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Two-Year Follow-Up Study on Neurodevelopmental Outcomes After Term Intrapartum Asphyxia Using Age and Stages Questionnaire
Zarrin Keihani-Doust, Maryam Saeedi, Tahere Esmaeilni, Massoud Habibi and Seyed Saeed Hashemi Nazari J Child Neurol published online 30 October 2012 DOI: 10.1177/0883073812461564 The online version of this article can be found at: http://jcn.sagepub.com/content/early/2012/10/18/0883073812461564

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Original Article
Journal of Child Neurology 00(0) 1-7 The Author(s) 2012 Reprints and permission: sagepub.com/journalsPermissions.nav DOI: 10.1177/0883073812461564 http://jcn.sagepub.com

Two-Year Follow-Up Study on Neurodevelopmental Outcomes After Term Intrapartum Asphyxia Using Age and Stages Questionnaire
Zarrin Keihani-Doust, MD1, Maryam Saeedi, MD, MPH1, Tahere Esmaeilni, MD1, Massoud Habibi, MD2, and Seyed Saeed Hashemi Nazari, MD, MPH, PhD3

Abstract Birth asphyxia is one of the multiple causes of neonatal encephalopathy. The objective of this study was to evaluate neurodevelopmental outcomes of newborn term infants with definitive asphyxia. Thirty infants met study criteria for asphyxia. The 5-year incidence of asphyxia was estimated to be 5.5 in 1000. According to the Age and Stage Questionnaire, 10.5% of 6-month-old infants, 14.3% of 12- and 18-month-old infants, and 5.3% of 24-month-old infants had neurodevelopmental delay in gross motor function in the absence of cerebral palsy. In 7.3% of 18-month-old infants, neurodevelopmental delay in problem-solving ability was observed. Higher values of Apgar score and bicarbonate levels were associated with higher Age and Stage Questionnaire total score. Delivery type, maternal age, gravidity of mother, and existence of mother disease during pregnancy were also associated with lower Age and Stage Questionnaire total score in different stages of life. Keywords neurodevelopmental delay, Age and Stage Questionnaire, Apgar, asphyxia, term infant, encephalopathy
Received June 18, 2012. Accepted for publication August 27, 2012.

Encephalopathy is the result of brain malfunction that can be classified as acute versus chronic or stable versus progressive. About 80% of full-term infants with encephalopathy have acute injuries, 3% have nonhypoxic ischemia and less than 1% have prenatal injuries. Different disorders in mother can cause fetal hypoxia, including low maternal blood pressure, inadequate oxygenation of maternal blood, inadequate relaxation of uterus caused by excessive administration of oxytocin, premature separation of placenta, placental insufficiency, and compression of cord.1 Birth asphyxia is one of the multiple causes of neonatal encephalopathy.2 Although in some studies these 2 terms are considered the same, in the literature on neonatal encephalopathy, once infants with major malformations, drugs, metabolic causes, and infections are excluded, the remaining cases are assumed to be asphyxia related.3 Hypoxic-ischemic encephalopathy is classified according to assessment of feeding, alertness, tone, body posture, tendon reflexes, myoclonus, Moro reflex, cornea situation, duration of signs, and electroencephalogram (EEG) abnormalities into 3 stages. The prognosis of stage 1 is good. Stage 2 has varied prognosis and stage 3 or persistence of stage 2 for more than 7 days or failure of EEG to revert to normal is associated with neurodevelopmental impairment or death.

Expected outcomes for a term newborn with intrapartum asphyxia are normality, death, or a neurodevelopmental disability.4 Hypoxic-ischemic encephalopathy usually occurs in 1 to 2 per 1000 newborn infants.5 Almost, 20% of infants with hypoxic-ischemic encephalopathy die during infancy and 25% suffer from permanent neurodevelopmental impairment. To our knowledge, few studies have been done on the neurodevelopmental function of term infant with asphyxia in developing countries and in our country this study is the first
1

Department of Pediatrics, Imam Hospital, Tehran University of Medical Sciences, Tehran, Iran 2 Iranian center for Breast Cancer, Academic Center for Education, Culture and Research, Tehran, Iran 3 Department of Epidemiology and Biostatistics, Tehran University of Medical Sciences, School of public Health, Tehran, Iran Corresponding Author: Maryam Saeedi, MD, MPH, Department of Pediatrics, Imam Hospital, Tehran University of Medical Sciences, Gharib Street, Keshavarz Boulevard, Tehran, Iran Email: m_saidi52@yahoo.com

2 in this field. The objective of our study was to evaluate neurodevelopmental outcomes of a cohort of newborn term infants with defined asphyxia. These outcomes were measured by Age and Stages Questionnaire.

Journal of Child Neurology 00(0)


intervals, in children from 25 to 36 months at 3-month intervals and in children from 37 to 60 months at 6-month intervals. This screening tool contains 5 questionnaires that assess 5 neurodevelopmental areas, including communication, gross motor function, fine motor function, problem-solving ability, and personal-social area. Each questionnaire contains 30 questions, grouped by developmental area, about the childs everyday activities. These questionnaires are designed to be completed by anyone who spends time with the child on a regular basis.11 In this study, we used this tool for 6-, 12-, 18-, and 24-month-old infants. The cut-off scores of the questionnaire are presented in the appendix.

Methods Study Population


All deliveries were scanned in a university-based pediatric hospital between 2007 and 2011 in the capital city of Iran, Tehran. Infants who met our criteria for definition of intrapartum hypoxia and were born at term (ie, greater than 36 weeks gestation) were enrolled in a prospective cohort study with a 24-month follow-up. Infants who suffered from metabolic diseases or congenital abnormalities were excluded from this study.

Predictive Variables
We assessed the effect of a number of maternal and neonatal variables on the Age and Stage Questionnaire score. The maternal variables included age at pregnancy, gestational age, delivery type (cesarean section versus normal vaginal delivery), gravidity, and existence of any chronic diseases during pregnancy (eg, infectious diseases with systemic manifestations, diabetes mellitus, chronic hypertension, eclampsia and pre-eclampsia, chronic renal diseases, hypothyroidism, hemoglobinopathies, asthma, platelet disorders, immunologic disorders, and other chronic and systemic disorders). The neonatal variables included birth weight, meconium stained liquor, Apgar score during the fifth minute, pH level of blood sample, base deficit, bicarbonate level, positive pressure ventilation, chest compression, intubation and occurrence of seizure.

Asphyxia Definition
There is not any global agreement on definition of asphyxia. Our review literature showed that 3 sets of criteria are used mostly for diagnosis of asphyxia. According to the American Academy of Pediatrics and the American College of Obstetrics and Gynecology in 1996,6 intrapartum hypoxia was defined by profound acidosis (cord pH <7.0), low Apgar score (<3) at 5 minutes or beyond, neonatal encephalopathy, and multiorgan system failure.7 According to the International Cerebral Palsy Task Force in 1999, intrapartum hypoxia is defined by metabolic acidosis (infant blood pH <7 in the first blood sample and a base deficit >12 mmol/L, and moderate to severe encephalopathy. According to the American College of Obstetrics and Gynecology, in 2003 the essential criteria for assigning the term of intrapartum hypoxia is as follows: metabolic acidosis (pH <7 and a base deficit >12 mmol/L), and moderate to severe encephalopathy.8 There is no consensus on pH levels of less than 7 for the definition of fetal hypoxia. In some studies, ischemic injuries have been observed with pH levels of more than 7,9 but the risk of neonatal morbidity and mortality in neonates with an umbilical arterial cord pH of less than 7 is higher.10 Other parameters that are used to diagnose intrapartum hypoxia include the presence of meconium stained liquor, fetal heart rate abnormalities, the need for immediate neonatal resuscitation, organ failure, abnormal EEG, and abnormal imaging studies, although none of them have acceptable sensitivity or specificity for diagnosis.4 In this study, considering all the above-mentioned definitions, 3 major and 5 minor criteria for defining hypoxia have been used. Cord blood pH of less than 7.2, infant blood pH of less than 7.2, and a base deficit more than 12 mmol/L in the blood sample from the first hour were the major criteria. Low Apgar scores (<5) at 5 minutes or beyond, the presence of meconium stained liquor, the need for immediate neonatal resuscitation, abnormal EEG, and acute changes in imaging studies were the minor criteria. The cases that had 1 major criterion and at least 2 minor criteria were diagnosed as intrapartum hypoxia.

Statistical Analysis
The questionnaires were scored by converting each answer to a numerical equivalent and comparing the totals for each area (eg, fine motor, personal-social) with the empirically derived cutoff points for that area. The cut-off scores of the questionnaire are presented in the appendix. The responses yes, sometimes, and not yet were converted to points 10, 5, and 0, respectively. The statistical analysis was performed with Stata software, version 10 (Stata Corporation, College Station, TX). The Student t test was used to compare means of subcategories of patients. Because the numbers of patients in subcategories were not large, we also compared means with the Kruskal-Wallis test for numerical variables. Categorical data were analyzed using chi-square and Fisher exact test where applicable. Univariate comparisons of maternal and neonatal variables with the Age and Stage Questionnaire scores were made using linear regression. A p value less than .05 was considered to be significant.

Results
Between 2007 and 2011, a total of 5455 term infants were born in the study location. From these infants, 30 met study criteria for asphyxia and were included in our study. The number of infants with each of the inclusion criteria is presented in Table 1. The 5-year incidence of asphyxia was estimated to be 5.5 in the 1000 term neonates. Of these children, 73.3% were male and 26.7% were female, 60% were born through cesarean section and 40% through normal vaginal delivery. The majority of these children (57%) were the first child of the family. Maternal disorder during pregnancy was found in 8 cases (diabetes mellitus, chronic hypertension, eclampsia, hypothyroidism, thalassemia, asthma, and platelets disorder). The mean gestational age was

Outcome Measurement
The Age and Stage Questionnaire was applied for measuring neurodevelopmental outcomes following asphyxia. This screening tool assesses cognitive, communicative, and motor development and helps identify the need for further social and emotional behavior assessment in children at a number of age intervals. Assessment in children older than 4 months and younger than 24 months is performed at 2-month

Keihani-Doust et al
Table 1. Numbers of Infants With Each of the Inclusion Criteria Range Inclusion criteria n (%) Min Max Average 7.1 12.2 6.1

3 was associated positively with the Apgar score. The fine motor score was associated negatively with delivery type (cesarean section vs normal vaginal delivery), gravidity of mother, and mother disease during pregnancy. The problem-solving ability score was associated negatively with the base deficit and positively with the bicarbonate level. The personal-social score was associated positively with the Apgar score and the bicarbonate level and negatively with the base deficit. The results of fitted models are presented in Table 3.

Cord blood pH <7.2 18 (60) 6.8 7.3 Base deficit >12 13 (43.3) 21 4.7 5-minute Apgar scores <5 2 (6.7) 2 9 Presence ofmeconium-stained liquor 4 (13.3) Immediate neonatal resuscitation 25 (83.3) Abnormal EEG 3 (10) Abnormal brain imaging 8 (26.6)
Abbreviation: EEG, electroencephalogram.

Age and Stage Questionnaire Scores in 12-Month-Old Infants


All the infants received higher than the cut-off score in communication, fine motor function, problem-solving ability, and personal-social area. In 14.3% of infants, gross motor function was lower than the cut-off score. Again, separate univariate models were fitted to define the maternal and neonatal variables that affect the Age and Stage Questionnaire score. From the maternal and neonatal variables, the mean bicarbonate level of the blood samples was associated positively with the total Age and Stage Questionnaire score and the base deficit was negatively associated. The results of fitted models are presented in Table 2. The communication score was associated positively with positive-pressure ventilation. The gross and fine motor scores were associated negatively with base deficit and positively with the bicarbonate level. The problem-solving ability score and the personal-social score were associated negatively with birth weight. The results of fitted models are presented in Table 3.

38.7 weeks; 26.7% had 37 weeks, 23.3% had 38 weeks, 16.7% had 39 weeks, 20% had 40 weeks, and 13.3% had more than 40 weeks. Twenty-five infants (83.3%) received positive-pressure ventilation at the time of delivery, 20% received cardiac resuscitation, and for 20% intratracheal intubation was performed. From these infants, 23.3% had seizures within 3 days following the delivery. Imaging studies were performed on the neonate who had clinical signs of hypoxia. Brain ultrasonography was performed on 24 infants and brain computed tomography was performed on 7 infants. Acute asphyxia changes including intraventricular hemorrhage, periventricular leukomalacia, choroid plexus cyst and ventriculomegaly were observed in 5 ultrasonographic and 3 computed tomographic scans. Of 30 infants with asphyxia, 3 (10%) died (2 on the first day and 1 on the 19th day of life). There was a statistically significant association between seizure (P .009), intubation (P .005), and abnormal finding in brain ultrasonography (P .022) and death outcome. We could not find any significant differences in the pH level, base deficit, and the Apgar score of infants who died in comparison to other infants.

Age and Stage Questionnaire Scores in 6-Month-Old Infants


All the infants received higher than the cut-off score in communication, fine motor function, problem-solving ability, and personal-social area. In 10.5% of infants, gross motor function was lower than the cut-off score. To define the predictors of neurodevelopmental outcomes, the association of the total score of the Age and Stage Questionnaire and the score in each of the 5 neurodevelopmental areas and maternal and neonatal variables were evaluated in separate univariate regression models. From maternal and neonatal variables, Apgar score and bicarbonate levels in blood were associated positively with the total Age and Stage Questionnaire Score and the base deficit was associated negatively with the total Age and Stage Questionnaire score. The results of fitted models are presented in Table 2. Age and Stage Questionnaire scores of each of the 5 neurodevelopment areas were also regressed on maternal and neonatal variables. The communication score was not associated with any of the defined maternal and neonatal variables. The gross motor score

Age and Stage Questionnaire Scores in 18-Month-Old Infants


In this age, only the gross motor function and problem-solving abilities were abnormal in 14.3% and 7.1% of infants respectively. Univariate analysis of the neonatal and maternal factors showed a positive effect for Apgar score on the Age and Stage Questionnaire score. The maternal age and the mothers disease during pregnancy demonstrated a negative effect. For a 5-year increment in mothers age, the Age and Stage Questionnaire score decreased by 4.25 points. The infants of mothers who had a disease during pregnancy, had, on average, an Age and Stage Questionnaire Score that was 14 points less than other infants. The results of fitted models are presented in Table 2. The communication score was associated negatively with the existence of a disease inside the mother during pregnancy. The gross motor score was associated positively with bicarbonate levels. The fine motor score was not associated with any of the defined maternal and neonatal variables. The problem-solving ability score was associated negatively with base deficit and positively with bicarbonate levels. The personal-social score was not associated with any of the defined maternal and neonatal variables. The results of fitted models are presented in Table 3.

Journal of Child Neurology 00(0)

Table 2. Regression of Age and Stage Questionnaire Total Scores on Maternal and Neonatal Factors in 6-, 12-, 18-, and 24-Month-Old Infants 6th month Coeff. (95% CI) Sex Maternal age Gestational age Birth weight Delivery type Gravidity Mother disease during pregnancy Meconium-stained liquor Apgar score in fifth minute pH Base deficit Bicarbonate level Positive pressure ventilation Chest compression Intubation Seizure
*P < .05, **P < .01, ***P < .001.

12th month Coeff. (95% CI) 3.7 0.5 2.2 4.5 3.7 0.2 5.0 0.8 2.0 29.8 1.0 1.2 0.7 2.7 6.7 3.1 (6.3, 13.6) (1.3, 0.3) (-1.0, 5.4) (10.8, 1.9) (11.9, 4.4) (10.4, 10.1) (16.6, 6.6) (17.1, 15.4) (0.5, 4.4) (12.3, 71.9) (0.2, 1.9)* (0.3, 2.1)* (10.9, 9.5) (14.5, 9.2) (9.0, 22.4) (13.2, 6.9)

18th month Coeff. (95% CI) 4.2 (6.7, 15.0) 0.9 (1.6, 0.1)* 1.8 (1.9, 5.4) 2.0 (9.4, 5.5) 6.0 (14.4, 2.5) 3.5 (14.4, 7.4) 14.1 (23.7, 4.5)** 1.0 (16.8, 18.8) 2.8 (0.4, 5.2)* 15.9 (33.3, 65.2) 0.7 (0.4, 1.8) 0.8 (0.4, 2.0) 2.2 (8.9, 13.3) 3.6 (16.5, 9.3) 5.3 (12.1, 22.8) 5.6 (16.2, 5.0)

24th month Coeff. (95% CI) 0.7 (5.4, 4.1) 0.0 (0.4, 0.4) 0.2 (1.3, 1.6) 0.5 (2.3, 3.3) 0.3 (4.1, 4.6) 0.2 (2.6, 3.0) 8.1 (16.5, 0.3) 1.6 (7.3, 4.1) 0.4 (2.7, 1.8) 11.3 (37.4, 14.8) 0.6 (0.0, 1.2)* 0.6 (0.0, 1.2)* 1.2 (4.5, 6.9) 0.3 (9.0, 9.7) 0.3 (9.0, 9.7) 0.0 (5.8, 5.7)

1.6 (5.7, 8.8) 0.3 (0.9, 0.2) 2.0 (0.1, 4.1) 1.2 (6.3, 4.0) 4.1 (9.9, 1.7) 0.4 (5.4, 4.5) 4.1 (10.5, 2.4) 1.7 (8.0, 11.3) 1.9 (0.2, 3.7)* 16.5 (9.9, 43.0) 0.7 (0.1, 1.3)* 0.7 (0.2, 1.3)* 2.4 (9.1, 4.2) 4.8 (12.5, 3.0) 3.2 (4.8, 11.2) 2.0 (10.1, 6.1)

Age and Stage Questionnaire Scores in 24-Month-Old Infants


At this stage, just the gross motor function was under the cut-off limit in 5.3% of infants and all other neurodevelopmental areas were normal. Univariate analysis showed a positive association between Age and Stage Questionnaire Score and bicarbonate levels and a negative weak association between base deficit and the Age and Stage Questionnaire Score. The results of fitted models are presented in Table 2. The communication score was associated negatively with the mother disease during pregnancy and positively with positive pressure ventilation. The gross motor score was associated positively with the Apgar score and negatively with maternal age and maternal disease. The fine motor score was not associated with any of the defined maternal and neonatal variables. The problem-solving ability score was associated negatively with the base deficit and the mothers disease and positively with the Apgar score and seizure occurrence in infants. The personalsocial score was associated negatively with the childs birth weight. The results of fitted models are presented in Table 3.

Discussion
Intrapartum asphyxia is only one of the many possible causes of neonatal encephalopathy.12 Approximately 15% to 20% of infants with neonatal encephalopathy will die during the newborn period, and 25% of the survivors will sustain permanent clinical deficits.5 Only 10% of infants with evidence of hypoxic ischemic encephalopathy develop cerebral palsy.13 In our study, 3 of 30 infants with asphyxia (10%) died. The lack of an objective marker of term intrapartum asphyxia has clouded efforts to clinically diagnose intrapartum asphyxia and to understand its potential range of adverse outcomes.

Some studies have shown that in the absence of cerebral palsy, a neurodevelopmental disability is a relatively common consequence of term intrapartum asphyxia, which occurs in approximately 41.5% of patients.12 Some other studies have documented much lower prevalence for a variety of adverse neurologic outcomes, including motor, cognitive, memory, language, learning, and behavioral deficits and limitations that may reach the threshold for the diagnosis of a specific neurodevelopmental disability (including global developmental delay, mental retardation or intellectual disability, attention deficit hyperactivity disorder, learning disabilities, developmental language impairment, autistic spectrum disorders, epilepsy, and secondary microcephaly) in absence of cerebral palsy in term intrapartum asphyxia.4,5 In the current study, 10.5% of 6-month-old infants, 14.3% of 12- and 18-month-old infants and 5.3% of 24-month-old infants had neurodevelopmental delay in gross motor function in the absence of cerebral palsy. In 7.3% of 18-month-old infants, neurodevelopmental delay in problem solving ability was observed. These findings are in accordance with other studies in this field.5,12 Prior studies have shown that clinical and biochemical variables, such as umbilical artery blood gases or Apgar scores, are of limited value in predicting neurodevelopmental outcomes.5 In our study, a higher value of Apgar score was a predictor of higher Age and Stage Questionnaire total score and also better gross motor and personal-social function and problem-solving ability. Higher level of bicarbonate was also a predictor of higher total Age and Stage Questionnaire score and better gross and fine motor function, problem-solving ability, and personal-social function. Base deficit was associated negatively with Age and Stage Questionnaire total score and also gross motor, personalsocial function and problem solving ability.

Table 3. Regression of Age and Stage Questionnaire Score in Each of 5 Neurodevelopmental Areas on Maternal and Neonatal Factors at 6-, 12-, 18-, and 24-Month-Old Infants 12th month Variable Positive pressure ventilation 3 9.2(2.1, 16.4)* Coeff. (95% CI) Variable Coeff. (95% CI) Variable 18th month 24th month Coeff. (95% CI) 49.4 (54.6, 44.3)*** Positive pressure ventilation3 5.3 (1.4, 9.3)* Motherage 1.7 (3.1, 0.3)* Bicarbonate level Mother disease 21.3 (42.5, 0.002)* Apgar score 6.6 (2.6, 10.5)** 16.0 (2.5, 29.5)*

Neurodevelopmental areas Coeff. (95% CI)

6th month

Variable

Communication

Mother disease 22.9 (38.7, 7.2)** Mother disease

Gross motor

Apgar score

1.0 (0.2, 1.9)*

Fine motor

Problem solving

Apgar score 7.3 (0.9, 13.7)* Base Deficit 2.8 (0.2, 5.4)* Bicarbonate level 3.1 (0.3, 5.9)* Delivery 7.7 (14.1, 1.4)* Base Deficit 1.4 (0.5, 2.3)** Gravidity 6.4 (11.5, 1.3)* Bicarbonate level 1.2 (0.0, 2.4)* Mother disease 7.7 (14.9, 0.5)* Base Deficit 0.9 (0.1, 1.7)* Birth weight 5.3 (8.8, 1.8)** Bicarbonate level 1.0 (0.3, 1.8)**

Base Deficit Bicarbonate level

1.4 (0.5, 2.2)** 1.1 (0.2, 2.1)*

Personal-social

Apgar score 3.2 (1.0, 5.4)** Birth weight Base Deficit 1.1 (0.3, 1.8)* Bicarbonate level 1.2 (0.5, 1.9)**

Base Deficit Mother disease Apgar score Seizure 5.2 (9.0, 1.4)* Birth weight

1.6 (0.2, 2.9)* 17.1 (32.1, 2.1)* 4.6 (1.5, 7.6)** 14.4 (27.3, 1.5)* 4.0 (7.9, 0.1)*

*P < .05, **P < .01, ***P < .001.

6 Neonatal encephalopathy is a clinical syndrome of impaired neurologic function of heterogeneous cause. Although birth asphyxia may be an important cause of neonatal encephalopathy, several other maternal and neonatal factors affect neurodevelopmental disability.14 In this study, the delivery type (cesarean section versus normal vaginal delivery), maternal age, gravidity of mother, and mother disease during pregnancy were associated with a lower total Age and Stage Questionnaire score in different stages of life. The importance of neonatal seizures in predicting abnormal outcome, even in the absence of overt neonatal encephalopathy, is supported by several previous cohort studies.5,15-17 In our study, there was a statistically significant association between seizure and death outcome and problem-solving ability in 18-month-old infants. In some studies, low arterial umbilical cord pH had a strong and temporal association with neonatal mortality and morbidity.18-21 We could not find any statistically significant differences between pH levels and base deficit and Age and Stage Questionnaire scores. Although some patients with term intrapartum asphyxia show manifestations of cerebral palsy, many others may demonstrate other adverse outcomes. Clinicians should be aware of a full range of these possible adverse outcomes and screen children for fast detection, rehabilitation and treatment. Maternal and neonatal risk factors can be a good predictor for higher rate of adverse neurodevelopmental outcomes in infants with term intrapartum asphyxia. Clinicians should observe all infants with this diagnosis at birth. We observed these infants for 2 years, but an extended followup duration is required to be sure of detecting all possible adverse outcomes. Acknowledgment
The authors thank the Imam Hospital staff of the pediatric ward and clinic who helped with patient follow-up.

Journal of Child Neurology 00(0) References


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Author Contributions
ZKD helped in patient follow-up, data gathering, and writing the Discussion section of the article. MS helped in data gathering, statistical analysis of data, and in writing the Results and Discussion sections of the article. TE helped in data gathering and writing the Introduction and Methods sections. MH helped in statistical analysis of data and in writing the Discussion section. SSHN helped in statistical analysis of data and in writing the Results section.

Declaration of Conflicting Interests


The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding
The authors received no financial support for the research, authorship, and/or publication of this article.

Ethical Approval
This project was confirmed by the ethical committee of the Tehran University of Medical Sciences.

Keihani-Doust et al
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