Abstract
Aluminum is a neurotoxic element that enters the human body due to its widespread usage in daily life. It has the potential to affect the neurological development of the fetus and infant adversely. This study aimed to evaluate the relationship between maternal and umbilical cord serum aluminum level and infant neurodevelopment. Over a period of March 2018 to September 2019, we conducted a prospective cohort study; 173 Mother-new-born pairs were enrolled. Aluminum levels were measured using Inductively Coupled Plasma Optical Emission Spectrometry (ICP-OES). The correlation with Bayley Scales of Infant Development (BSID) -3rd edition score and maternal and cord serum aluminum were assessed via linear regression model. The mean concentration of maternal and cord serum aluminum was 2.58 ± 1.14 µg/dL and 1.44 ± 0.62 µg/dL, respectively. There was a significant correlation in aluminum level between maternal and umbilical cord serum (Pearson’s r = 0.591, p < 0.000). There is no significant correlation between maternal and serum aluminum level, and BSID-3rd edition (cognitive, motor, language, and social-emotion) score at the average age of 6.5 months. In conclusion, maternal and cord serum aluminum levels were significantly correlated but did not correlate with infant neurodevelopment. Thus, low serum aluminum concentration and their association with child neurodevelopment deserve further investigation longitudinally in a large cohort.
Graphical Abstract
Supplementary Information
The online version contains supplementary material available at 10.1007/s12291-021-01002-y.
Keywords: Umbilical cord, maternal, Serum, Aluminum, Neurodevelopment, Infant
Introduction
Human exposure to aluminum from various sources is widespread and potentially entered into the biotic cycle. The typical exposure sources are aluminum-based cosmetics, food packaging, herbal and hygiene products, aluminum cookware, and antiperspirants [1]. Aluminum, known as a defined neurotoxic metal, enters the human body and is deposited in various body parts, including the brain [2]. Aluminum can increase the blood–brain barrier's permeability by changing its ultrastructure and occludin and F-actin expression [3], allowing aluminum to reach the central nervous system. Aluminum can cross the placental barrier during pregnancy, and, in utero, development is a period of organogenesis and increased hormonal activity; aluminum showed an adversarial effect [4, 5]. A recent study has investigated toxic metals, including aluminum exposure, as a potential cause of miscarriage [6]. The impact of prenatal toxic metal exposure might persist long after birth and adversely affect other life stages of neurological development [7].
The growing fetus is at an increased risk of aluminum toxicity during intrauterine and prenatal life due to its immaturity related to anatomical and physiological factors [1]. Despite this, prenatal exposure to aluminum during pregnancy has not been studied in detail in humans. Nevertheless, research evidence reinforces the well-accepted vulnerability of the growing unborn infant and may have adverse neurodevelopment effects in the early and late-life stages.
The neurological consequences of aluminum exposure induce behavioral changes, reduce mental development index performance and encephalopathy [8–11]. However, literature is scarce regarding prenatal aluminum exposure and its association with infant neurodevelopment in early infancy. Therefore, this exploratory study aimed to assess whether prenatal aluminum and cord blood aluminum concentration correlated with infant neurodevelopment (cognitive, motor, language, and social-emotional domain) of an infant at early infancy.
To the best of our knowledge, this is the first study that examines prenatal and umbilical cord blood’s aluminum concentration at low levels and its correlation with infant neurodevelopment in a cohort of Rajasthan, India.
Material and Method
Participants and Recruitment
One-seventy-three (173) mother–child pairs residing in western Rajasthan, India, were included in this prospective cohort study. Mothers were at least 19 years of age, without a history of smoking, drug abuse, drug addiction, serious health issues, or pregnancy complications like twin gestation, congenital malformations. All mothers were enrolled in their third trimester or at the time of admission to the hospital for delivery at All India Institute of Medical Sciences (AIIMS) Jodhpur. A study researcher explained the study's objectives, and the written informed consent was obtained from the volunteer mother after their routine checkup.
Maternal Interview and Medical Record Abstraction
A pre-defined questionnaire was used to record detailed information on obstetric and birth outcomes. Complications during pregnancy and delivery, the health status of the newborn child, were noted. A standard protocol was used to measure newborns' and mother's anthropometry. Maternal anthropometric measures were recorded after delivery. Among these 173 mother-pairs, 117 infants (67.2%) completed the neurodevelopmental assessment at an average of 6.5 months of age. The primary characteristics of the study samples are shown in Table1. The maternal body mass index (BMI) was calculated as the post-pregnancy weight divided (in kilograms) by the square of height (in meters).
Table 1.
Obstetric, birth variable of the study population
| Characteristics N = 173 | Mean (SD) | Range |
|---|---|---|
| Maternal age (years) | 25.4 (3.8) | 19–38 |
| Maternal weight (kg) | 65.0 (9.8) | 42.9–95.0 |
| Maternal height (cm) | 158.3 (6.1) | 143–187 |
| Maternal BMI | 25.9 (3.9) | 16.50–39.50 |
| Gestational age (weeks) | 38.8 (1.3) | 34.3–41.6 |
| Birth weight (g) | 3098.5 (408.7) | 2086–4080 |
| Birth length (cm) | 48.3 (0.8) | 46–50 |
| Birth head circumference | 34.1 (1.4) | 30–37.1 |
| Birth chest circumference | 33.5 (1.6) | 28–38 |
| Sex (% female) | 51.8 | |
| Parity | ||
| 0 | 59.4 | |
| 1+ | 40.6 |
| Concentration of Aluminum (µg/dL) | Mean (SD) | Range | GM | 95%CI |
|---|---|---|---|---|
| Mother (n = 173) | 2.58 (1.14) | 0.70–8.70 | 2.37 | 2.36; 2.80 |
| Umbilical cord (n = 173) | 1.44 (0.62) | 0.35–5.65 | 1.20 | 1.37; 1.56 |
Maternal and Umbilical Cord Serum Aluminum Concentration
Aluminum estimation was carried out by diluting 0.5 mL of serum sample with three-fold ultrapure MilliQ water (18.2 MΩ.cm). The diluted serum sample was analyzed to detect aluminum concentration using ICP-OES (Prodigy 7, Teledyne Leeman Labs, USA).
The serum aluminum level was measured in axial mode at 396.156 nm wavelength. The calibration was performed using 2.5, 5.0, 10.0, 20.0, 40.0 and 80.0 µg/dL concentration standard of aluminum. The calibration curve fitting was linear (R2 = 0.999). For quality control, the commercial reference material “ClinCheck serum controls for trace elements" level 1 and level 2 were used for quality assurance of the aluminum determination. Quality control level 2 was analyzed with every analytical run in the interval of 20 samples for the result's accuracy. The limit of detection (LoD), limit of quantification (LoQ) was 0.35 µg/dL and 0.57 µg/dL, respectively. Quantification was free of analytical interference, and the average recovery rate was 92 to 106%.
Infant’s Neurodevelopmental Evaluation
The infant’s cognitive, motor, language, and social-emotion domains of neurodevelopmental were assessed using the BSID-III at an average age of 6.5 months. The test was performed on 117 children by the trained Bayley researcher. Before starting to evaluate neurodevelopment, it was ensured that the infant was sober and not hungry. Each infant was assigned a composite score of a particular domain (cognitive, language, motor, and social-emotion) of BSID-III. The preterm baby's age (birth that occurs before the 37th week of pregnancy) was adjusted before performing the test. The cutoff point for differentiating normal development and for development delay was a score of 70.
Statistical Analysis
The study participants' obstetric and birth outcomes were reported using means, standard deviation, and range. The Kolmogorov–Smirnow test was used to assess the distribution of the data. The distribution composite scores were calculated by mean, standard deviation. The infant neurodevelopment delay was measured in percentage (%). The umbilical cord and maternal serum aluminum concentration were calculated by mean, standard deviation, range, geometric mean (GM), and 95% confidence interval (CI).
To assess the possible relationship between maternal and umbilical cord blood Pearson's correlation coefficient was calculated. In addition, we constructed separate linear regression models for each of the four outcomes to assess the association of umbilical cord and maternal serum aluminum levels with infant cognitive, motor, language, and social-emotional domains of neurodevelopment. Their neurodevelopment outcomes were considered as dependent variables and aluminum level as the independent variable. The obtained data were analyzed using the Statistic Package for the Social Sciences for Windows V21.0 (SPSS Inc., Chicago). a p-value of < 0.05 was considered statistically significant."
Results
Obstetric and Birth Outcome of the Study Participant
Table 1 describes the obstetric and birth outcome of the study samples. In this baseline (n = 174), the average maternal age was 25.4 ± 3.8 years. Maternal anthropometry; average height, weight was 158.3 ± 6.1 cm and 65.0 ± 9.8 cm, respectively. The average BMI of the mother was 25.9 ± 3.9. 59.4% of mothers were primiparous. The average gestational age of the mother at the time of delivery was 38.8 ± 1.3 weeks. The newborn weight, length, and head circumference, chest circumference were 3098 ± 408.7 g, 48.3 ± 0.8 cm, 34.1 ± 1.4 cm, and 33.5 ± 1.6 cm, respectively. Among the infants, 51.8% were female.
Maternal and Umbilical Cord Serum Aluminum Levels
In the study cohort, the average aluminum level in maternal serum was 2.58 ± 1.15 µg/dL with geometric mean (GM) 2.37 µg/dL with 95% confidence interval (CI): 2.36–2.80, range; 0.70–8.70 µg/dL. The mean aluminium concentration in umbilical cord serum was 1.44 ± 0.62 µg/dL with GM of 1.20 µg/dL with 95% CI: 1.37;1.56, range; 0.35–5.65 µg/dL. Detail is given in Table 1. There was a significant correlation in aluminum level between maternal and umbilical cord serum (Pearson’s r = 0.591, p < 0.000), i.e., as the maternal concentrations of aluminum increase, the cord blood aluminum levels also tend to increase (Supplementary Fig. 1). Linear regression modal also showed significant positive correlation with β coefficient 0.591 (95% CI: 0.801, 1.362), p-value 0.000.
Neurodevelopmental Outcome of Infants
Table 2 shows the distribution of BSID-III scores of the infants. One hundred seventeen infants had a developmental assessment at 6.5 months of age. The standardized mean of the composite score for the cognitive, motor, language, and social-emotion domains were 105 ± 14.0, 124 ± 11.1, 108.7 ± 12.4, and 74 ± 10.5, respectively. The development delay frequency was 0% in the language domain, with a degree of 0.8% in motor, 1.7% in cognitive, and 11% in the social-emotional domain.
Table 2.
Distribution of the BSID-III composite scores for 117 infants aged 6.5 months of age
| Neurodevelopmental domains | Mean ± SD (range) | Normal* (n (%)) | Development delay** (n (%)) |
|---|---|---|---|
| Cognitive | 105.0 ± 14.0 (65–135) | 115 (98.3) | 2 (1.7) |
| Motor | 124 ± 11.1 (91–148) | 116 (99.2) | 1 (0.8) |
| Language | 108.7 ± 12.4 (70–138 | 117 (100) | 0 (0) |
| Social-emotion | 74 ± 10.5 (55–115) | 104 (89) | 13 (11) |
*Normal, > 70
**Development delay, ≤ 70
Relationship of Maternal and Umbilical Cord Aluminum Concentration with Infants Neurodevelopment
Table 3 shows the association of umbilical cord and maternal blood’s aluminum concentration with child neurodevelopment at 6.5 months of age. Maternal and cord serum aluminum concentration was not associated with the composite score of any of four (cognitive, motor, language, and social-emotional) developmental domain scores of BSID-III.
Table 3.
Association between the umbilical cord and maternal serum aluminum concentration and score of BSID-III at 6.5 months of age
| Neurodevelopmental domains (n = 117) | Aluminium ug/dL | |||
|---|---|---|---|---|
| Mother’s blood | Umbilical cord blood | |||
| β (95% CI) | p-value | β (95% CI) | p-value | |
| Cognitive | 0.087 (− 0.12, 0.345) | 0.331 | − 0.029 (− 0.756, 0.546) | 0.734 |
| Motor | 0.169 (− 0.009, 0.574) | 0.061 | 0.127 (− 0.239, 1.404) | 0.181 |
| Language | 0.128 (− 0.080, 0.446) | 0.168 | 0.139 (− 0.157, 1.300) | 0.103 |
| Social-emotion | 0.037 (− 0.256, 0.330) | 0.701 | − 0.004 (− 0.906, 0.867) | 0.925 |
Discussion
This research study has explored the correlation of cord serum aluminum and maternal serum aluminum with neurodevelopment of infants from western Rajasthan, India. The maternal serum aluminum concentration was higher than the cord blood serum. No correlation was found with the neurodevelopment of children. The obtained concentration of serum aluminum was higher than the recommended reference level. According to Agency for Toxic Substance and Disease Registry (ATSDR), Atlanta, USA, serum aluminum levels in a healthy individual (not in pregnant mothers) range from 0.1 to 0.3 µg/dL. Aluminum level <5.0 µg/dL is considering toxic [12]. No safe reference ranges are mentioned for pregnant women.
There was a statistically significant correlation between maternal and cord serum aluminum levels. Separate linear regression analysis concludes neither maternal nor cord serum aluminum levels were associated with a score of BSID-III of cognitive, motor, language, and social-emotional developmental domains. These results are similar to those reported by the Karwowski et al. [13]; blood aluminum level 1.54 µg/dL was not correlated with a composite score of BSID-3rd Edition at 9–12 months of age. Recent evidence shows that the infant's nail aluminum level was associated with low fine motor development at six months of age [14]. One previous study reported the adverse neurodevelopment effect of aluminum exposure among premature infants [10].
Epidemiological evidence from a cohort of pregnant women in the 3rd trimester belonging to the coastal region of South African [15] had a mean serum aluminum level of 1.1 µg/dL, which is lower than our observation. Rahbar et al. [16] characterized serum aluminum concentration in cord blood (mean level 1.09 μg/dL), which is close to our finding. However, in both of these studies, the neurodevelopment of the child was not measured.
We have characterized the prenatal aluminum concentration and its correlation with the infant's neurodevelopment (cognitive, motor, language, and social-emotional domains) at 6.5 months of age. As a strength of the study, evidence on prenatal aluminum exposure and its association with infant neurodevelopment is scarce in literature from India. A trained Bayley researcher with a senior phycologist and pediatrician measured infant cognitive, motor, language, and social-emotional developmental domains. As per our knowledge, this is the first study on the correlation between serum aluminum level of the maternal and umbilical cord and infant neurodevelopment in early infancy from India.
Conclusions
The present study has evaluated the serum aluminum level in pregnant women in the third trimester and newborn umbilical cord. The scientific consensus indicates that aluminum has a toxic effect in all the development stages, even at low concentrations. Furthermore, as aluminum is known to cross the placental barrier, a pregnant mother should avoid pre-and post-natal aluminum exposure to prevent adverse effects on the fetus and newborn. From a public health perspective, low prenatal aluminum exposure and their correlation with infant neurodevelopment deserve further investigation over a longer period of time.
Supplementary Information
Below is the link to the electronic supplementary material.
Acknowledgements
The authors express their gratitude to all study participants, their relatives, staff of Pediatrics, Obstetrics and Biochemistry, AIIMS Jodhpur. Special thanks to the Director of AIIMS Jodhpur for Institutional support and to Director Defence Laboratory Jodhpur, Defence Research and Development Organization (DRDO), for providing the ICP-OES facility. We also thank Dr. Akhil Kumar Goel from AIIMS Jodhpur for guidance in statistical analysis.
Funding
No financial support was received for this study.
Data Availability
All data are presented in the manuscript.
Declarations
Conflict of Interest
The authors have no conflicts of interest.
Ethical Approval
The study protocol was approved by the Institutional Ethics Committee of the institution. And the study was performed in accordance with the approved protocol.
Footnotes
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Contributor Information
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Supplementary Materials
Data Availability Statement
All data are presented in the manuscript.