 0.61 (0.05, 7.10) 0.694 | ||
Education | 3.81 (0.433) | |||||
Never | 18(16.67) | 13 (12.04) | 31 (14.35) | |||
Primary | 20 (18.52) | 17 (15.74) | 37 (17.13) | 0.85 (0.32, 2.23) 0.740 | ||
JHS | 46 (42.59) | 54 (50.00) | 100 (46.30) | 0.62 (0.27, 1.39) 0.242 | ||
SHS | 16 (14.81) | 11 (10.19) | 27 (12.50) | 1.05 (0.37, 3.00) 0.927 | ||
Tertiary | 8 (7.41) | 13 (12.04) | 21 (9.72) | 0.19 (0.14, 1.38) 0.161 | ||
Occupation | 6.80 (0.147) | |||||
Unemployed | 16(14.81) | 26 (24.07) | 42 (19.44) | |||
Farming | 32 (29.63) | 18 (16.67) | 50 (23.15) | 2.89 (1.24, 6.75) 0.014 | 1.03(0.31, 3.42) 0.964 | |
Trading | 32 (29.63) | 32 (29.63) | 64 (29.63) | 1.63 (0.74, 3.59) 0.230 | 0.87(0.31, 2.45) 0.801 | |
Artisanship | 14(12.96) | 18(16.67) | 32(14.81) | 1.26 (0.50, 3.22) 0.624 | 0.67(0.20, 2.22) 0.513 | |
Civil Servant | 14 (12.96) | 14 (12.96) | 28 (12.96) | 1.63 (0.62, 4.28) 0.325 | 1.18(0.33, 4.31) 0.797 | |
Marital Status | 8.89 (0.012) | |||||
Single | 30 (27.78) | 47 (43.52) | 75 (35.65) | |||
Married | 78 (72.22) | 61 (56.48) | 139 (64.35) | 2.00 (1.14, 3.53) 0.016 | 1.57(0.73, 3.40) 0.244 | |
Nutrition and Lifestyle | ||||||
Smoking | 1.02 (0.313) | |||||
No | 105(97.22) | 107(99.07) | 212(98.15) | |||
Yes | 3(2.78) | 1(0.93) | 4(1.85) | 3.06 (0.31, 29.86) 0.337 | ||
Alcohol consumption | 0.22 (0.636) | |||||
No | 103(97.17) | 106 (98.15) | 209(97.66) | |||
Yes | 3(2.83) | 2(1.85) | 5(2.34) | 2.57 (0.49, 13.56) 0.265 | ||
Fatty foods | 25.97(<0.001) | |||||
NO | 53 (52.9) | 83 (76.85) | 136 (62.96) | |||
Yes | 55 (47.1) | 25 (23.15) | 80 (37.04) | 3.45 (1.92, 6.18)<0.001 | 4.42 (2.25, 8.66) <0.001 | |
Family history of diabetes | 16.47 (<0.001) | |||||
No | 82 (77.82) | 101 (93.52) | 183 (84.72) | |||
Yes | 26 (22.18) | 7 (6.48) | 33 (15.28) | 2.07 (0.68, 6.33) 0.202 | ||
Family history of hypertension | 25.99 (<0.001) | |||||
No | 75 (72.75) | 99 (91.67) | 174 (80.56) | |||
Yes | 33 (27.25) | 9 (8.33) | 42 (19.44) | 4.84 (2.18, 10.73) 0.001 | 4.41 (1.83, 10.58) 0.001 | |
Maternal Health | ||||||
Cardiac Disease | 1.04 (0.307) | |||||
No | 102 (94.44) | 105 (97.22) | 207 (95.83) | |||
Yes | 6 (5.56) | 3 (2.78) | 9 (4.17) | 1.43 (0.50, 8.45) 0.316 | ||
Anemia | 0.74 (0.390) | |||||
No | 34 (31.48) | 40 (37.04) | 74 (34.26) | |||
Yes | 74 (68.52) | 68 (62.96) | 142 (65.74) | 1.28 (0.73, 2.25) 0.390 | ||
Diabetes | 2.04 (0.153) | |||||
No | 99(91.67) | 104 (96.30) | 203 (93.98) | |||
Yes | 9 (8.33) | 4 (3.70) | 13 (6.02) | 1.95 (0.35, 10.79) 0.443 | ||
History of Adverse Birth Outcome |
||||||
Stillbirth | 3.92 (0.141) | |||||
No | 89 (84.0) | 95 (87.96) | 184 (85.19) | |||
Yes | 19 (16.0) | 13 (12.04) | 32 (14.81) | 1.56 (0.73, 3.34) 0.253 | ||
Preterm Delivery | 6.41 (0.041) | |||||
No | 92 (85.07) | 103 (95.37) | 195 (90.28) | |||
Yes | 16 (14.94) | 5 (4.63) | 21 (9.72) | 3.58 (1.26, 10.16) 0.016 | 4.66 (1.37, 15.86) 0.014 |
Risk factors of pregnancy induced hypertension
Pregnant women who consumed high amounts of trans fatty food were 4.42 times more likely to develop PIH as compared to those who did not and the effect was statistically significant (AOR = 4.42; 95% CI = 2.25-8.66; p<0.001).
Pregnant women with a family history of hypertension were 4.41 times more likely to develop PIH and the effect was statistically significant (AOR = 4.41; 95% CI = 1.83-10.58; p= 0.001). Pregnant women with a history of previous preterm delivery were 4.66 times more likely to develop PIH and the effect was also statistically significant (AOR = 4.66; 95% CI = 1.37- 15.86; p=0.014).
DISCUSSION
Pregnancy-induced hypertension (PIH) complicates many pregnancies, especially in the developing world. The cause of this condition is not clear. Several studies have therefore sought to evaluate the risk factors of PIH in different parts of the world. Some risk factors have been commonly reported in the developed world while others are common to the developing countries. Since the cause of PIH is not clear, primary prevention largely depends on the identification of its risk factors. This study, therefore, sought to identify the risk factors of PIH in the Hohoe Municipality.
In this study, women with a family history of hypertension were at a significantly increased risk of developing PIH. This corroborates with other epidemiological studies in which a family history of chronic hypertension was reported as an independent risk factor for PIH [19]. Additionally, history of previous preterm delivery was found to be a significant risk factor in this study. Several studies have maintained that PIH, intra uterine growth restriction (IUGR), and preterm delivery are overlapping and closely related clinical phenomena [28,29].
Also, this could be explained that a history of preterm delivery could have been caused as a result of an undiagnosed PIH. Thus, mothers with previous history of preterm delivery are more likely to develop PIH as a result of the previous condition. Dietary patterns characterized by high consumption of trans fatty foods was also found to be a risk factor in this study. Reports by [27] have shown that, the trans fatty acids increases the low-density lipoprotein (LDL) cholesterol in the blood which pre-disposes them to cardiovascular diseases such as hypertension. While this relationship awaits further clarifications, pregnant women are advised to adhere to recommended dietary patterns.
LIMITATIONS OF THE STUDY
One of the limitations of this study was that information on the consumption of trans fatty foods which was only obtained from the women and was not observed and measured by the researcher and this could affect the outcome. In addition, data on gestational age of onset of PIH as well as PIH during previous pregnancies was not collected.
CONCLUSION
In this study, maternal age group 35-39 years, a family history of hypertension, history of previous pre-term delivery and high consumption of trans fatty foods predisposed women to PIH. Early detection and timely management of PIH and its risk factors at antenatal care would improve maternal and perinatal health. Screening of all pregnant women at ANC to identify potential cases of PIH and initiating timely management would be required. Healthcare providers at ANC should intensify counselling and continuous education on the choice of food during pregnancy.
RECOMMENDATIONS
We recommend that all pregnant women should be screened in order to identify cases of PIH and initiate timely management. Healthcare providers at ANC should intensify counselling on the choice of food. Continuous education on how to manage PIH among cases should be provided. Also, there is the need for further studies to determine types of trans fatty foods consumed by pregnant women in the Hohoe Municipality
DECLARATIONS
Ethics and consent statement
Ethical clearance was obtained from the Ghana Health Service Ethical Review Committee (GHS-ERC: 14/03/2017) with the approval identity (GHS-ERC). Permission was also sought from the Municipal Health Directorate and the Municipal Assembly. Moreover, the participants themselves consented to be part of the study.
Availability of data and material
Available upon request
Competing interests The authors declare that they have no competing interests. Funding None
ACKNOWLEDGEMENT
We are grateful to the staff of Health and Allied Sciences. We are also grateful to Dr. Pius Mensah the Medical Superintendent and the staff of the Municipal Hospital. We would like to thank the interviewers and the pregnant women who participated in the study.
DISCLOSURE
The authors declare no conflicts of interest.