How Does B12 Deficiency of Mothers Affect Their Infants?

AUTHORS

Hikmet Gulsah Tanyildiz 1 , * , Sule Yesil 1 , Iclal Okur 2 , Deniz Yuksel 3 , Gurses Sahin 1

1 Dr. Sami Ulus Maternity and Children’s Education and Research Hospital, Pediatric Hematology Oncology, Ankara, Turkey 06080

2 Dr. Sami Ulus Maternity and Children’s Education and Research Hospital, Pediatrics, Ankara, Turkey 06080

3 Dr. Sami Ulus Maternity and Children’s Education and Research Hospital, Pediatric Neurology, Ankara, Turkey 06080

How to Cite: Tanyildiz H G, Yesil S, Okur I, Yuksel D, Sahin G. How Does B12 Deficiency of Mothers Affect Their Infants?, Iran J Pediatr. 2017 ; 27(5):e12898. doi: 10.5812/ijp.12898.

ARTICLE INFORMATION

Iranian Journal of Pediatrics: 27 (5); e12898
Published Online: October 22, 2017
Article Type: Research Article
Received: May 9, 2017
Revised: July 26, 2017
Accepted: August 14, 2017
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Abstract

Background: Vitamin B12 cannot be synthesized in the body and it is essential for growth and development in humans.

Objectives: To evaluate the vitamin B12 levels between the mothers and their infants who presented to the Pediatric Hematology outpatients department due to the symptoms of vitamin B12 deficiency. We also compared the effects of low B12 levels in both the mother and the child, compared to the effects of normal B12 levels in the mother and low levels in the child.

Methods: We enrolled 303 children aged 2 - 18 months between January 2013 and September 2015. Patients with a vitamin B12 level < 200 pg/mL in both the mother and the child and patients with a B12 level that was low in the child and normal in the mother were compared.

Results: The birth weight of the children was low in the group where the B12 level of both the mother and the child (n = 163) was low and presentation to the clinic with neurologic signs and symptoms such as tremor, restlessness, seizure, hypotonia, and macrocephaly not related to another etiologic reason was common (P < 0.05). A remarkable finding was the simultaneous low levels of vitamin B12 in the mother in 55 of the 69 children who presented with neurological symptoms (P < 0.05). A generalized or focal epileptic pathology was found in the EEGs and MR images including retardation in myelination, demyelination, atrophic findings or ventricular dilatation in children whose mothers have B12 deficiency simultaneously.

Conclusions: It is difficult to explain such complicated clinical pictures due to malnutrition especially in developing countries. Detecting and treating vitamin B12 deficiency early in mother and child is very important in prevention of potential irreversible neurological problems.

Keywords

Vitamin B12 Infancy Clinical aspects

Copyright © 2017, Iranian Journal of Pediatrics. This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License (http://creativecommons.org/licenses/by-nc/4.0/) which permits copy and redistribute the material just in noncommercial usages, provided the original work is properly cited.

1. Background

Vitamin B12 cannot be synthesized in the body and is essential for growth and development in humans; therefore, vitamin B12 must be supplied by diet. B12 deficiency that is related to insufficient red meat consumption or malabsorption can be seen in adults; however, this deficiency can be tolerated in adults and the symptoms take a long time to manifest. The most important reason for infant vitamin B12 deficiency is maternal B12 deficiency. For example, the babies of vegetarian mothers and those with intestinal malabsorption or a cobalamin transport defect will be born with deficient B12 storage, and the deficiency symptoms can therefore appear within the first 6 months of life (1-5). In older children, other factors may be associated with vitamin B12 deficiency, such as the absence of animal derived foods or fortified foods, a vegetarian diet, low socio-economic level and infection by gastrointestinal parasites (6).

Vitamin B12 deficiency mainly affects the central nervous system (due to its rapid mitotic activity), the hematopoietic system, and the gastrointestinal system. Vitamin B12 is especially involved in essential functions of the central nervous system, such as DNA synthesis, the homocysteine methylation cycle, and neurotransmitter synthesis. B12 is therefore important for enabling central nervous system functions, and it is not surprising that central nervous system deficits appear in vitamin B12-deficient infants. B12 deficiency can cause growth retardation, neutropenia, skin lesions, frequent infections, tremors, irritability, hypotonia, and seizure, among other symptoms (7-11). Simultaneous investigation of the mother and infant especially an infant breastfed by a mother with vitamin B12 deficiency is important for the early detection of vitamin B12 deficiency and initiation of nutritional support before significant neurological symptoms develop. We, therefore, first aimed to evaluate the vitamin B12 levels between the mothers and their infants who presented to the pediatric hematology outpatients department due to the symptoms of vitamin B12 deficiency. We also compared the effect of low B12 levels in both mother and child, compared to that of normal B12 levels in the mother and low levels in the child.

2. Methods

2.1. Study Population and Study Design

We enrolled 303 mother-infant pairs who presented to the pediatric hematology outpatients department from January 2013 to September 2015. The study design was cross sectional. A structured questionnaire was administered through face-to-face interview to the mothers. It included demographic characteristics (child’s sex, age, etc), socio-economic status, history of breastfeeding, frequency of habitual food intake, and birth weight of the infant. Accompanying presenting symptoms and signs (growth retardation, loss of appetite, frequent infection, hypotonia, irritability, and seizures) were also queried. EEG and MR evaluations were performed for patients with neurological signs and symptoms and results registered. Those with a different underlying chronic disease such as a metabolic, hematologic or neurologic disorder were excluded. Group 1 represented low B12 levels in both the mother and child while Group 2 represented normal B12 levels in the mother and low levels in the child. We compared two groups in terms of presenting signs and symptoms. Approval from the ethics committee and consent from the families were obtained.

2.2. Anthropometric Assessment

Anthropometric measurements (presentation weight, height, head circumference) were performed by trained pediatric assistants following standardized procedures using calibrated equipment. Among children aged < 24 months, recumbent length was measured using a locally made infant measuring board; weight was measured with an electronic pediatric scale. Each measurement was repeated and the mean value was calculated.

2.3. Biochemical Measures

Peripheral smear, blood count, and serum vitamin B12, folic acid, homocysteine, iron and LDH levels were evaluated for the diagnosis of B12 deficiency. Blood B12 levels of the mothers of the same patients were also determined at the time of diagnosis. Approximately 5 mL of fasting venous blood was collected from mother-infant pairs by nurses. Serum folate and vitamin B12 concentrations were measured using the method of direct chemiluminescence (ADVIA Centaur XP, SIEMENS Immunoassay). This method offers high sensitivity and is less costly, easier to implement and safer than microbiological, chromatographic or spectrophotometric assays (12). A level of 200 pg/mL was identified as the cut-off B12 level.

2.4. Statistical Methods

Data analysis was performed using the SPSS for Windows 15 package software (Chicago, IL; SPSS, ©2006). Descriptive statistics were presented as the mean ± standard deviation for variables with a normal distribution and as the median (minimum - maximum) for variables without a normal distribution. Nominal variables were presented as the number of patients and percentages.

When there were two groups, the significance of the difference between mean values was evaluated using student’s t test and the significance of the difference between median values was evaluated using the Mann-Whitney U test. Categorical variables were compared with dependent variables using Logistic Regression analysis. A P value < 0.05 was accepted as statistically significant.

3. Results

There were 190 (62.7%) male and 113 (37.3%) female patients. The age range was 2 month to 18 months (median = 7 months). The mean B12 level was 127.34 ± 31.153 (45 - 199) pg/mL in the mothers and 150.72 ± 32.43 (45 - 196) pg/mL in the children when the B12 level was under 200 in both the patient and the mother (Group 1). The mean B12 level was 283.81 ± 81.52 (200 - 600) pg/mL in the mothers and 158.07 ± 29.38 (46 - 199) pg/mL in the children when the B12 level was normal in the mother but low in the child (Group 2). The mean birth weight was 2778 ± 625 (1000 - 4280) gr in the group 1, and 2986 ± 545 (1300 - 4200) gr in the group 2 (P = 0.001) (Table 1).

Table 1 . Mean B12 Levels and Birth Weights in Group 1 and Group 2a
Patient B12 Level pg/mL, Mean ± SD (Range)Mother B12 Level pg/mL, Mean ± SD (Range)Birth Weight (gr), Mean ± SD (Range)
Patient < 200 pg/mL150.72 ± 32.43127.34 ± 31.1532778 ± 625
Mother < 200 pg/mL(45 - 196)(45 - 199)(1000 - 4280)
Patient < 200 pg/mL158.07 ± 29.38283.81 ± 81.522986 ± 545
Mother ≥ 200 pg/mL(46 - 199)(200 - 600)(1300 - 4200)

aP value = 0.001; Group 1, The B12 level was under 200 in both the patient and the mother; Group 2, The B12 level was normal in the mother but low in the child.

No significant relationship with vitamin B12 level was found in terms of weight, height and head circumference at the time of diagnosis. The presenting symptoms of the patients were anemia in 62.3% (n = 189) patients, seizure in 9.9% (n = 30), hypotonia in 7.9% (n = 24), growth retardation in 4.3% (n = 13), tremor in 0.7% (n = 2), irritability in 2% (n = 6). The presenting signs were macrocephaly in 2.3% (n = 7), dermatitis in 2.3% (n = 7), frequent lower respiratory tract infection in 1.3% (n = 4), loss of appetite in 0.3% (n = 1), and pica in 0.3% (n = 1) patients. Neutropenia in 5.9% (n = 18) and thrombocytopenia in 0.3% (n = 1) patients were observed (Table 2). Anemia, neutropenia and thrombocytopenia improved following vitamin B12 treatment. A total of 55 children presented with neurological symptom in Group 1, but these symptoms were manifested in only 14 children in Group 2 (P = 0.000). The neurologic signs and symptoms were macrocephaly (n = 6), irritability (n = 6) and tremor (n = 2) in Group 2 whereas neurologic signs and symptoms were mostly seizure (n = 30), hypotonia (n = 24) and macrocephaly (n = 1) which were more complex in Group 1. The clinic distribution of the 30 patients with seizure was generalized tonic clonic seizure in 18, generalized tonic seizure in 6 and simple partial seizure in 6 patients. EEG abnormalities were found in 12 patients; generalized epileptic activity was observed in 9 of them and focal epileptic activity in 3. A total of 69 patients with neurologic symptoms in both Group 1 and 2 underwent a MR evaluation, and 55 of these patients were in Group 1. Retardation in myelination (n = 18), demyelination (n = 4), thinning of the corpus callosum (n = 16) or ventricular dilatation (n = 7) findings were present on MR in Group 1 patients. No pathological findings were found in the remaining 10 patients (Table 3). Patients presented with macrocephaly (n = 6), irritability (n = 6) and tremor (n = 2) in Group 2. MR findings included ventricular dilatation (n = 3), retardation in myelination (n = 2) and normal (n = 9) results (Table 4). The logistic regression test revealed a close to significant or significant relationship in terms of low birth weight (P = 0.069) (OR; 1.0, 95% CI (0.99 - 1.0)), breastfeeding (P = 0.058) (OR; 2.27, 95% CI (0.972 - 5.333)) and frequent neurological signs and symptoms (P = 0.000) (OR; 4.1, (95% CI 2.11 - 7.96)) in Group 1 (Table 5).

Table 2. Clinical Symptoms, Signs and Results of investigation at Presentation in Group 1 and Group 2a
Patient < 200 pg/mL, Mother < 200 pg/mLPatient < 200 pg/mL, Mother ≥ 200 pg/mLTotal
Anemia89 (54.6%)100 (71.4%)189 (62.4%)
Neurological symptoms55 (33.7%)14 (10.0%)69 (22.8%)
Growth retardation3 (1.8%)13 (9.3%)16 (5.3%)
Increased infections3 (1.8%)1 (0.7%)4 (1.3%)
Dermatitis3 (1.8%)4 (2.9%)7 (2.3%)
Neutropenia10 (6.1%)8 (5.7%)18 (5.9%)
Total163 (100%)140 (100%)303 (100%)

aP Value = 0.009.

Table 3. Neurologic Signs and Symptoms at Presentation in Group 1 Patients
No.SymptomsType of SeizureEEG ResultsMR Results
1SeizureGTCGEARetardation in myelination
2SeizureGTCGEADemyelination
3SeizureGTCGEAAtrophy of corpus callosum
4SeizureGTCNormalAtrophy of corpus callosum
5SeizureGTCNormalRetardation in myelination
6SeizureGTCNormalVentricular dilatation
7SeizureGTCNormalAtrophy of corpus callosum
8SeizureGTCGEADemyelination
9SeizureGTCGEAVentricular dilatation
10SeizureGTCNormalRetardation in myelination
11SeizureGTCNormalVentricular dilatation
12SeizureGTCNormalRetardation in myelination
13SeizureGTCNormalNormal
14SeizureGTCGEAAtrophy of corpus callosum
15SeizureGTCNormalAtrophy of corpus callosum
16SeizureGTCNormalAtrophy of corpus callosum
17SeizureGTCGEAVentricular dilatation
18SeizureGTCNormalVentricular dilatation
19SeizureGTFEARetardation in myelination
20SeizureGTNormalRetardation in myelination
21SeizureGTNormalNormal
22SeizureGTGEADemyelination
23SeizureGTNormalNormal
24SeizureGTGEAAtrophy of corpus callosum
25Seizuresimple partialNormalAtrophy of corpus callosum
26Seizuresimple partialFEANormal
27Seizuresimple partialNormalRetardation in myelination
28Seizuresimple partialFEANormal
29Seizuresimple partialNormalRetardation in myelination
30Seizuresimple partialNormalAtrophy of corpus callosum
31Hypotonia--Normal
32Hypotonia--Retardation in myelination
33Hypotonia--Atrophy
34Hypotonia--Retardation in myelination
35Hypotonia--Retardation in myelination
36Hypotonia--Demyelination
37Hypotonia--Normal
38Hypotonia--Atrophy of corpus callosum
39Hypotonia--Retardation in myelination
40Hypotonia--Normal
41Hypotonia--Atrophy of corpus callosum
42Hypotonia--Atrophy of corpus callosum
43Hypotonia--Retardation in myelination
44Hypotonia--Retardation in myelination
45Hypotonia--Atrophy of corpus callosum
46Hypotonia--Normal
47Hypotonia--Retardation in myelination
48Hypotonia--Retardation in myelination
49Hypotonia--Atrophy of corpus callosum
50Hypotonia--Ventricular dilatation
51Hypotonia--Normal
52Hypotonia--Retardation in myelination
53Hypotonia--Atrophy of corpus callosum
54Hypotonia--Retardation in myelination
55Macrocephaly--Ventricular dilatation

Abbreviations: FEA, focal epileptic activity; GEA, generalized epileptic activity; GT, generalized tonic; GTC, generalized tonic clonic.

Table 4. Neurologic Signs at Presentation in the Group 2 Patients
Patient No.Neurologic SignsMR Results
1MacrocephalyNormal
2MacrocephalyVentricular dilatation
3MacrocephalyNormal
4MacrocephalyNormal
5MacrocephalyVentricular dilatation
6MacrocephalyVentricular dilatation
7IrritabilityNormal
8IrritabilityRetardation in myelination
9IrritabilityNormal
10IrritabilityNormal
11IrritabilityNormal
12IrritabilityRetardation in myelination
13TremorNormal
14TremorNormal
Table 5. Logistic Regression Results with OR and P Value
OR95% CIP Value
LowerUpper
Birth weight1.000.9991.0000.069
Breastfeeding2.270.9725.3330.058
Neurologic signs4.102.1137.9610.000

4. Discussion

Optimal vitamin B12 status during infancy is important for many aspects of child health, growth and development. Infants are dependent on the mother for vitamin B12 during pregnancy and while breastfeeding. B12 is transmitted from the mother to the infant especially through the transplacental route and stored in sufficient quantities to meet the needs of the child during the first 12 months. The symptoms of deficiency are therefore usually not seen in the initial 6 - 12 months of life in a healthy child; therefore, deficiency in the first 6 - 12 months only occurs in infants with maternal vitamin B12 deficiency (1, 13, 14). B12 deficiency not treated during pregnancy can lead to growth retardation, hypotonia, important neurological and functional losses in infants, and the symptoms can be permanent if only detected at a late stage (15).

Prevention of common vitamin deficiencies in the first two years of age is an important priority for developing countries. The relatively low concentrations of plasma vitamin B12 in younger infants identified by this study may be due to low maternal intake of vitamin B12 rich foods during pregnancy and lactation. Cultural beliefs and food taboos restrict intake of foods that are rich in vitamin B12 during pregnancy and breastfeeding, and low consumption of meat, fish and other animal source foods may also cause poor maternal nutritional status during pregnancy and breastfeeding. Furthermore, the relatively low coverage of vitamin B12 supplementation in younger children (6 to 12 months) may also contribute to the low concentrations of plasma vitamin B12 reported in this population (16).

Some studies suggest that vitamin B12 deficiency and marginal deficiency are highly prevalent worldwide and vitamin B12 deficiency is also of public health concern. Vitamin B12 deficiency may be more prevalent in vegetarians, vegans, and people living in low-income communities where they may have limited purchasing power to acquire animal food sources or may not have access to fortified foods or supplements (17, 18). Koc et al. found B12 deficiency in 41% of newborns in the Southeastern Anatolia Region of Turkey where B12 deficiency is common (5). They emphasized that detecting B12 deficiency and its early treatment in the regions where the socioeconomic level is low is important to prevent any developmental sequelae that could develop in the baby. Vitamin deficiency during pregnancy in the mother has similarly been reported to affect the infant starting in the intrauterine period in many studies (19, 20).

Although there is no complete consensus regarding the normal cut-off level of vitamin B12, we accepted < 200 pg/mL as the cut-off in laboratory evaluations (21). We found vitamin B12 deficiency in 163 (53%) mothers of the 303 patients who were diagnosed with B12 deficiency under the age of two years. The most important characteristics in the group with low B12 level in both the mother and infant was the low birth weight of the infants (P = 0.001). Similar results are reported in different studies because the B12 deficiency of the mother during pregnancy may lead to many metabolic and neurological problems starting with the intrauterine period and especially low birth weight in the newborn (22, 23).

The vitamin B12 levels in breast milk and the mother are parallel in the lactation period and sufficient B12 cannot be obtained from breast milk (the most important B12 source of the infant) when the mother has B12 deficiency (24). We found that 274 children had received breast milk regularly during the first 3 - 6 months; breastfeeding was not regular and formula was started early in the other 27 patients. We found a high rate (91%) of breastfeeding in the group with low vitamin B12 levels in both the mother and the child in our study (P = 0.058). The deficiency in the mother affects the baby during the intrauterine period at the first stage and complicated clinical pictures can be encountered if the deficiency is not treated during the breast feeding period.

The cells that are mostly affected by vitamin B12 deficiency are the central nervous system cells with rapid mitotic activity. The clinical findings include lethargy, apathy, hypotonia, tremor, and convulsions. In individuals with B12 deficiency, methylmalonyl-CoA accumulates and is used in the synthesis of fatty acids instead of acetyl-CoA. This results in unstable myelin that degrades more easily and negatively affects the brain development and cognitive performance of growing children (25).

The exact mechanism underlying neurological deficits in Vitamin B12 deficiency is not clearly understood. However, vitamin B12 deficiency is thought to cause imbalance between the growth factors influencing the central nervous system and neurotoxic cytokines, and increased lactate, glutamate and excitatory amino acids (26-28). Therefore, epilepsy is triggered and EEG abnormalities are manifestations of vitamin B12 deficiency in pediatric patients. Several studies currently exist describing an association between vitamin B12 deficiency and EEG abnormalities and epilepsy (29-34). We encountered central nervous system signs and symptoms especially in rapidly growing infants in the early period between 2 and 18 months. A remarkable finding was the simultaneous low levels of vitamin B12 in the mother in 55 of the 69 children who presented with neurological symptoms (P < 0.05). The presenting signs and symptoms of these 55 patients were seizure, hypotonia, and macrocephaly. The type, severity and duration of involuntary movements related to vitamin B12 deficiency varies considerably. In this study seizures types were generalized tonic clonic, generalized tonic and simple partial. EEG evaluations of the 30 infants revealed generalized epileptic activity in 9 and focal activity in 3. Atrophy of corpus callosum, retardation in myelination, demyelination areas and ventricular dilatation findings were seen on the MR images. Cortical atrophy, hypoplasia of the corpus callosum, delayed myelination, and ventricular dilatation are the most common neuroradiological findings in the literature (3, 30, 31, 34). Patients only presented with macrocephaly, irritability and tremor and we did not observe any seizure in the group where B12 levels of mothers were normal. MR findings were mostly normal apart from ventricular dilatation and demyelination. Neurologic findings were more severe and complex in the group where B12 levels were low both in the mother and infant rather than the group where B12 levels normal in mother. The fact that neurological symptoms can be detected before the emergence of megaloblastic anemia symptoms is critical for clinicians. The rate of presentation with neurologic findings but without anemia was high in studies conducted on adults. Anemia may not be a presenting symptom or its rate can be lower than other symptoms (2, 9, 35). However, the most common symptom in this study was anemia (62.4%) followed by neurological findings (22.8%). Although there is no clear consensus regarding the treatment of vitamin B12 deficiency, we administered vitamin B12 parenterally to our patients as recommended. The dose was 100 µg per day for 7 days, 100 µg per week for 4 weeks, and then 100 µg per month for 3 months (1, 36). The mothers were also prescribed vitamin B12 parenterally. The head circumference of 3 of the 7 patients that had presented with macrocephaly was within the normal percentile range during follow-up. Those who showed the fastest response to vitamin B12 treatment were the hypotonia and tremor patients. The seizures did not recur, and the antiepileptic drugs were discontinued during the follow-up with vitamin B12 treatment in patients who had experienced a generalized tonic clonic seizure. No other complications were observed during a median follow-up duration of 1 year (6 months to 2.5 years).

Detecting B12 deficiency and starting treatment early is important for preventing irreversible symptoms. B12 deficiency in mothers particularly is a risk factor in infants developing neurologic symptoms, thus mothers should be checked after delivery and during lactation as well as their infants. Nutritional deficiency patients can present with confusing signs and symptoms such as macrocephaly or microcephaly, hypotonia, tremor, irritability, and seizure that can make things difficult for the clinicians and require further investigations for the differential diagnosis. Physicians should be aware that attempts to solve the problem should start during pregnancy, and a social consciousness needs to be developed to prevent B12 deficiency. It is known that irreversible complications can develop if the diagnosis and treatment of B12 deficiency are delayed. Early screening of blood vitamin B12 levels will obviously improve the health of mother and child and make things easier for clinicians.

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