Factors associated with major structural birth defects among newborns delivered at Muhimbili National Hospital and Municipal Hospitals in Dar Es Salaam, Tanzania 2011 – 2012

Factors associated with major structural birth defects among newborns delivered at Muhimbili National Hospital and Municipal Hospitals in Dar Es Salaam, Tanzania 2011 – 2012

 

Rogath Saika Kishimba^1,2,&, Rose Mpembeni³, Janneth Mghamba^1,2

 

¹Field Epidemiology and Laboratory Training Programme (FELTP), Tanzania, ²Ministry of Health and Social Welfare, Tanzania, ³Muhimbili University of Health and Allied Sciences (MUHAS), Tanzania

 

 

^&Corresponding author
Rogath Saika Kishimba, Field Epidemiology and Laboratory Training Programme (FELTP), Tanzania

 

 

 

 

A birth defect is an abnormality of structure or function which originates during intrauterine development and is evident before birth, at birth or manifests later in life. Structural birth defects (SBD) may be clinically obvious at birth [1]. The most common major structural birth defects include congenital heart disease (CHD), neural tube defects, orofacial clefts and limb reduction defects [1, 2]. Birth defects have adverse effects on the wellbeing and survival of children born with those anomalies. Almost all birth defects (94%) and deaths due to the birth defects among children (95%) occur in low and middle income countries [2]. The March of Dimes (MOD) and World Health Organization (WHO) estimate that at least 3.3 million children under age of five years die from serious genetic or partly genetic birth defects and 3.2 million of those who survive may be disabled for life without appropriate care; exacting a severe human and economic toll on those affected, their families and their communities [2, 3]. In Tanzania, it is estimated that the prevalence of birth defects is 60.5 per 1,000 live births [3]. Studies done at Muhimbili National Hospital neonatal unit in Dar es salaam have shown a birth defects prevalence of 3.3%, With eight percent of the overall mortality in the neonatal unit attributed to birth defects [4, 5]. However, there is currently no surveillance system in Tanzania to describe the population prevalence of birth defects.

 

Birth defects due to teratogens are among the most preventable defects and are more likely to be found in middle and low income countries compared to high income countries [6, 7]. This is because pregnancies in these countries are more likely to be exposed to potential teratogens and other risk factors [6, 7]. Potential teratogens/factors that have been identified in developing countries as contributors to birth defects include low socioeconomic and educational levels, malnutrition (mineral and vitamin deficiencies), intrauterine infections, lack of environmental protection policies, environmental pollution, unsafe working conditions during pregnancy, access to medicines without medical indication or prescription (self-medication), and common use of home remedies of unknown composition [7]. Clearly documenting the magnitude of known risk factors that influence the occurrence of birth defects will help inform developing preventive strategies [6, 7]. In developed countries, there are well established prevention programs which address non genetic factors influencing birth defects. However, Tanzania's ability to establish prevention strategies for birth defects is hampered by limited information on the magnitude and factors that influence the occurrence of birth defects. This study helps increase understanding of the magnitude of known risk factors, hence contributing to developing data driven birth defects prevention activities and demonstrating the value of developing a surveillance system for birth defects in Tanzania.

 

 

This study, a retrospective case-control study nested within that birth cohort, included all newborns delivered October, 2011 through February, 2012 in Dar es salaam at Muhimbili National Hospital (MNH) and the three Municipal hospitals (Temeke, Mwananyamala and Amana). None of these hospitals are referral hospitals for mother's identified with a birth defects affected fetus. Sample size was calculated using the Fleiss formula with a case control ratio of 1:3; assuming the proportion of controls exposed was 54% [8], the minimum odds ratio to be detected was 2.0, power of 80% and significance level of 95%. Computed sample size was 412, (Cases 103 and Controls 309). A case was defined as any newborn of a Dar es salaam resident with a neural tube defect, orofacial clefts, limb reduction defects or musculo-skeletal defects born at participating hospitals during the study period. A control was defined as the next three newborns (delivered after the case) to Dar es Salaam residents without birth defects born at participating hospitals during the study period. Newborns who met the case/control definition and whose mother's gave informed consent were included in the study. Newborns that met the case/control definition, but whose mother's could not be interviewed because they were very sick, emotionally upset, mute or died post delivery were excluded from the study. A Dar es salaam resident mother was considered to be any pregnant woman who lived in Dar es Salaam for the 6 months prior to delivery.

 

To avoid duplication of interviews when a mother delivered more than one newborn, the following rules were implemented: if all newborns met the case definition, only the first born was included in the study; if only one newborn met the case definition while the other did not, only the case was included in the study; if all newborns met the control definition, only the first born was included in the study. A structured questionnaire was used to interview mothers whose newborns participated in the study. The information included maternal and paternal demographic data and also information on factors that influence structural birth defects. The outcome (major structural birth defects, MSBD) was defined as any newborn with diagnosis of a neural tube defect, an orofacial cleft, a musculo-skeletal defect, or any combination of these defects. Bivariate and multivariate analyses were employed, and factors which had a p-value of ≤ 0.2 in the bivariate analysis were included in the multivariate analysis. P-values of less than or equal to 0.05 were considered statistically significant. Newborns with ambiguous genitalia were excluded from analysis. Data were analysed using Epi Info version 3.5.1.

 

 

A total of 400 newborns participated in the study - 100 cases and 300 controls - with a 97.1% consented to be interviewed.

 

Socio demographic characteristics of the study sample

 

Out of the 400 mothers whose newborns were included, 310 (77.5%) were ages 20 to 35 years with a mean age of 25.9±5.9 years and 361(90.3%) were married. More than half (73.3%) of the 400 mothers had primary education (Table 1). None of the socio demographic characteristics were statistically significantly different between cases and controls.

 

Factors associated with major structural birth defects

 

Bivariate and multivariate analyses were employed to assess associations between factors and MSBD (Table 2). Factors significantly associated with MSBD included maternal fever (adjusted odds ratio (AOR) = 1.99; 95% confidence interval (CI): 1.14-3.52), maternal hypertension (AOR=3.99; 95% CI: 1.67-9.54), and low birth weight (AOR=3.48; 95% CI: 1.77-6.85). Antimalarial use during pregnancy had a protective association (AOR=0.48; 95% CI: 0.28-0.84), although the gestation at which the mother took antimalarial was not ascertained during interview. Folic acid supplementation during pregnancy irrespective of gestational age had a protective association, but only in bivariate analysis (crude odds ratio (COR) = 0.56; 95% CI: 0.32-0.96). Paternal age, consanguineous marriage, maternal HIV/AIDS, maternal Syphilis, maternal use of: alcohol, multivitamin, antiepileptic, antihypertensive, antibiotics and antiretroviral drugs during pregnancy, newborn sex and prematurity were not significantly associated with major structural birth defects.

 

 

Maternal hypertension, maternal fever during pregnancy, and low birth weight newborns had higher odds of developing structural birth defects, after accounting for other factors; while antimalarial use during pregnancy was associated with lower odds of structural birth defects. Mothers who reported fever during pregnancy had significantly higher odds s of giving birth to babies affected with congenital anomalies even after adjusting for other factors. Studies conducted in a variety of settings around the world have observed a significant association between maternal fever and birth defects that is consistent with our findings [9 - 14]. A population based case control study done in Shanxi province Northern China on risk factors for neural tube defects found that a history of fever during the periconceptional period was associated with almost a threefold increase in risk for neural tube defects, which persisted even after controlling for other covariates [15, 16 ]. We also found that hypertensive pregnant mothers had significantly higher odds of giving birth to children affected with birth defects than the non- hypertensive mothers. Our results are consistent with findings of a study done in the USA looking at maternal factors and disparities associated with oral clefts [17]. This may be explained by the fact that hypertension in pregnancy compromises uteroplacental perfusion, interfering with foetal development. Hypertension in pregnancy had also been shown to significantly increase the risk for other birth defects such as hypospadias, aesophageal atresia/stenosis and congenital heart disease [18-21]. In this study, use of an antimalarial during pregnancy had a significant protective association with birth defects that remained after controlling for other covariates. While in this study antimalarial use was verbally reported and timing as well as duration was not ascertained, there is biological plausibility. Malaria parasites require folic acid for replication, potentially competing with the fetus which also requires folic acid to support embryonic growth. A study done to evaluate toxicological consequences of chloroquine and ethanol on the developing rat fetus has shown a teratogenic effect of antimalarials resulting in structural birth defects such as cleft palate, wrist drop, clubbed foot and brain liquification [22]. However there is currently insufficient evidence on the potential teratogenic effects of antimalarials other than tetracycline at standard doses [23]. Mothers who took folic acid supplementation tablets during pregnancy were more than 50% less likely to have children with MSBD as compared to those who did not take supplemental folic acid tablets. Though, the association with folic acid supplementation was not significant in our multivariate analysis, the direction and magnitude of association is consistent with other studies that have shown folic acid supplementation is protective against birth defects [24 - 30]. The lack of a statistically significant finding in our study might be due to the omission of about one third of women who took multivitamins (which might also contain folic acid), as this is not in Tanzania's standard Reproductive and Child Health Antenantal package recommendation. In places where preconception or periconception use of folic acid supplements is absent, high rates of neural tube defects have been described [24]. In contrast, places where preconception use of folic acid supplementation has been implemented have shown decreased rates of neural tube defects [26-28]. In our environment, preconception use of folic acid supplementation is an effective approach as 68.9% of pregnancies are wanted [31]. Periconceptional folic acid supplementation is in practice in Tanzania for all pregnant women attending antenatal clinics to counteract anaemia in pregnancy; however, because the neural tube closes in the first 28 days of conception, a time when most women do not yet recognize that they are pregnant, periconceptional folic acid likely only provides limited protection against neural tube defects in Tanzania.

 

There was an association between newborn birth weight and MSBD. Low birth weight babies (<2500 grams) had higher odds of congenital defects compared to normal birth weight babies (≥2500 grams). This can be potentially explained by several factors. Some birth defects included in our study may increase the risk of polyhydramnios which can result in preterm labour [32 - 34]. Preterm labour and birth defects may also share other risk factors such as maternal fever, maternal hypertension and maternal infections. In contrast to our findings, preterm infants are at increased risk of birth defects [32, 35]. A significant association which we found between low birth weight and birth defects can not necessarily be implied to a relationship between prematurity and birth defects due to the fact a third variable i.e. intrauterine growth retardation can distort this relationship [35]. In contrast to our findings, other studies conducted in a variety of countries have found an association between structural birth defects and advanced maternal age (≥35 years), paternal age >30 years, consanguineous marriage, alcohol consumption and antiepileptic drugs use during pregnancy [36 - 39]. This might be due to differences in the study populations in terms of included behaviors and diseases.

 

Strengths and limitations of the study

 

In Dar es sallam, 90.2% of pregnant mothers deliver at a health facility and majority (72%) of them particularly delivered at Muhimbili National Hospital and the three Municipal hospitals respectively [31, 40]. The strength of this study is the fact that it involved multiple public hospitals, where the majority of deliveries occur, covering people with a diversity of demographic characteristics and health related behaviours. This study had limitations, one being the reliance on self reported mother's information of the risk factors. The result is potential recall bias; however mother's whose newborns participated in the study either as a case or control were interviewed within 24 hours post delivery to help minimize the bias. It was difficult for mothers to remember exactly at what gestational age they took which medication or they fell sick. While cigarette smoking and tobacco use have been widely implicated with birth defects, we could not examine these exposures in our study because none of our respondents reported cigarette or tobacco use [38, 41].

 

 

This study identified maternal hypertension, maternal fever during pregnancy, and low birth weight newborns as risks factors associated with major structural birth defects in Dar es Salaam, Tanzania; while antimalarial use during pregnancy was associated with protection against major structural birth defects. By increasing early screening of pregnant mothers for hypertension and other causes of low birth weight or prematurity, through strengthening of the Primary Health Care system where antenatal care visits are done, it may be possible to reduce major structural birth defects in Dar es Salaam, Tanzania. In addition, we recommend promoting utilization of proven reproductive and child health and advocacy strategies to address the identified factors.

 

 

The authors declare that they have no competing interests. The findings and conclusions in this report are those of the authors and do not necessarily represent the official position of the Centers for Disease Control and Prevention.

 

 

Drs Rogath, Rose and Janneth designed and conducted the study, including newborns recruitment, data collection, and data analysis. Dr Rogath prepared the manuscript draft with important intellectual input from Drs Rose and Janneth. Dr Rogath had complete access to the study data. All authors approved the final version of the manuscript.

 

 

We thank Tanzania Ministry of Health (MoHSW), Tanzania - Field Epidemiology and Laboratory Program (TFELTP), Muhimbili University of Health and Allied Sciences (MUHAS), and CDC-Tanzania for financial and technical support. We thank the CDC-USA, Division of Reproductive Health, Maternal and Child Health Epidemiology Program for technical support.

 

 

Table 1: socio demographic characteristic of case and control groups

Table 2: crude and adjusted odds ratios for factors associated with birth defects

 

 

1. Perinatal Education Programme, Birth Defects, A learning programme for professionals. 2009. Cape Town. PDF ebook edition. PubMed | Google Scholar


2. Christianson A, Howson CP, Modell B. March of Dimes Global Report on Birth Defects, '' The Hidden Toll of Dying and Disabled Children? 2006. New York. Google Scholar


3. WHO, Joint WHO-March of Dimes meeting on the management of birth defects and haemoglobin disorders. 2006. Geneva. Google Scholar


4. Kinasha AD, Manji K. The Incidence and Pattern of Neural Tube Defects in Dar es Salaam, Tanzania. Eur J Pediatr Surg. 2002; 12 (Suppl 1): S38-9. PubMed | Google Scholar


5. Karim Manji P, Georgina LRM. An audit of congenital malformations at the Neonatal unit in Dar Es Salaam, Tanzania. Postgraduate Doctor Africa. 1997. Google Scholar


6. Christianson AL, Modell B. ''Medical Genetics in Developing Countries.'' Annual Reviews in Genomics & Human Genetics. 2004; 5:219-65. PubMed | Google Scholar


7. Penchaszadeh VB." Preventing Congenital Anomalies in Developing Countries? Community Genetics. 2002; 5:61-69. PubMed | Google Scholar


8. Omo-Aghoja VW, Omo-Aghoja LO, Ugboko VI, Obuekwe ON, Saheeb BDO, Feyi-Waboso P, Onowhakpor A. Antenatal determinants of oro-facial clefts in Southern Nigeria. African Health Sciences. March 2010; 10(1):31-39. PubMed | Google Scholar


9. Fischer M, Hedberg K, Cardosi P, et al. Tobacco smoke as a risk factor for meningococcal disease. Pediatr Infect Dis J. 1997; 16(10):979-983. PubMed | Google Scholar


10. Thorsen P, Vogel I, Molsted K, et al. Risk factors for bacterial vaginosis in pregnancy: a population-based study on Danish women. Acta Obstet Gynecol Scand. 2006; 85(8):906-911. PubMed | Google Scholar


11. Larsson PG, Fahraeus L, Carlsson B, et al. Predisposing factors for bacterial vaginosis, treatment efficacy and pregnancy outcome among term deliveries; results from a preterm delivery study. BMC Women's Health. 2007; 7:20. PubMed | Google Scholar


12. Botto LD, Lynberg MC, David Erickson JD. Congenital Heart Defects, Maternal Febrile Illness, and Multivitamin Use: A Population-Base Study. Epidemiology. 2001 Sep; 12(5): 485-490. PubMed | Google Scholar


13. Lorenzo Botto D, David Erickson J, Joseph Mulinare, Michele Lynberg C and Yecai Liu. Maternal Fever, Multivitamin Use, and Selected Birth Defects: Evidence of Interaction? Epidemiology. 2002 Jul; 13(4):485-488. PubMed | Google Scholar


14. Julie Werenberg Dreier, Anne-Marie Nybo Andersen, Gabriele Berg-Beckhoff. "Systematic Review and Meta-analyses: Fever in Pregnancy and Health Impacts in the Offspring". Pediatrics. 2014; 133(3): e674 - e688. PubMed | Google Scholar


15. Zhiwen Li , Aiguo Ren, Le Zhang , Zhanying Guo, Zhu Li. A population-based case-control study of risk factors for neural tube defects in four high-prevalence areas of Shanxi province China. Paediatric and Perinatal Epidemiology. 2006; 20(1): 43-53. PubMed | Google Scholar


16. Wei Wang, Peng Guan, Wei Xu, Baosen Zhou. Risk factors for oral clefts: a population-based case-control study in Shenyang China. Paediatric and Perinatal Epidemiology. 2009; 23(4): 310-320. PubMed | Google Scholar


17. Kimberly Lebby D, Fei Tan, Perry Brown C. "Maternal Factors and Disparities Associated with Oral Clefts". Ethnicity and Disease. 2010; 20(1 Suppl 1): S1-146-9. PubMed | Google Scholar


18. Czeizel AE, Banhidy F. Chronic hypertension in pregnancy. Curr Opin Obstet Gynecol. 2011 Apr; 23(2): 76-81. PubMed | Google Scholar


19. Caton AR, Bell EM, Druschel CM, Werler MM, Mitchell AA, Browne ML, McNutt LA, Romitti PA, Olney RS, Correa A, and the National Birth Defects Prevention Study. Maternal hypertension, antihypertensive medication use, and the risk of severe hypospadias. Birth Defects Research part A, Clin Mol Teratol. 2008 Jan; 82(1): 34-40. PubMed | Google Scholar


20. Aschim EL, Haugen TB, Tretli S, Daltveit AK, Grotmol T. Risk factors for hypospadias in Norwegian boys - association with testicular dysgenesis syndrome? Int J Androl. 2004 Aug; 27(4): 213-21. PubMed | Google Scholar


21. Alissa Caton R, Erin Bell M, Charlotte Druschel M, Martha Werler M, Angela Lin E, Marilyn Browne L, Louise-Anne McNutt, Paul Romitti A, Allen Mitchell A, Richard Olney S, Adolfo Correa. "Antihypertensive Medication Use during Pregnancy and the Risk of Cardiovascular Malformations". Hypertension. 2009 Jul 11; 54(1): 63-70. PubMed | Google Scholar


22. Sharma A, Rawat AK. Toxicological consequences of chloroquine and ethanol on the developing fetus. Pharmacol Biochem Behav. 1989 Sep; 34(1): 77-82. PubMed | Google Scholar


23. Phillips-Howard PA, Wood D. The safety of antimalarial drugs in pregnancy. Drug Saf. 1996 March; 14(3): 131-45. PubMed | Google Scholar


24. Njamnshi AK, Djenticheu Vde P, Lekoubou A, Guemse M, Obama MT, Mbu R, Takongmo S, Kago I. Neural tube defects are rare among black Americans but not in sub-Saharan black Africans: the case of Yaounde - Cameroon. J Neurol Sci. 2008 Jul 15; 270(1-2): 13-7. PubMed | Google Scholar


25. MRC Vitamin Study Research Group. Prevention of neural tube defects: Results of the Medical Research Council Vitamin Study. The Lancet. 1991; 338(8760):131 - 137. PubMed | Google Scholar


26. Lilah Besser M, Laura Williams J, and Janet Cragan D. Interpreting changes in the epidemilogy of ancephaly and spina bifida following folic acid fortification of the US grain supply in the setting of long-term trends, Atlanta, Georgia, 1968-2003. Clinical and Molecular Teratology. 2007; 79(11): 730-736. PubMed | Google Scholar


27. Zouhair O, Amarina and Ahmed Obeidatb Z. Effect of folic acid fortification on the incidence of neural tube defects. Paediatric and Perinatal Epidemiology. 2010; 24: 349-351. PubMed | Google Scholar


28. Ubbink JB, Christianson A, Bester MJ, Van Allen MI, Venter PA, Delport R, Blom HJ, Van der Merwe A, Potgieter H, Vermaak WJ. Folate status, homocysteine metabolism, and methylene tetrahydrofolate reductase genotype in rural South African blacks with a history of pregnancy complicated by neural tube defects. Metabolism. 1999 Feb; 48(2): 269-74. PubMed | Google Scholar


29. Anna Verster. Food Fortification in Tanzania Opportunities and needs. World Bank consultant. Google Scholar


30. Sayed AR, Bourne D, Pattinson R, Nixon J, Henderson B. Decline in the prevalence of neural tube defects following folic acid fortification and its cost-benefit in South Africa. Birth Defects Res A Clin Mol Teratol. 2008 Apr; 82(4) :211-6. PubMed | Google Scholar


31. Tanzania Demographic and Health Survey (TDHS), 2010. Google Scholar


32. Pierro A, Cozz F, Colarossi G, Irving IM, Pierce AM, Lister J. Does fetal gut obstruction cause hydramnious and growth retardetaion? J Pediatr Surg. 1987; 22(5) : 454-7. PubMed | Google Scholar


33. Mazor M, Ghezzi F, Maymon E, Shoham-Vardi I, Vardi H, Hershkowitz R, et al. Polyhydramnios is an independent risk factor for perinatal mortality and intrapartum morbidity in preterm delivery. Eur J Obstet Gynecol Reprod Biol. 1996 Dec; 70(1) :41-7. PubMed | Google Scholar


34. Cheng W, Mya GH, Saing H. Does the amniotic fluid protein absorption contribute significantly to the fetal weight? J Paediatr Child Health. 1996 Feb; 32(1) :39-41. PubMed | Google Scholar


35. Khoury MJ, Erickson JD, Cordero JF, McCarthy BJ. Congenital malformations and intrauterine growth retardation: a population study. Paediatrics. 1988 Jul; 82(1) :83-90. PubMed | Google Scholar


36. Bittles AH, Mason WM, Greene J, Rao NA. ''Reproductive Behaviour and Health in Consanguineous Marriages.'' Science. 1991; 252(5007) :789-94. PubMed | Google Scholar


37. WHO/World Alliance for the Prevention of Birth Defects. 1999. Services for the Prevention and Management of Genetic Disorders and Birth Defects in Developing Countries. WHO, Geneva, Switzerland. PubMed | Google Scholar


38. Hernández-Díaz S, Werler MM, Walker AM, Mitchell AA. "Folic Acid Antagonists during Pregnancy and the Risk of Birth Defects". New England Journal of Medicine. 2000; 343(22) :1608-1614. PubMed | Google Scholar


39. WHO, ''Community approaches to the Control of Hereditary Diseases.'' Report of the Advisory Group. 1985. WHO. Geneva. PubMed | Google Scholar


40. Nyamtema AS, Urassa DP, Massawe S, Massawe A, Mtasiwa D, Lindmark G, Van Roosmalen J. "Dar es Salaam perinatal care study: needs assessment for quality of care". East Afr J Public Health. 2008 Apr; 5(1) :17-21. PubMed | Google Scholar


41. Man LX, Chang B. Maternal cigarette smoking during pregnancy increases the risk of having a child with a congenital digital anomaly. Plast Reconstr Surg. 2006 Jan; 117(1) :301-8. PubMed | Google Scholar