|Year : 2015 | Volume
| Issue : 3 | Page : 174-178
Foetal congenital anomalies: An experience from a tertiary health institution in north-west nigeria (2011-2013)
Swati Singh1, Daniel Nnadi Chukwunyere1, Joel Omembelede2, Ben Onankpa3
1 From the Department of Obstetrics and Gynaecology, Usmanu Danfodiyo University Teaching Hospital, Sokoto, Nigeria
2 From the Departments of Obstetrics and Gynaecology, Usmanu Danfodiyo University Teaching Hospital, Sokoto, Nigeria
3 From the Department of Paediatrics, Usmanu Danfodiyo University Teaching Hospital, Sokoto, Nigeria
|Date of Web Publication||30-Nov-2015|
From the Department of Obstetrics and Gynaecology, Usmanu Danfodiyo University Teaching Hospital, Sokoto
Source of Support: None, Conflict of Interest: None
Background: Structural or functional defects present at birth may lead to physical or mental disabilities. They contribute significantly to perinatal morbidity and mortality.
Aims and Objectives: The study aimed to determine the prevalence of congenital anomalies among women delivering in the labour room suites of a tertiary health institution in North-Western Nigeria. Various maternal risk factors were also correlated and analysed.
Subjects and Methods: This was a 3-year hospital-based prospective study carried out in the Department of Obstetrics and Gynaecology in association with the Department of Paediatrics in a tertiary health care centre in North-Western Nigeria. All neonates delivered in the labour rooms were examined for congenital abnormalities (CAs) soon after birth. The study group included all live births along with stillbirths delivered after the 28th week of gestation. Those diagnosed with congenital anomaly were admitted to the special care baby unit for observation and documentation.
Results: A total of 72 congenital anomalies were documented among 10,163 deliveries. Central nervous system (CNS) anomalies had the highest prevalence 34.7% (25/72) and were followed by those of the musculoskeletal system 22.2% (16/72). Spina bifida/meningocoele were the most common anomalies of the CNS 44% (11/25) followed by hydrocephaly 28% (7/25). Most of the anomalies involved single organs 59/72 (81.9%). Majority of the CA 84.7% (61/72) were prevalent within the maternal age range of 16–35 years, while 12.5% were seen in teenage pregnancy. Diagnosis of most of the anomalies was made after delivery 69.4% (50/72). History of maternal febrile illness during pregnancy was present in 75% (54/72) and in 50% (27/54) of cases with CNS anomaly.
Conclusion: Central nervous system anomalies were the most prevalent congenital anomalies observed. Improved maternal health, pre-conception care, folic acid supplementation and routine foetal anomaly scan may help to reduce these anomalies.
Keywords: Congenital anomalies, Nigeria, prevalence
|How to cite this article:|
Singh S, Chukwunyere DN, Omembelede J, Onankpa B. Foetal congenital anomalies: An experience from a tertiary health institution in north-west nigeria (2011-2013). Niger Postgrad Med J 2015;22:174-8
|How to cite this URL:|
Singh S, Chukwunyere DN, Omembelede J, Onankpa B. Foetal congenital anomalies: An experience from a tertiary health institution in north-west nigeria (2011-2013). Niger Postgrad Med J [serial online] 2015 [cited 2022 Dec 6];22:174-8. Available from: https://www.npmj.org/text.asp?2015/22/3/174/170743
| Introduction|| |
In most cultures, child birth is a major and welcome event. Thus, a mother giving birth to a malformed baby poses a great dilemma not only to her immediate family, but also to the entire community. The mothers of such babies would feel unfulfilled, humiliated and sometimes ostracised from their community. A parent giving birth to an abnormal baby is seen as a reproductive failure and may be saddled with the high cost of taking care of such a child. The child faces an uncertain future in a highly competitive society. Thus, children in developing countries born with severe congenital anomalies could be abandoned, concealed, neglected and even murdered by their own parents. Congenital anomalies contribute immensely to perinatal and neonatal mortality and disability, especially in resource-poor countries. The interest in congenital malformations dates back to antiquity. The National Congenital Anomalies System was established in 1964 in the USA in the wake of the thalidomide disaster as a surveillance system intended to identify hazards such as thalidomide quickly.
Congenital anomalies are also known as birth defects, congenital disorders or congenital malformations. Congenital anomalies can be defined as structural or functional anomalies (e.g., metabolic disorders) that occur during intrauterine life and can be identified prenatally, at birth or later in life. These anomalies may result from disruptions of the normal chromosomal pattern, for example, Down's syndrome, interference with an originally normal developmental process by teratogens such as drugs, alcohol, viral and bacterial infections such as rubella, cytomegalovirus and by ionizing radiations. However, the aetiology of most congenital malformations is multifactorial. They may result in serious, adverse effect on the health, development, or functional ability of the child. Congenital malformations are a significant component of the global burden of disease (GBD) among children accounting for 25 million disability-adjusted life years worldwide. The World Health Organization's recent GBD study reports that anomalies rank 17th in the causes of disease burden. They are mainly responsible for hospital admission and prolonged stay in the special care baby unit (SCBU).
Congenital anomalies may present as either single isolated defects or as multiple organ system anomalies in a single individual. The prevalence of these anomalies differs across the various races of the world, but the total incidence appears similar among the Caucasian and Japanese races. It is estimated that 1 in 40, or 2.5% of newborns have a recognizable malformation or malformations at birth. Structural birth defects affect about 3% of births in the United States of America (USA) and the United Kingdom and are a major contributor to infant mortality., They rank 2nd among the common causes of infant mortality in the UK with a rate of 1.39 per 1000 live births in 2007.,, In China, 1.03% of neonates are born with congenital anomalies, while in Egypt an incidence of 2.5% has been documented.,, The overall prevalence of congenital malformations in rural Kenya was 6.3 per 1000 children  and the most prevalent condition in the survey was club foot, whereas spina bifida had the highest burden of disease. In Nigeria, prevalence rates ranging from 2.1% to 5.6% have been reported for different types of malformations., The frequency of the occurrence of congenital anomalies is usually quoted as birth prevalencerather than incidence., This is because many foetusesaffected by a congenital anomaly will miscarry, the miscarriage may occur before the pregnancy is confirmed and even if the miscarriage occurs later, the anomaly may not be diagnosed. The term birth prevalence, therefore, acknowledges that not all cases of congenital anomalies can be diagnosed and counted in an incidence rate. The denominator for the calculation of birth prevalenceis usually taken as all births which exclude miscarriages and terminations of pregnancy.
This study was performed to determine the prevalence and types of congenital malformations in a tertiary health centre, identify subgroups that are disproportionately affected and provide information that can be used for prevention, grief management and counselling.
| Subjects and Methods|| |
The study was performed at the Department of Obstetrics and Gynaecology in association with the Department of Paediatrics of the Usmanu Danfodiyo University Teaching Hospital, Sokoto, a tertiary health institution in North-West Nigeria.
It was a 3-year prospective study conducted in the two labour room suites of the Department of Obstetrics and Gynaecology and the SCBU of the Paediatrics Department from January 1, 2011, to December 31, 2013. The hospital has 600 bed spaces and provides tertiary and secondary health care services to neighbouring states and also runs a residency training program for doctors in the various sub-specialists including Surgery, Obstetrics and Gynaecology, Internal Medicine, Paediatrics, among others. All neonates delivered in the labour rooms were examined for congenital abnormalities (CAs) soon after birth. The study group included all live births along with stillbirths delivered after the 28th week of gestation. Those diagnosed with congenital anomaly were admitted into the SCBU for observation and documentation.
All babies delivered in the hospital during the period of study were included. Diagnosis of CA was based on clinical evaluation, radiographic examination, echocardiography and chromosomal analysis of the newborn, whenever recommended. Data collected included the sociodemographics of the parents, gestational age, sex of the babies; ethnicity, birth order and consanguinity were documented. The data were recorded in a pre-designed proforma. Statistical analysis of the collected data was performed using the SPSS IBM version 20 (IBM version 20.0. Armouk, NY: IBM Corp.). The results were expressed in frequencies, means, percentages, tables, figures and charts. The Chi-square test (χ2) was used for association at P = 0.05 at 95% confidence interval. The Hospital's Ethical and Research Committee approved the study.
| Results|| |
During the 3-year study period, there were 10, 163 deliveries consisting of 5640 males and 4523 females. Congenital anomalies were present in 72 of the neonates, thus giving a birth prevalence of 0.71%. There were 42 (58.3%) males and 30 (41.7%) females, thus giving a male to female ratio of 1.4:1. Neonates with congenital malformations were highest in the 2nd to 3rd birth order. Two babies from a different set of twins had congenital malformations. Multiple organ system anomalies (multiple congenital anomalies [MCAs]) were present in 18.1% (13/72) of the neonates. The most common congenital anomaly was that of the central nervous system (CNS) 34.7% (25/72), which was followed by the musculoskeletal (MSK) 22.2% (16/72), gastrointestinal (GIT) 11.1% (8/72%), genitourinary system (GUS) 8.3% (6/72) and the cardiovascular system (CVS) 5.6% (4/72) in that order. This was shown in [Table 1]. Among the CNS anomalies, the most common was spina bifida and meningocoele 44% (11/25) and was followed by hydrocephaly 28% (7/25). One of the rarest forms of congenital anomalies known as diprosopus (craniofacial duplication) was among the CNS malformations. This was present in a 39-year-old booked multiparous woman who was delivered by emergency caesarean section (CS). There were five babies with anencephaly. Talipes equinovarus was the most common anomaly 37.5% (6/16) of the MSK observed and was followed by polydactyly 18.8% (3/16).
The ages of the mothers vary from 16 to 46 years and above with a mean age of 27.7 (standard deviation = 7.4) years, as shown in [Table 2]. Most of the CA 66.7% (48/72) was found in babies delivered to mothers within the age range of 20–34 years, while babies delivered by teenage mothers (≤19 years) accounted for 12.5% (9/72) of all the malformations as shown in [Table 2]. Congenital anomalies were observed in 20.8% (15/72) of babies of mothers' age ≥35 years. The relationship between age of the mother and the prevalence of birth anomalies shows a significant association between advanced maternal age and birth defects as shown in [Table 3] (P = 0.002). Teenage pregnancy accounted for 24.2% (8/33) of all the CNS malformations.
History of parental consanguinity was present in eleven cases (15.3%) of the malformations. There was no association between parental consanguinity and presence of congenital anomalies in the study (P < 0.05). Mothers of Para 2 and above accounted for 69.4% (50/72) of the malformations, while the primigravida had 13.9% (10/72). A positive family history of birth defects was present in 3 (4.2%) cases. Most of the birth defects of the CNS, GIT and GUS anomalies were diagnosed using ultrasonography during antenatal care; however, the MSK and cardiovascular anomalies were diagnosed after birth clinically and by echocardiography soon after birth. Majority of the babies 72.2% (52/72) were delivered vaginally, 20.8% (15/72) by CS, while the rest were by destructive operations (craniotomy, etc.). Out of the 52 babies delivered vaginally, 18 (34.6%) had CNS anomalies, while 17 (32.7%) had malformations of the MSK system. In contrast, most of the babies delivered through CS 73.3% (11/15) had anomalies of the CNS. Only 2 out of the 72 babies with congenital anomalies were pre-term deliveries, the rest were term and post-term births.
There was antecedent maternal febrile illness of about 3 to 32 episodes per woman throughout the trimesters of pregnancy in 75% (54/72) of the affected neonates, especially among those with CNS 50% (27/54) and MSK 24.1% (13/54) anomalies as shown in [Table 2]. There was no significant association between maternal febrile illness and the prevalence of congenital anomalies in this study (χ2 = 3.146, df = 1, P = 0.076). All the patients tested negative to human immune-deficiency virus (HIV). Thus, there was no relationship between maternal HIV sero-status and the presence of congenital anomalies.
| Discussion|| |
In this study, the birth prevalence of congenital anomalies was 0.71% (72/10,163). In a previous study from this institution, a prevalence rate of 2.1% was noted. This was relatively higher because the study included cases of congenital malformations referred from elsewhere and admitted into the SCBU. The low prevalence may also be due to the nature of the study, which is institutional-based. Institutional delivery is very low in the health institution, as many parturients prefer to labour at home under the watch of traditional birth attendants (TBAs). However in both studies, the CNS abnormalities were the most common, followed by those of the MSK system. These findings are comparable to the studies conducted by other researchers in Jos, North Central Nigeria, Iran and Pakistan where there is a higher incidence of CNS anomalies.,, However, in a similar report from Ilorin also in North Central Nigeria, there was a high prevalence of malformations of the GIT, while from Egypt, India, Kuwait and Saudi Arabia, the MSK system was the most commonly involved followed by the CNS, GIT and the GUS system, but the most common cause of death was from anomalies of the CVS., 15, ,, Involvement of more than one system was observed in 28.6% cases in the Egyptian study, but in this report, multiple system anomalies were noted in 18.1% of cases. There was a male preponderance among congenitally malformed babies, and this is in conformity with other studies, but in the study from Egypt, there was no significant difference in the frequency of congenital anomalies between the sexes. The differences in the results could be attributed to racial and social factors that are known to affect genetic disorders. Similarly, the smaller sample size and the shorter duration of observation in the Egyptian study may have influenced these variations. There is also a higher prevalence of parental consanguinity and thus more congenital anomalies (2.5%) in Egypt.
The most common CNS abnormality observed in this study was spina bifida and meningocoele in 44% (11/25) and was followed by hydrocephaly. Similar findings were noted from Jos in the North-central part of the country. In a previous study from this centre and the South-West region of the country, hydrocephaly was the most prevalent anomaly of the CNS., This shows the geo-ethnic variations in the prevalence of congenital anomalies in Nigeria.
Teenage pregnancies (≤19 years) accounted for 12.5% (9/72) of all the anomalies and 24.2% (8/33) of all the CNS malformations. Adolescent pregnancy constitutes a high-risk maternity. Nutritional anaemia among others complicates such pregnancies. A large proportion of the population in Sokoto state live in rural areas with high levels of poverty among most women. This means that many pregnant women in the state cannot assess antenatal care due to financial reasons and a large proportion of those who do so, would not afford the essential drugs. Similarly, some cultural practices prohibit pregnant women from eating certain meals and foods. These factors contribute to malnutrition and poor maternal health. Concerted efforts at poverty alleviation at both community and state levels, improved maternal health status as enshrined in the millennium developmental goals, consumption of food fortified with folic acid and increased intake of folic acid vitamin supplements among other measures will produce a decline in neural tube defects (NTDs).
Foetal diprosopus (craniofacial duplication) an extremely rare form of CA that results in partial or total duplication of the face was recorded in this study. The female baby was delivered by emergency CS when the mother had polyhydramnios and placental abruption. The baby died on the second day of life from acute respiratory distress. Talipes equinovarus was the most common anomaly of the MSK observed and was followed by polydactyly. Similar observations were noted from studies in Eastern India, as was in this study.
First cousin type of consanguineous marriage is a very common practice in the state, especially among the Hausa/Fulani who constitute the major ethnic group. History of parental consanguinity was present in eleven cases (15.3%) of malformations, especially among those with NTDs in this study. There was no association between parental consanguinity and the presence of congenital anomalies in the study (P < 0.05). The risk for birth defects in the offspring of first-cousin mating has been estimated to increase sharply compared to non-consanguineous marriages. This has been attributed to the preservation of rare mutations. This calls for adequate pre-marital genetic counselling.
The hallmark of the diagnosis of congenital disease is maternal history and any history of recent exposure to ill-individuals, physical findings in the newborn and appropriate laboratory testing. In the present study, there was antecedent maternal febrile illness of an average of 15 episodes per woman throughout the trimesters of pregnancy in 75% (54/72) of the affected neonates, especially among those with CNS 50% (27/72) and MSK 24.1% (13/54) anomalies. Even though the association with congenital anomaly was not statistically significant in this study (P < 0.05), high fever-related maternal diseases, especially during the first trimester of pregnancy have been known to result in an increased risk of MCAs, particularly NTDs and orofacial clefts. Poor maternal recall of the exact occurrence of the febrile illnesses in relation to the trimesters of pregnancy could have been one of the limitations of this study. Recurrent attacks of malaria which is endemic in Nigeria may have also been responsible for the febrile illnesses. The incidence of congenital rubella syndrome decreased dramatically in the United States of America because of routine rubella vaccination. Such a policy has not been adopted in most countries of the developing world including Nigeria.
| Conclusion and Recommendations|| |
The birth prevalence of congenital malformations in this study was 0.71%. CNS anomalies were the most common anomalies observed. Improved maternal health, pre-conception care including folic acid supplementation and early diagnosis of most of these anomalies are recommended.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Adeniran JO, Odebode TO. Congenital malformations in paediatric and neurosurgical practices. Sahel Med J 2005;8:4-8.
Obu HA, Chinawa JM, Uleanya ND, Adimora GN, Obi IE. Congenital malformations among newborns admitted in the neonatal unit of a tertiary hospital in Enugu, South-East Nigeria – A retrospective study. BMC Res Notes 2012;5:177.
Ryan L, Cragan J. Update on overall prevalence of major birth defects – Atlanta, Georgia, 1978-2005. MMWR Morb Mortal Wkly Rep 2008;57:1-5.
Sartorius GA, Nieschlag E. Paternal age and reproduction. Hum Reprod Update 2010;16:65-79.
Lobo I, Zhaurova K. Birth defects: Causes and statistics. Nat Educ 2008;1:18.
Wu VK, Poenaru D, Poley MJ. Burden of surgical congenital anomalies in Kenya: a population-based study. J Trop Pediatr 2013;59:195-202.
Murray CJ, Vos T, Lozano R, Naghavi M, Flaxman AD, Michaud C, et al.
Disability-adjusted life years (DALYs) for 291 diseases and injuries in 21 regions, 1990-2010: a systematic analysis for the Global Burden of Disease Study 2010. Lancet 2012;380:2197-223.
Gillani S, Kazmi NH, Najeeb S, Hussain S, Raza A. Frequencies of congenital anomalies among newborns admitted in nursery of Ayub Teaching Hospital Abbottabad, Pakistan. J Ayub Med Coll Abbottabad 2011;23:117-21.
Hoyert DL, Mathews TJ, Menacker F, Strobino DM, Guyer B. Annual summary of vital statistics: 2004. Pediatrics 2006;117:168-83.
Kurinczuk JJ, Hollowell J, Boyd PA, Oakley L, Brocklehurst P, Gray R. Inequalities in infant mortality project briefing paper 4. The contribution of congenital anomalies to infant mortality. Oxford: National Perinatal Epidemiology Unit; 2010.
Boyd PA, Rounding C, Kurinczuk JJ. Second Report of the Congenital Anomaly Register for Oxfordshire, Berkshire and Buckinghamshire (CAROBB) Births 2005 to 2008. Oxford: National Perinatal Epidemiology Unit, University of Oxford; 2009.
Bower C, Rudy E, Callaghan A, Quick J, Cosgrove P, Nassar N. Report of the Birth Defects Registry of Western Australia, Number 16: 1980-2008. Subiaco, Perth: King Edward Memorial Hospital; 2009.
Luo XL, Zhang WY. Obstetrical disease spectrum in China: an epidemiological study of 111,767 cases in 2011. 2015;128:1137-46.
El Koumi MA, Al Banna EA, Lebda I. Pattern of congenital anomalies in newborn: a hospital-based study. Pediatr Rep 2013;5:e5.
Binitie OP. Congenital malformations of the central nervous system at the Jos University Teaching Hospital, Jos Plateau State of Nigeria. West Afr J Med 1992;11:7-12.
Onankpa BO, Adamu A. Pattern and outcome of gross congenital malformations at birth amongst newborns admitted to a tertiary hospital in Northern Nigeria. Niger J Paediatr 2014;41:337-40.
Khatemi F, Mamorri GA. Survey of congenital major malformations in 10, 000 newborns. Iran J Pediatr 2005;15:315-20.
Agrawal D, Mohanty BB, Sarangi R, Kumar S, Mahapatra SK, Chinara PK. Study of incidence and prevalence of musculoskeletal anomalies in a tertiary care hospital of eastern India. J Clin Diagn Res 2014;8:AC04-6.
Madi SA, Al-Naggar RL, Al-Awadi SA, Bastaki LA. Profile of major congenital malformations in neonates in Al-Jahra region of Kuwait. East Mediterr Health J 2005;11:700-6.
Al-Sheri MA. Pattern of major congenital anomalies in South Western Saudi Arabia. Bahrain Med Bull 2005;27:302-7.
Adeloye A, Odeku EL. Congenital malformations of the central nervous system in Nigeria. West Afr Med J Niger Med Dent Pract 1972;21:73-7.
Nwobodo EI, Adoke KU. Obstetric outcome of teenage pregnancies at a tertiary hospital in Sokoto, Nigeria. Trop J Obstet Gynaecol 2005;22:168-70.
Shamaki MA, Buang A. Socio-cultural practice in maternal health among women in a less developed economy: An overview of Sokoto State, Nigeria. Malays J Soc Space 2014;10:1-14.
Onankpa BO, Ukwu AE, Singh S, Adoke AU, Tahir A. Fetal diprosopus (double-face): A case report. Int J Res Health Sci 2014;3:461-3.
Stoll C, Alembik Y, Roth MP, Dott B. Parental consanguinity as a cause for increased incidence of births defects in a study of 238,942 consecutive births. Ann Genet 1999;42:133-9.
Czeizel AE, Puhó EH, Acs N, Bánhidy F. Delineation of a multiple congenital abnormality syndrome in the offspring of pregnant women affected with high fever-related disorders: a population-based study. Congenit Anom (Kyoto) 2008;48:158-66.
Creasy RK, Resnik R, Iams JD, Lockwood CJ, Moore T, editors. Creasy and Resnik's Maternal-Fetal Medicine: Principles and Practice. 6th
ed. Philadelphia, PA: Saunders; 2008.
[Table 1], [Table 2], [Table 3]
|This article has been cited by|
||Birth prevalence of omphalocele and gastroschisis in Sub-Saharan Africa: A systematic review and meta-analysis
| ||Chalachew Tiruneh, Teshome Gebremeskel, Mogesie Necho, Yossef Teshome, Daniel Teshome, Asmare Belete |
| ||SAGE Open Medicine. 2022; 10: 2050312122 |
|[Pubmed] | [DOI]|
||Prevalence and Trends of Congenital Anomalies Among Neonates at Jimma Medical Center, Jimma, Ethiopia: A Three-Year Retrospective Study
| ||Mulualem Silesh,Tesfanesh Lemma,Belete Fenta,Tsegaw Biyazin |
| ||Pediatric Health, Medicine and Therapeutics. 2021; Volume 12: 61 |
|[Pubmed] | [DOI]|
||10 ( On ) Hafta ve Üzeri Gebelik Terminasyonlarinin Analizi ve Terminasyon Sirasinda Kullanilan Intravajinal Mizoprostol Etkinliginin Arastirilmasi
| ||Cem YENER,Sinan ATES,Cenk SAYIN,Süheyla GÖRMEZ,Füsun VAROL |
| ||Mustafa Kemal Üniversitesi Tip Dergisi. 2020; |
|[Pubmed] | [DOI]|
||Value and Diagnostic Efficacy of Fetal Morphology Assessment Using Ultrasound in A Poor-Resource Setting
| ||Yahia Zakaria Abdelalim Ukweh,Yahia Zakaria Abdelalim Ugbem,Yahia Zakaria Abdelalim Okeke,Yahia Zakaria Abdelalim Ekpo |
| ||Diagnostics. 2019; 9(3): 109 |
|[Pubmed] | [DOI]|
||Incidence, spectrum and outcome of congenital anomalies seen in a neonatal intensive care unit in Southern Nigeria
| ||RosenaOlubanke Oluwafemi,MosesTemidayo Abiodun |
| ||Nigerian Postgraduate Medical Journal. 2019; 26(4): 239 |
|[Pubmed] | [DOI]|
||Association of consanguineous marriages with congenital anomalies
| ||Maryam Naveed,Sajeeha Nadeem,Amber Hassan,Imrana Tanvir |
| ||Pakistan BioMedical Journal. 2019; 2(1) |
|[Pubmed] | [DOI]|
||Medical genetics and genomic medicine in Nigeria
| ||Adebowale A. Adeyemo,Olukemi K. Amodu,Ekanem E. Ekure,Olayemi O. Omotade |
| ||Molecular Genetics & Genomic Medicine. 2018; |
|[Pubmed] | [DOI]|
||Global hydrocephalus epidemiology and incidence: systematic review and meta-analysis
| ||Michael C. Dewan,Abbas Rattani,Rania Mekary,Laurence J. Glancz,Ismaeel Yunusa,Ronnie E. Baticulon,Graham Fieggen,John C. Wellons,Kee B. Park,Benjamin C. Warf |
| ||Journal of Neurosurgery. 2018; : 1 |
|[Pubmed] | [DOI]|