Maternal Serum Zinc Deficiency and Low Birth Weight Outcomes

Introduction

One of the most prominent concerns in neonatology is premature births, low birth weight (LBW), and small for gestational age (SGA) births. Infants who present in aforementioned categories of underdevelopment are more likely to demonstrate substantial impairment with regards to levels of cognitive and neuromotor function when compared to infants whose weight is appropriate for gestational age (AGA) (Upadhyay, P., Naik, G., Choudhary, T.S., et al. 2019). Additionally, SGA and LBW infants are at an increased risk for neonate mortality and childhood morbidity. Initial complications associated with LBW include difficulties gaining weight, trouble keeping warm, sudden infant death syndrome (SIDS), and gastrointestinal inflammation often followed by necrosis. Long-term complications or risks associated with preterm LBW include but are not limited to sensory deficits (blindness or deafness), cognitive developmental delays, hypertension, diabetes, and asthma (Chang, H., Sung, H., et al, 2015). Being of LBW is classified as weighing less than 2500g at the time of birth. VLBW refers to weight being below 1500g at time of birth (Chang, 2015).

Research shows a positive trend and increase in LBW infants throughout Canadian populations. In the year 2000, 5.6 percent of all live births were classified as LBW, compared to 2017 that same statistic rising to 6.5 percent of all births. During the same time period, the average birth weight dropped 2.6 percent from 3,413grams to 3,327 grams (Statistics Canada, 2018). This affects a rather large population demographic in Canada and its healthcare costs are significant. A Canadian study conducted between 2006 and 2007 shows preterm LBW newborn hospitalizations cost on average 19,463$ and were typically 21.2 days in duration. Whereas AGA hospitalization costs on average 1011$ and were on typically 2.1 days in duration (Gillian Lim, Jacinth Tracey, Nicole Boom, Sunita Karmakar, Joy Wang, Jean-Marie Berthelot and Caroline Heick, 2009).  Although these statistics are from 2007, the gap between cost for preterm LBW care and AGA care is astronomical and still persists today in 2019. In order to reduce the risk of LBW complications, maternal prevention strategies need to be put in place as the behavior and habits of an expecting mother have the ability to influence certain fetal growth and birth outcomes.

Intrauterine growth restriction (IUGR) is a known precursor for LBW and SGA. There are various contributing factors and indicators of an infant’s birth weight. The mother’s age is one indicator as research shows geriatric pregnancies (mothers between the ages of 35-40) are more inclined to deliver preterm infants of LBW compared to mothers of prime reproductive age (Statistics Canada, 2016). Additionally, parity has been found to influence birth weight, first-order infants are more inclined to be of LBW than those of second-order (Hinkle, S. N., Albert, P. S., Mendola, P., Sjaarda, et al. 2014). One of the most influential factors would be the mother’s prenatal care and physical condition. Maternal pneumonia, hypertension, tobacco exposure, placental nutrient insufficiencies as well as genetics can be risk factors for LBW outcomes.  Zinc is a necessary element required during early development for cell growth and differentiation. Studies have shown adverse infant outcomes resulting from maternal dietary zinc deficiencies (Wang.H, et al., 2015).  Although there are many determinants of LBW, this systematic review will question the effects of maternal dietary Zinc deficiency on infant birth weights and growth restriction.

Methods

Research Strategy

A literature review conducted from November 4th until November 17th presented authors with numerous relevant online scientific journals and studies from sources including but not limited to PubMed NCIB, ScienceDirect, Statistics Canada, and Pediatric Journals. Key phrases and vocabulary were used to search for relevant scholarly articles on each database, including: “pregnancy”, “pregnant”, “zinc deficiency”, “maternal alimentary zinc deficiency”, “low birth weight”, “Small for gestational age”, and “intrauterine growth restriction”.  To ensure novelty of this literature review, filters for each database and search engine were used so ensure only scholarly articles published within the last ten years were included. The author of this review primarily examined the methods section of each study in order to determine if all inclusion criteria were met. 

Inclusion Criteria

All literature included in this study had to be written in English and available online inclusively. Only cohort studies such as double-blind randomized trials, cross sectional studies and case control studies were used (including dose-finding trials). Studies utilizing animal data were not included in this review. Furthermore, each study which was consulted had to be peer reviewed in order to maintain a certain degree of legitimacy and accuracy. Each study’s results must present and assess maternal zinc serum levels as well as the infants initial birth outcomes (preterm, LBW, neonate serum zinc levels). The exposure variable was maternal serum zinc levels during pregnancy measured in [μg/dL], and the outcome variable was the weight of the newborn infant classified as: low birth weight ( >2500g) , very low birth weight (>1500g), or AGA ( <2500g). Both aforementioned variables must be central to each study in order to be included in this review. Data extraction included maternal zinc serum levels (normal: [≥56 μg/dL] and low: [<56 μg/dL]), fetal serum Zinc levels were retrieved and analyzed from the Methods and Results sections of each study (Wang, H. et al. 2015). Additional maternal information such as socioeconomic class, smoking habits, and BMI were additionally looked at in each study.  Principal summary measures for assessing LBW outcomes and maternal serum zinc levels (both sufficient and deficient) include incidence and relative risk. Certain studies additionally used mean and standard deviation as primary measurements.

Results

While conducting research, exclusion criteria was required in order to generate and pick the most relevant studies for this review in an efficient manner. The original search on the scholarly database NCIB PubMed generated 187 results. The results were further screened by excluding all papers written before November 2009, 74 results remained. All studies regarding animal data or written by veterinary institutions were excluded. Studies which did not address fetal growth restriction and effects of maternal zinc deficiency throughout each gestational stage of pregnancy as well as initial birth outcomes were excluded.  Search results were further refined to solely include those of which were peer-reviewed cohort studies such as RCTs or clinical trials. Following preliminary screening, fourteen articles remained. Of the fourteen articles, eight were excluded as their variables and outcomes focused on infants after birth and throughout their first year(s) of life and development. One was additionally excluded as it focused on risk of preterm birth associated with Zinc deficiency and not LBW or IUGR.  Five studies remained and met the preset inclusion and exclusion criteria.

Study Outcomes

Of the five studies included in this review, three found a strong and significant association between maternal zinc deficiency and increased rates of neonate LBW and zinc deficiency. Additionally, the three studies determined zinc to be a strong indicator of preterm birth and SGA as zinc is known to impact many body processes such as intrauterine growth, fetal development and cell differentiation (Upadhyay, P., Naik, G., 2019).

Sabra.S, et al. studied the impacts of heavy metal exposures on fetal growth restriction. They conducted a cohort study and found when maternal placental cord serum zinc levels were low, they were predisposed to higher rates of LBW outcomes compared to mothers with sufficient placental cord serum zinc levels. Researchers tested mothers who had IUGR complications and found they were usually deficient in zinc, presenting with 935 (μg/dL) on average, whereas mothers who had not experienced IUGR complications presented with an average serum zinc level of 1181 (μg/dL). Their data also concluded AGA fetuses had on average zinc serum levels around 1518 (μg/dL) in comparison to fetuses who experienced IUGR who had average serum zinc measuring around 935 (μg/dL) at birth (Sabra, S. et al. 2017). Wang, H. et al. found similar results in their population-based cohort study. They concluded dietary maternal zinc deficiency during pregnancy (particularly during the first trimester) significantly elevates the risk of LBW and SGA infants. They additionally identified an association between serum zinc and placental inflammation. Researchers conducting this study identified the incidence rate of LBW and SGA infants born to zinc deficient mothers to be 7.3% of total births, whereas the incidence rate of LBW infants born to zinc sufficient mothers was 2.2%. The adjusted relative risk (rr) of LBW outcomes for zinc deficient mothers was found to be 3.41 comparative to a rr of 1.0 for mothers sufficient in zinc (Wang, H. et al 2015). The third study that found a statistically significant association was Jyotsna, S. et al. 2015. Their study consisted of one hundred mother/ newborn pairs. 46 were LWB neonates and 54 were AGA neonates. Mothers of the LBW neonate group presented with very low serum Zn levels (67.02±15.99 μg/dl), comparative to  the mothers of AGA neonates (83.59±18.46 μg/dl) (p= <0.05). The study found a strong correlation between low maternal Zn levels, low fetal zinc levels and increased risk of LBW outcomes (Jyotsna, S. et al. 2015).

Two out of the five studies showed minimal or no significant correlation between maternal zinc levels and LBW outcomes. Prawirohartono, E.P. et al 2012 conducted a double-blind randomized control trial on the impact of prenatal vitamin A and zinc supplementation. Their study population was 2173 pregnant women and they assessed fetal birth outcomes. Their study concluded that zinc supplementation improved neonate length at birth (48.8cm on average) whereas the non-supplemented or placebo group showed no improvement on neonate length (48.2cm on average). This study was one that showed minimal or no significant association between neonate weight and maternal serum zinc (Prawiroharton, E.P. et al., 2012). Sorouri, Z. et al. conducted a study in Iran on the birth outcomes of mothers who had taken Zinc supplements from the 16th week of gestation until delivery. Their randomized control trial concluded with similar results to that of Prawirohartono, E.P. et al., that the mean difference in birth weight between the zinc supplemented group and the non-supplemented group was insignificant (p= 0.863) therefore the researchers could not accept that zinc had a significant impact on birth weight outcomes (Sorouri, Z., et al. 2015).

Discussion

Of the five relevant studies depicted in this review, three found significant correlations between the exposure and outcome variable. Two out of the five dismissed any correlation and found no significant association between variables. This mixed bag of results proves a need for further observational studies and testing to determine a definite relationship between variables. LBW neonates are more susceptible to further complications and are at increased risk for morbidity and SIDs which can affect future quality of life (Chang, H, 2015). Their care and hospital stays can become expensive, so it is critical all methods of LBW prevention are explored and accurately tested. Although there were differing results between the reviewed studies, commonalities in key findings exist. It was universally confirmed in each study that Zinc deficiencies can lead to fetal IUGR which can cause complications such as growth retardation. All studies took into account and used strategies to control externals factors such as maternal BMI, and location. Each study followed the pregnant women until delivery, taking serum samples from both neonate and mother. 

Control testing for a pregnant population demographic is difficult and opens the study up to a multitude of bias.  It becomes difficult to account for the behavioral habits of the mom during the study. When it comes to RCTs or observational control studies, researchers will never be able to achieve a complete degree of control (as they would in a laboratory) because of external variables and influences. This can impose bias and put the validity of the study’s results into question. Another possible source of bias is sample size. Both Sabra. S., et al. (2017) and  Jyotsna, S. et al. (2015) had miniscule sample populations (less than 200 participants) which was a substantial limitation. Both of these small-scale studies found the strongest associations between exposure and outcome variables. The two largest studies Wang, H., Hu, Y.F., et al. (2015), and Prawiroharton, E.P. et al. (2012) acquired over 2100 participants and concluded with miniscule results and weak variable associations. Bias can also stem from lack of confounder identification. Each study set up controls for external factors and possible confounders, however perhaps not all were identified. For example, Sabra. S. et al. did not adjust for pollution levels in the area of study or account for any additional supplements the mother may be on.

Hospital stays and treatment of LBW and VLBW neonates is increasingly expensive and difficult. Figuring out whether LBW outcomes can be influenced by maternal micronutrient or trace-element supplementation would be cost effective and would limit complications for fetuses and mothers. This would be of the utmost importance to provincial government officials as it could save healthcare systems money and reduce stress on hospitals. It would also be of interest to those who create prenatal care supplements as well as the transgressional guidelines for their usage.

It is difficult to form a general interpretation of the results of this literature review as there were mixed results presented throughout each study. Overall, there is some evidence of LBW rate reduction with adequate levels of maternal serum zinc. Of course, additional studies and research should be conducted in order to confirm a tangible relationship between the two variables.  This is a novel topic of research of which there are still many unanswered questions and lots of potential for improved prenatal care.

References

Chang, H., Sung, H., et al (2015). Short- and Long-Term Outcomes in Very Low Birth Weight  Infants with Admission Hypothermia. PubMed NCIB, doi:  10.1371/journal.pone.0131976.  https://www.ncbi.nlm.nih.gov/pubmed/26193370

Collins, A., Weitkamp, J. H., & Wynn, J. L. (2018). Why are preterm newborns at increased risk   of infection?. Archives of disease in childhood. Fetal and neonatal edition, 103(4),    F391–F394. doi:10.1136/archdischild-2017-313595

Gillian Lim, Jacinth Tracey, Nicole Boom, Sunita Karmakar, Joy Wang, Jean-Marie Berthelot and Caroline Heick. (2009) CIHI Survey: Hospital Costs for Preterm and Small-for-Gestational Age Babies in Canada. Healthcare quarterly. doi:10.12927/hcq.2013.21121

Hinkle, S. N., Albert, P. S., Mendola, P., Sjaarda, L. A., Yeung, E., Boghossian, N. S., & Laughon, S. K. (2014). The association between parity and birthweight in a longitudinalconsecutive pregnancy cohort. Paediatric and perinatal epidemiology, 28(2), 106–115.doi:10.1111/ppe.12099 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3922415/

Jyotsna, S,. et al. (2015) Study of Serum Zinc in LowBirth Weight Neonates and Its Relation with Maternal Zinc. NCIB. doi: 10.7860/JCDR/2015/10449.5402 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4347141/

Prawiroharton, E.P. et al. (2012) The Impact of Prenatal Vitamin A and Zinc Supplementation of Birth Size and Neonatal Survival. NCIBPubMed. doi: 10.1024/0300-9831/a000141. https://www.ncbi.nlm.nih.gov/pubmed/24220161/

Sabra. S., et al. (2017). Heavy Metals Exposure Levels and Their Correlation with Different Clinical Forms of Fetal Growth Restriction. NCIB PubMed doi: 10.1371/journal.pone.0185645https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5630121/

Sorouri, Z. et al. (2015) The Effect of zinc Supplementation on Pregnancy Outcome : A Randomized Control Trial. Reproductive Health Research Centre, Alzahra hospital. Doi: 10.3109/14767058.2015.1079615. https://www.ncbi.nlm.nih.gov/pubmed/26365330

Statistics Canada (2019) Low Birth Weight Newborns in Canada, 2000 to 2013). Minister of Industry, 2016. Catalogue no. 82-625-X. https://www150.statcan.gc.ca/n1/pub/82-625-x/2016001/article/14674-eng.htm

Statistics Canada (2018). Births, 2017.Component of Statistics Canada Catalogue No. 11-001-x https://www150.statcan.gc.ca/n1/en/daily-quotidien/ 180928/dq180928c-eng.pdf?st=KGQ4wcEe

Upadhyay, P., Naik, G., Choudhary, T.S., et al. (2019) Cognitive and Motor Outcomes in Children Born Low Birth Weight: a Systematic Review and Meta-Analysis of Studies From South Asia. BMC PEDIATR 19,35. DOI: 10.1186/S12887-019-1408-8 https://bmcpediatr.biomedcentral.com/articles/10.1186/s12887-019-1408-8#citeas

Wang, H., Hu, Y.F., et al. (2015) Maternal zinc Deficiency During Pregnancy Elevates the Risks of Fetal Growth Restrictions: a Population Based Cohort Study. PMID: 26053136 doi: 10.1038/srep11262 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4459238/