Maternal Risk Factors Associated with Neural Tube Defect at Debre Berhan Referral Hospital, North Shewa, Ethiopia. A Hospital Based Case Control Study

doi:10.21203/rs.3.rs-1822236/v1

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Maternal Risk Factors Associated with Neural Tube Defect at Debre Berhan Referral Hospital, North Shewa, Ethiopia. A Hospital Based Case Control Study

https://doi.org/10.21203/rs.3.rs-1822236/v1

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Background: - Birth defects are congenital anomalies that are present at birth of the neonate, and can be structural, functional, or metabolic. Structural birth defects are those that affect the development of body part. Failure of the neural tube to close at different regions result in positional variations of neural tube defects (NTDs). It is caused through multifactorial disorders, arising from a complex combination of genetic determinants and environmental factors. Therefore, the purpose of this study was to assess the maternal risk factor associated with NTDs among pregnant outcome in Debre Berhan Referral Hospital, North Shewa, Ethiopia.

Methods: - Hospital based unmatched case control study was conducted among 50 cases and 100 controls for associated risk factors of NTDs. The study was carried out at Debre Berhan Referral Hospital from August 30/2017 to August 30/2019. The data was checked for completeness and consistencies, and cleaned, coded and entered using Epi data version 4.2 and was exported to Statistical Package for Social Sciences software version 20 for analysis. Variables having p<0.05 was consider as statistically significant.

Results: - In this study 50 cases and 100 controls were employed. Logistic regression analysis showed that maternal age, <20 (p=0.046), maternal age 31-35 (p=0.028), no education (p=0.014), family history of NTDs (p=0.034), history of multiparous (p=0.002), history of abortion (p=0.024) and still birth (p=0.009), No ANC follow up, unplanned pregnancy (p=0.000), history of medical illness (p=0.001), hyperthermia (p=0.000), used antipyretics drugs (p=0.002), Never use of folic acid and oral contraceptive use (p=0.001), exposure to smoking (p=0.001) and pesticides (p=0.000), and use of local alcohol (p=0.000) had significant association with NTDs.

Conclusions: - Family history of NTDs, coffee and alcohol consumption, maternal no education, maternal hyperthermia and disease, maternal antipyretic use, maternal age <20 and 31-35, exposure to pesticides and smoking were associated with the increasing the risk of NTDs. Comprehensive preventive strategies focused on the identified risk factors should be established and early preconceptional maternal screening for genetic factors and medical illness as well as preconceptional folic acid supplementation are the effective possible approaches to bring about the required reduction in NTDs.

Neural tube defect

Folic acid

maternal factors

Central Nervous System

Birth defects are congenital anomalies that are present at birth of the baby, and can be structural, functional, or metabolic. Structural birth defects are those that affect the development of body part(s). Birth defects usually begin during organogenesis. Birth defects may be visible before birth, at birth or later in life, and are major causes of children’s hospital admissions and deaths (1). Failure of the neural tube to close at different regions results in the clinical variation seen in the anatomical locations of neural tube defects (NTDs). These defects are classified as open and closed type (2). It is caused through multifactorial disorders, arising from a complex combination of genetic determinants and environmental factors (3). Many studies showed that NTD risk is higher among families of lower socioeconomic status (SES). Nutritional deficiency that come through poverty and poverty related problems could predispose these mothers to NTDs during pregnancy (4–6). Maternal age > 35 years (4) and being overweight/obesity was significantly associated with an increase of NTD’s rate (5). Some genetic syndromes such as Trisomy 13, Trisomy 18 and other aneuploidy are thought to be associated with NTDs (6). Folic acid supplementation (7) and maternal obesity were significantly associated with NTDs (8). Other studies showed that maternal reproductive history (history of abortion, still birth, early neonatal loss, multiparty) is associated with increase of risk factors for NTDs (9–11) and chemicals used as pesticides (insecticides, herbicides, and fungicides) can cross the placenta and impact embryonic development.(2). Maternal hyperthermia (MHTN) can arise from either febrile illnesses or external exposure to heat. A recent meta-analysis evaluated that the NTD risk was increased almost three fold in cases of maternal fever during the first trimester.(10, 12). Maternal medical and drug factors such as maternal epilepsy (13) and use of oral contraceptive (14) were associated with neural tube defects. Maternal life style factors such as alcohol consumption, caffeine consumption, smoking and external exposure to tobacco smoke are associated to NTDs. Meta-analyses review show that maternal factors confirms a small increased risk for spina bifida (12). Therefore, the purpose of this study was to assess the maternal risk factors associated with NTDs among pregnant outcome in Debre Berhan Referral Hospital, North Shewa, Ethiopia.

Study Setting and Study Population

Case control study design was conducted and carried from March 1 to August 30, 2019 at Gynecological and Obstetrics ward of Debre Berhan Referral Hospital, North Shewa, Ethiopia. The Hospital was selected purposely based on the availability of patients from all parts of the zone as it use as referral and specialized teaching hospital in North Shewa.

Sample size of the study was calculated, using Epi Info, Stat Calc., and considering 95% confidence level (CI), 80% power, control to case ratio of 2, maternal abortion history of similar study which give large sample size compared to other exposure leads to estimate case exposure status 20% and control exposure status 5%. By considering 5% non-responding rate, calculated minimum sample size was 50 cases of NTDs and 100 controls.

Respondents who could not hear and talk and critically ill during the data collection, and children's admitted with other care giver/other than the mother, cases with any ambiguity or multiple congenital anomalies, gestational age of medically terminated fetus < 12 weeks and a control group with other congenital anomalies other than NTDs were excluded during data collection.

Data collection

All intern doctors, residents, midwives, and clinical nurses informed to report to the principal investigator whenever they encounter suspected cases of NTDs in study period. Data was collected using pretested a semi structured questionnaire. Standard questionnaire was adapted from the WHO birth defect surveillance tool. Five trained BSc midwives conducted face to face interview with parents of the neonates. Respondent got a brief orientation on the purpose of the study and its significance. Before data collection, pretest was done in 10% (15) of the sample size population (5 cases and 10 controls) at Wollo Referral Hospital, which was not include the study area before the actual data collection period and necessary adjustments was done on the study tool.

Data analysis and processing

The data was checked for completeness and consistencies, cleaned, coded and entered using Epi data version 4.2 and was exported to statistical package for social sciences software version 20 for analysis. Odds ratio (OR) with 95% CI was used to assess the relationship between factors associated with the occurrence of outcome variable. Logistic regression model was used mainly multinomial and bivariate logistic regression was done to determine association between each independent variable with outcome variable. Variables having p < 0.05 was consider as statistically significant.

Socio Demographic Factors of Cases and Controls Associated with Neural Tube defect

A total of 150 (50 cases and 100 controls) were included with 100% response rate. As it is shown in the table1; the socio demographic factors, maternal age < 20 (OR = 3.09, CI = 0.95–10.08, P = 0.046), maternal age 31–35 (OR = 0.53, CI = 0.16–1.7, P = 0.028) were strongly associated to risk of neural tube defects. Compare to maternal education of case to control, no education (OR = 2.98, CI = 0.95–9.35, P = 0.014) were significant association with neural tube defects.

Table-1. Socio demographic factors of cases and controls with NTDs at DBRH, North Shewa, Ethiopia, 2020

Variables	Case. N (%)	Control. N (%)	OR	CI (95%)	P- value
Maternal age
< 20 20–25 26–30 31–35 > 35	17 (34)	11 (11)	3.09	0.95–10.08	0.046
	6 (12)	27 (27)	0.44	0.125–1.58	0.210
	11 (22)	14 (14)	1.57	0.47–5.23	0.461
	9 (18)	34 (34)	0.53	0.16–1.70	0.028
	7 (14)	14 (14)	Ref
Maternal educational status
No education Primary school Secondary school Occupational training Diploma/degree /other	16(32)	17 (17)	2.98	0.95–9.35	0.014
	15 (30)	20 (20)	2.37	0.76–7.39	0.136
	11 (22)	24 (24)	1.45	0.45–4.64	0.530
	2 (4)	20 (20)	0.32	0.06–1.77	0.190
	6 (12)	19 (19)	Ref
Maternal occupation
House wife Farmer Factory workers Office workers Others	21 (42)	33 (33)	0.96	0.15–6.19	0.657
	7 (14)	20 (20)	0.53	0.07–3.82	0.961
	14 (28)	7 (7)	3.00	0. 40–22.30	0.525
	6 (12)	36 (36)	0.25	0.03–1.82	0.283
	2 (4)	3 (3)	Ref
Gender of Birth
Female Male	27 (54)	52 (52)	0.58	0.22–1.57	0.287
Female Male	23 (46)	48 (48)	Ref
Birth order
First Second Third and above	12 (24)	41 (41)	0.36	0.21–0.60	0.220
	11 (22)	35 (35)	0.38	0.32 - 0.67	0.440
	27 (54)	24 (24)	Ref
Ref:-Reference point which is given by Logistic regression software

Maternal Reproductive and Genetic Factors Associated with Neural Tube Defects

Family history of NTDs (OR = 4.21, CI = 1.11–15.88, p = 0.034) and history of multiparous (OR = 3.96, CI = 1.60–9.28, p = 0.002) had significant association with NTDs. Regarding abortion (OR = 1.78, CI = 0.68–4.60, p = 0.024) and still birth (OR = 3.92, CI = 1.33–11.51, p = 0.009) were risk factors for NTDs. Mother who had unplanned pregnancy ( OR = 6.29, CI = 2.95–13.44, p = 0.000) and no ANC follow-up were strong significance association with occurrence of NTDs (Table-2).

Table-2. Maternal Reproductive, Obstetric and Genetic history association with NTDs, at DBRH, North Shewa, Ethiopia, 2020.

Variables	Case N (%)	Control N (%)	OR	CI (95%)	P- value
1. Maternal Genetic Factors
1.1 Family Hx of NTDs
Yes	17 (34)	12 (12)	4.21	1.11–15.88	0.034
No	33 (66)	88 (88)	Ref
1.2 Consanguinity
Yes	1(2)	2 (2)	1.00	0.09–11.30	1.000
No	49(98)	98 (98)	Ref
1.3 Hx of NTDs
Yes	10 (20)	3 (3)	6.58	0.91–47.68	0.062
No	40 (80)	97 (97)	Ref
2. Maternal reproductive and obstetric history
2.1 Parity
Nulliparous	12 (24)	42 (42)	Ref
Multiparous	26 (52)	22 (22)	3.96	1.68–9.28	0.002
2.2 History of abortion
Yes	14 (28)	10 (10)	1.78	0.68–4.6	0.024
No	36 (72)	90 (90)	Ref
2.3 History of still birth
Yes	8 (16)	5 (5)	3.92	1.33–11.51	0.009
No	42 (84)	95 (95)	Ref
2.4 History of neonatal loss
Yes	4 (8)	3 (3)	2.81	1.33–11.51	0.170
No	46 (92)	97 (97)
2.5 Planned pregnancy
Yes	21 (42)	82 (82)	Ref
No	29 (58)	18 (18)	6.29	2.95–13.44	0.000
2.6 ANC follow up
Yes	16 ( 32)	78 (78)	Ref
No	34 (68)	22 (22)	7.53	3.53–16.1	0.000
Ref:-Reference point which is given by Logistic regression software; Hx: History

Maternal Medical and Drug History Factors Associated with Neural Tube Defects

A significance risk of NTDs was high among mothers who had history of medical illness (OR = 3.8, CI = 1.75–8.25, p = 0.001), such as history of HTN, hyper/hypothyroidism, UTIs, Epilepsy, and DM and drug use associated to each medical illness (OR = 2.72, CI = 1.94–10.67, P = 0.000). There was a significant difference (OR = 4.65, CI = 1.32–16.43, p = 0.001) between cases (90%) and controls (71%) for never use of folic acid in preconception period. A significantly high risk association was observed for maternal periconceptional oral contraceptive use (OR = 3.4, CI = 1.67–7.05, p = 0.001) (Table-3).

Table-3. Maternal Medical and Drug History factors and NTDs, at DBRH, North Shewa, Ethiopia, 2020.

Variables	Case. N d (%)	Control. N (%)	OR	CI (95%)	P- value
Disease history
Yes No	21 (42)	16 (16)	3.8	1.75–8.25	0.001
Yes No	29 (58)	84 (84)	Ref
Medication taken
Yes No	18 (85.7)	11 (68.75)	2.72	1.94–10.67	0.000
Yes No	3 (14.3)	5 (31.25)	Ref
History of fever
Yes No	37 (74)	17 (17)	13.89	6.12–31.54	0.000
Yes No	13 (26)	83 (83)	Ref
Anti-pyretic use
Yes No	31 (62)	43 (28.7)	11.96	5.21–27.45	0.002
Yes No	19 (38)	88 (71.3)	Ref
Oral contraceptive use
Yes No	26 (52)	24 (24)	3.4	1.67–7.05	0.001
Yes No	24 (48)	76 (76)	Ref
Folic acid consumption
Never Preconceptional intake After 3 months of conception	45 (90)	71 (71)	4.65	1.32–16.43	0.001
	2 (4)	7 (7)	2.09	0.29–15.19	0.464
	3 (6)	22 (22)	Ref
Ref:-Reference point which is given by Logistic regression software

Maternal Environmental Factors Associated with Neural Tube Defects

Among environmental factors considered in this study, maternal pesticide exposure, caffeine use, alcohol consumption and Exposure to Smoking are significantly correlated with NTDs at p < 0.05 (Table-4)

Table 4

Environmental factors and NTDs, at DBRH, North Shewa, Ethiopia, 2020.
Variables	Case N (%)	Control N (%)	OR	CI (95%)	P-value
Sauna/hot bath use
Yes	1 (2)	1 (1)	2.02	0.37–6.15	0.615
No	49 (98)	99 (99)	Ref
Pesticides exposure
Yes	35 (70)	23 (23)	7.81	3.61–16.76	0.000
No	15 (30)	77 (77)	Ref
Radiation exposure
Yes	2 (4)	3 (3)	1.35	0.22–8.33	0.748
No	48 (96)	97 (97)	Ref
Living near to waste disposal
Yes	12 (24)	15 (15)	1.79	0.76–1.79	0.176
No	38 (76)	85 (85)	Ref
Herbal medication use
Yes	14 (28)	16 (16)	2.04	0.90–4.62	0.083
No	36 (72)	84 (84)	Ref
Pre-pregnancy weight
Under weight	7 (14)	52 (52)	1.10	0.16–6.97	0.850
Normal weight	17 (34)	42 (42)	0.932	0.27–5.25	0.954
Over weight	24 (48)	6 (6)	1.21	0.28–6.18	0.787
Obese	2 (4)	0 (0)	Ref
Caffeine taken
Yes	48 (96)	36 (36)	42.67	9.80 -18.98	0.000
No	2 (4)	64 (64)
Alcohol consumption
Yes	35 (70)	20 (20)	9.33	4.28–20.32	0.000
No	15 (30)	80 (80)	Ref
Exposure to Smoking
Yes	25 (50)	23 (23)	3.35	1.62–6.91	0.001
No	25 (50)	77 (77)	Ref
Ref:-Reference point which is given by Logistic regression software

This study was done through unmatched hospital based case control study consisted of 50 case and 100 control of NTDs. Despite that birth defects are major cause of mortalities before five years of age and neural tube defects (NTDs) are one of the most common major birth defects next to congenital heart diseases, adequate surveillance data are needed to develop effective prevention strategies (16). This study revealed that maternal age, < 20 (OR = 3.09, CI = 0.95–10.08, p = 0.046), maternal age 31–35 (OR = 0.53, CI = 0.16–1.7, p = 0.028) were strongly associated to risk of NTDs, but it had age differences study done in Genoa showed that maternal age < 25 years (OR = 3.36) and > 35 years; (OR = 5.21) Italy (17) and Tigray region > 35 years (OR = 2.5, p = 0.0004) (4). Possible correlation can be established between pregnancy at lower age groups < 20 and NTDs risks, this might be due to low socioeconomic status, low educational level, lack of knowledge regarding potential risk factors and preventive measures.

A Hospital based case–control study conducted at Genoa, Italy, showed that maternal low educational level (OR = 4.87) (6) had association to NTDs similar to this study which was no education (OR = 2.98, CI = 0.95–9.35, p = 0.014).

According to this study the maternal reproductive history of abortion 28% (OR = 1.78, p = 0.024), still birth 84% (OR = 3.92, p = 0.009) and multiparous 52% (OR = 3.96, p = 0.002) were associated with mothers whose birth outcome are with NTD, this result is inconsistent with study conducted in Catania, Italy study multiparous (84.8%), spontaneous abortion (21%),and still birth (16%) (18), and somewhat it had similarity in study done in Tigray multiparous (P = 0.000) and three hospitals of Addis Ababa multiparous (p = 0.049) (4, 11).

In this study, maternal hyperthermia was associated to NTDs risk, 74% cases mothers develop fever during early pregnancy (OR = 13.89, CI = 6.12–31.54, p = 0.000) due to different causes. This finding is consistence with other case control studies conducted in California (OR = 2.02)(19), China (OR = 3.36) (20) and Zewditu Referral Hospital, Ethiopia (OR 65.5, CI 4.48–957.9, p = .002) (21). This study also showed that coffee consumption was significantly associated with NTDs risk (OR = 42.67, CI = 9.8-18.98, p = 0.000) which is supported by study conducted in Italy (18) and had similarity in study done in Addis Ababa, Ethiopia (OR 2.49, p = .020) (21). The major caffeine source is coffee. Several studies revealed that coffee consumption during pregnancy can cause abortion, decrease folate absorption and metabolism and disturbed maternal food intakes (22–25).

Regarding to maternal consumption of alcohol (mainly local alcohol “Arki” in the study area around North Shewa) (OR = 9.33, CI = 4.28–20.32, p = 0.000) associated with NTDs and it had consistencies in study done in other area such as Italy (OR = 3.69) (18).

Concerning to maternal exposure to smoking had risk to NTDs ((OR = 3.35, CI = 1.62–6.91, p = 0.001) which is in line with the findings the study done in China (OR = 1.6) (20) and Addis Ababa, Ethiopia (OR 2.49, p = .020) (21).

In conclusion, this study showed that family history of NTDs, coffee and alcohol consumption, maternal no education, maternal hyperthermia and disease, maternal antipyretic use, maternal age < 20 and 31–35, exposure to pesticides, and smoking were associated with increasing risk of NTDs. Comprehensive preventive strategies focused on the identified risk factors should be established and early preconceptional maternal screening for genetic factors and medical illness as well as preconceptional and conceptional folic acid supplementation are the effective possible approaches to reduce the risk of NTDs.

Ethics approval and consent to participate

Ethical clearance was obtained from the Department Research Ethics Review Committee (DRERC), Institutional Review Board (IRB), Addis Ababa University, and Department of Anatomy (ANA/0015/2011, on April 16, 2019). Formal letter or clearance was sent to the Department of Gynecological and Obstetrics of Debre Berhan Referral Hospital to get consent for data collection. Then permission was taken from hospitals higher management. Written Informed consent to participate in the study was taken from each study participants. All the methods were carried out in accordance with relevant guidelines and regulations.

Consent for publication

Not applicable

Availability of Data and Materials

The datasets used and analyzed for this study are available from the corresponding author upon reasonable request.

Conflicts of Interest: The authors declare that they have no conflict of interests.

Funding: This research received no external funding.

Author Contributions

Abay Mulu conceived the study, draft and edit the manuscript and arrange references. Zerihun Kindie develop a proposal and data collection sheet, collect the data, analyzed it and wrote the draft of the manuscript. Samuel Bezabh conceived the study and prepared the tables. Yossef Teshome and Fikre Bayu reviewed and edited the manuscript. All authors read and approved the final draft of the manuscript.

Acknowledgments

The authors would like to extend their deepest appreciation to staff members of Department of Gynecology and Obstetrics of Debre Berhan Referral Hospital for their cooperation, in providing the necessary information for this study. We are grateful to thank Addis Ababa University for facilitating the issue of IRB and writing letters of cooperation to get samples from DBRH and the authors are also very grateful to all the study participants at DBRH.

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No competing interests reported.

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Maternal Risk Factors Associated with Neural Tube Defect at Debre Berhan Referral Hospital, North Shewa, Ethiopia. A Hospital Based Case Control Study

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Abstract

Background

Methods

Study Setting and Study Population

Data collection

Data analysis and processing

Results

Socio Demographic Factors of Cases and Controls Associated with Neural Tube defect

Maternal Reproductive and Genetic Factors Associated with Neural Tube Defects

Maternal Medical and Drug History Factors Associated with Neural Tube Defects

Maternal Environmental Factors Associated with Neural Tube Defects

Discussion

Conclusions

Declarations

References

Additional Declarations

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