PEDIATRICS Vol. 106 No. 4 October 2000, pp. 774-781

The Tagum Study I: Analysis and Clinical Correlates of Mercury in Maternal and Cord Blood, Breast Milk, Meconium, and Infants' Hair

Gloria B. Ramirez, MD, MHA^*, Ma. Cristina Vince Cruz, MD^*, Olive Pagulayan, MS STAT, Enrique Ostrea, MD^§, and Crispin Dalisay, MD

From the ^* Neonatology Division, Philippine Children's Medical Center, Quezon City, Philippines;  School of Statistics, University of the Philippines, Manila, Philippines; ^§ Department of Pediatrics, Wayne State University, and Department of Pediatrics, Hutzel Hospital, Detroit Michigan; and  University of the Philippines, Philippine General Hospital, Manila, Philippines.

	ABSTRACT

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Objectives.  To compare the indicators and levels of mercury (Hg) exposure in the mother with those in the fetal compartments, and determine its effects on the newborn.

Methods.  Hg levels using atomic absorption spectrophotometry were determined in maternal blood, breast milk, cord blood, infants' hair, and meconium of 78 consecutive mother-infant pairs in a community with high Hg pollution. The prevalence and levels of Hg both in meconium and in cord blood were correlated with maternal and infant risk factors.

Results.  The prevalence of Hg in the fetal compartments was higher than in the maternal fluid compartments. Hg was present in 6.4% of maternal blood and 6.4% of breast milk, as compared with 16.7% of cord blood, 31.6% of infants' hair, and 46.1% of meconium. Forty-six percent of infants with Hg in cord blood had none in meconium, whereas 80.6% with Hg in meconium had none in cord blood. Hg was not present in the maternal blood of all infants (n = 36) with Hg in their meconium. Among those with detectable Hg, the mean levels were: mothers' blood 24 parts per billion ± 5.47, cord blood 53.3 parts per billion ± 37.49, and meconium 48.6 ± 43.48. Quantitative measurement in hair was not done because of insufficient sample. Paired comparisons were all significant between Hg levels in the mothers' blood and meconium, mothers' blood and cord blood, and cord blood and meconium. Regression analysis showed Hg levels in meconium to be correlated with prevalence of Hg in infants' hair, length of stay in Tagum, and meconium-stained amniotic fluid. Fisher's Exact probability test showed that the prevalence of Hg in meconium was significantly related to the prevalence of Hg in the mothers' blood and length of stay in Tagum. The prevalence of Hg in cord blood was significantly related to the prevalence in the mothers' blood. Regression analysis of levels of Hg in cord blood showed a significant relation to levels in mothers' blood (.0001), prevalence in infants' hair (.0126), gestational age (GA) (.0091), and head circumference (HC) (.0469). By quadrant analysis of weight against HC in 66 full-term infants all of 4 infants weighing an average of >3000 g at birth and with HCs lower than the fifth percentile had Hg in meconium.

Conclusion.  The higher prevalence and levels of Hg in the fetal compartments reflect the ease of placental transfer with fetal trapping. Hg determinations in the mothers' blood underestimate the degree and extent of fetal exposure. There is a significant difference in each compartment's ability to reflect Hg exposure of the fetus. A small HC may be associated with the presence of Hg in meconium. Hg in meconium should be measured in addition to cord blood to determine the load of fetal Hg.  Key words:  maternal-fetal Hg transfer, Hg in meconium.

The evolution of an environmental disaster attributable to the unregulated use of mercury (Hg) by small-scale miners in Tagum started in the early 1980s. To extract the gold, ores mined from the surrounding mountains were processed in Apokon Valley, Tagum, by ball milling, mixing with Hg to form an amalgam, followed by roasting, releasing mercury vapor (Hg°). In 1986, sporadic cases of Hg poisoning were reported at the height of the gold rush. By 1989, levels as high as 1664 (SD 855) µg per cubic meter of air were reached in the valley where there are no airflows (N. C. Maramba and E. Torres. A cross sectional study of the health impact of mercury exposure among workers in gold processing in Davao del Norte, unpublished data, July 1989, College of Public Health Library, University of the Philippines). The upper limit for occupational exposure is 100 µg per cubic meter with a time weighted average of 50 µg per cubic meter, as above this level,^1-5 classic signs of Hg toxicity are observed. Eighty percent of inhaled Hg is taken up by the alveoli.¹

The waste water from processing operations is stored in tailings ponds. Impounded materials are washed into the main tributary draining Tagum, especially during rains and floods. In 1989, water samples from this river were below the national limits of 2 µg/L for receiving bodies of water and the 5 µg/L for effluents because the Hg in waste water quickly fell downstream. However, continuous dumping into the river system, estimated at 140 tons of methyl mercury (MeHg) flux by 1999,⁴ resulted in large quantities of inorganic Hg in the river sediment where organisms change the inorganic Hg to organic Hg, which then is biomagnified, and is ingested by fish that are ingested by humans at the top of the food chain. About 80% to 100% of organic Hg is absorbed by the gastrointestinal tract, but much of this is subsequently secreted in bile.¹

A recent study by Akagi⁴ in 1999 (1 year after our sample collection) showed that water samples from the river had increased to a level of 78.4 µg/L, exceeding the national standards for both receiving bodies of water and effluent. Sediment samples from the river system contained .155 to 1.36 µg/g weight. The acceptable standard in The Netherlands is .3 µg/g. Hg levels in a market basket sampling of fish in Apokon ranged from 1.07 parts per billion (ppb) to 438.8 ppb, which were all within the recommended US Food and Drug Administration's standards of 500 ppb for Hg content. However, the levels in the fish samples exceeded the environmental criteria of the World Health Organization for Hg concentrations in fresh water fish from nonpolluted areas of 100 to 200 ppb.^3,4

The problem of exposure to Hg in this area is particularly serious for the pregnant women because there are no barriers to the transfer of Hg from the mother to the fetus. Both MeHg and vapor of inorganic Hg (Hg°) pass easily through the blood-brain barrier^5,6 and the placenta.^6-10 Maternal ingestion of contaminated fish,^1,11,12 pork,^13,14 or bread^15-17 resulted in microcephaly, cerebral palsy, seizures, and mental retardation^9,10 in the infants reported. Epidemic brain damage has also been described in infants of mothers with little or no evidence of toxicity.¹⁵

In the West, exposure is generally at a low level and results primarily from Hg containing dental amalgam fills. In this population, Hg blood levels are directly related to the number of amalgam fillings. Furthermore, maternal blood levels, breast milk levels, as well as tissue levels of Hg in fetuses and infants who died of unrelated causes correlated significantly with the number of amalgam fillings in mothers.^18,19 Currently, the pathophysiologic significance of constant low level exposure through continuous Hg release from amalgam fillings remains a focus of international research.

Studies on paired maternal and cord blood Hg levels^{2,5,6,18,19,21} and on meconium²⁴ of infants of mothers who have no known exposure to Hg reveal measurable levels in mothers and infants pointing to the ease of Hg transfer through the placenta. There were however no simultaneous determination of levels in other fetal compartments.

Unlike all previous investigations, this is the first study to determine Hg in maternal blood and breast milk, cord venous blood, hair, and meconium, to demonstrate the toxicodynamics of Hg. Aside from determining what adverse effects are present at birth, the study was also done to determine the importance of levels of Hg in meconium vis a vis other compartment levels.

Participants

All of the participants lived within a 5 km radius from Apokon Valley. Drinking water is from piped in spring water, and/or well water. The community primarily eats fish and vegetables. Hg exposure of pregnant women therefore is from the atmosphere, polluted drinking water, and contaminated plant and animal food sources, with fish being the major source of dietary Hg. Seventy-two percent of the mothers were housewives, while the rest were teachers and office workers. There were no smokers, alcohol drinkers, and none had diabetes mellitus. Informed consent was obtained. The mothers were examined by the attending obstetrician and one of the authors (C.D.) using standard physical examination and basic neurologic examination. No clinical signs of nervous system pathology defined as mental retardation, tremors, ataxia, seizures or mild paresthesias were found. Each participant was interviewed and completed a questionnaire that included demographic data (age, parity, job, length of stay in current residence, categorized by <5 and >5 years of stay), past medical and obstetric history (eg, incidence of premature rupture of membranes [PROM], meconium-stained amniotic fluid [MSAF], hypertension, and hemorrhage). The infants' data included sex, Apgar scores (1 and 5 minutes), anthropometric measurements and outcome (sepsis, jaundice, asphyxia, seizures, tremulousness, hypoglycemia) in the first 48 hours.

	METHODS

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This was a prospective cohort study evaluating the long-term effects of Hg exposure in Tagum. We present the baseline data as a cross-sectional study of 78 mothers who delivered consecutively from September to October 1997 in Davao Regional Hospital located in Tagum, together with their infants.

Handling of Samples and Measurement of Hg

One of the authors (C.D.) stayed in Tagum during the study for the collection of samples. At delivery, blood was withdrawn from the antecubital vein of the mother into heparinized glass vacuum tubes (Becton Dickinson, Muntinlupa, Philippines). The presence or absence of MSAF was noted at delivery. After hand-washing, disposable latex gloves (Qualatex, Malaysia) were used for the collection of each sample. About 5 mL of venous blood was extracted from the double-clamped umbilical cord and put into the same type of vacutainer tubes (Becton Dickinson). A single brand of disposable diapers (Pampers, Proctor and Gamble Philippines Inc, Makati, Philippines) were given to the mothers and meconium from 1 diaper was transferred to rubber-stoppered autoclaved vials using individually packed tongue depressors as soon as passed. Five to six strands of hair were obtained from the newborns' occiput using sterile scissors. Hair samples were wrapped in Saran Glad Wrap (Life System Medical Distributor, Philippines) and stored dry until analysis. Breast milk was squirted directly into plastic milk sample containers using manual expression by the mother after hand-washing. Containers were immediately sealed. When necessary, mothers who were discharged <24 hours after delivery were followed at home for breast milk collection. All infants were examined within 30 minutes of delivery and again at 24 to 36 hours. All the liquid samples and meconium were frozen immediately and transported to the National Science Research Institute in Manila in a frozen state and kept in a 20° freezer until analysis.

Atomic absorption spectrophotometry (AAS) was used to analyze all samples. AAS measures total Hg to a minimum concentration of 2 ppb. The procedure involves oxidative digestion, wet ashing, followed by reduction, aeration, and measurement of Hg° absorption through the quartz cell of an AAS. The procedure is free from interference from organic matter or other volatile constituents of the sample. This method is rapid with high sensitivity and specificity.^7,20,21 Internal quality control standards using mercuric chloride were run with each determination.

Statistical Analysis

To test for significant difference in Hg levels between maternal and infant compartments, paired t test was used. Descriptive statistics were applied to all variables. Frequencies and cross-tabulations were constructed for categorical or binary data namely: infant sex, Hg prevalence in different compartments, length of stay in Tagum, demographic factors in mother, ie, gravidity, abortion, civil status, mode of delivery, incidence of PROM, MSAF, and prenatal check-ups. Percentages were used to summarize prevalence. Cross-tabulation tables were constructed to establish relationships with Hg prevalence in meconium and cord blood, and Fisher's Exact probability test was used for 2 level categories and the ² test for cross tabulation with variables with >2 levels.

Statistical measures (mean and standard deviation) were computed for continuous data namely: maternal age, length of stay in Tagum, Hg levels in various compartments, and anthropometric measurements in the infants.

Correlation coefficients were computed to establish relationships between continuous variables. The Pearson Product Correlation coefficient was used for variables that demonstrate linear relationships, while Spearman Rank Correlation was used for nonlinear, nonnormal variables. To determine which variable would affect Hg levels when taken all together, linear regression was performed. The dependent variable was Hg level while the independent variables were maternal and infant indicators. The binary variables were treated as dummy variables.

The regression model for Hg level in meconium was not developed further because it was not significant (P = .1062). However, the result that there were 3 significant variables (MSAF, length of stay and prevalence of Hg in infants' hair), all being dummy variables, were noted and interpreted. The regression model for Hg level in cord was significant (P = .0012). However, development of the model was not pursued because only 16.7% of the participants had Hg in cord blood. More participants and more variables should be included in further studies to develop a predictive model for both.

	RESULTS

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Prevalence of Detectable Hg Levels

Measurable amounts of Hg (6.4%) were detected in the mothers' blood. Hg prevalence was higher in the fetal compartments, with meconium having the highest at 46.15%, and cord blood, the lowest at 16.7% (Fig 1). All the mothers of the 36 infants with Hg in meconium had no Hg in their blood. The presence of Hg in the mothers' blood was significantly associated with the absence of Hg in meconium (P = .04). Six of 13 (46%) cord blood samples positive for Hg had no Hg in meconium, while 29 of 36 (80.6%) positive in meconium were negative in cord blood. The prevalence in the 2 compartments were not found to be associated (P = .379).

View larger version (25K): [in this window] [in a new window]   Fig. 1.   Y-axis: percent positive for Hg.

There were no significant associations between Hg in meconium and demographic factors in the mother, specifically, age, abortions, marital status, prenatal check-up, and hypertension. However, there was a higher prevalence of detectable levels of Hg in meconium (P = .027) among those who stayed in Tagum for <5 years (16/36) as compared with those who stayed for >5 years (9/42). The mothers who have lived in Tagum >5 years had a significantly higher gravidity than those who stayed <5 years (2.88 vs 1.99; P = .03).

The following infant risk factors namely, GA, PROM, mode of delivery, Apgar score, and presence of sepsis were not significantly associated with the presence of Hg in meconium. There was no association of MSAF with maternal demographic factors. The presence of cord blood Hg was significantly related to the presence of Hg in the mothers' blood (P = .03).

Hg Levels

Among those positive for Hg, levels were highest in cord blood (53.3 ppb ± 37.49) and in meconium (48.6 ppb ± 43.48). Quantitative measure of Hg in hair was not performed because of inadequate sample size. The mothers' blood concentration was lowest (24 ppb ± 5.47). Breast milk level was 36 ppb ± 18.16 (Table 1). The paired comparisons between the levels of Hg in meconium and the mothers' blood revealed significant differences in level as measured in the 2 compartments (P = .001). Likewise, the level in cord blood was significantly higher than in the mothers' blood (P = .0068). The Hg levels in cord blood was significantly higher than the levels found in meconium (P = .01).

Regression analyses of maternal demographic and infant risk factors were performed to search for predictors of levels of Hg in meconium (Table 2). However, only MSAF (P = .0064) was significantly related to levels of Hg in meconium. The mothers' length of stay (.0495) and prevalence in infants' hair (P = .0405) indicated a negative relationship with Hg levels in meconium.

Because we wanted to determine any clinical effects of Hg in the fetus, we investigated the relationship of prevalence of Hg in meconium and neonatal head circumference (HC) above and below the 10th percentile for Filipino full-term newborn infants. On cross tabulation, we did not find a significant association between the two. Similarly, regression analysis did not reveal any significant association. However, a plot of weight against the HC in the 66 full-term infants was made (Fig 2). The 12 infants who were <38 weeks old were excluded in the quadrant analysis because the only figures available in Filipinos are for full-term infants. The quadrants were set at a HC of 31 cm as the vertical dividing line and weight of 3000 g as the horizontal dividing line, representing the 5th percentile and 50th percentile, respectively, for the full-term Filipino newborn.²² Quadrants 2 and 4 show proportional HC and weight values. Quadrant 3 shows an equal number of positive and negative Hg in meconium in infants with high HC and low birth weight. On the other hand, quadrant 1 shows that all 4 infants weighing >3000 g at birth and with HCs lower than the 5th percentile had Hg in meconium.

View larger version (14K): [in this window] [in a new window]   Fig. 2.   Plot of weight and head circumference. , Positive for Hg. , Negative for Hg. HC in cm, weight in g.

Regression analysis for cord blood showed a positive relationship to HC and Hg levels in the mothers' blood but negative relationships with GA and prevalence in infants' hair (Table 3).

	DISCUSSION

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The risk for fetal exposure to Hg is a cause for concern because of the increasing amount of Hg in the environment attributable to anthropogenic activities, natural emissions from oceans, and geological sources. Hg in the atmosphere can circulate up to a year and therefore be widely dispersed from its sources of emission. Hg in aquatic environs is methylated by bacteria and enters the food chain.^12,26,27 Even after it is deposited on the earth's crust, Hg reenters the atmosphere in association with particles and is redeposited elsewhere on the earth's crust in a continuous cycle. The annual global input to the atmosphere from all sources is 5500 tons, with the United States contributing 3% of this. One third or 52 tons is deposited within the US, while two thirds or 107 tons are transported outside the United States where it diffuses into the global reservoir.^27,28 The magnitude of emissions and deposits of Hg, a substance known for its fetotoxicity, are alarming. Both MeHg and Hg° easily pass through the blood-brain barrier and placenta.^7,28 Furthermore, environmental pollution usually involves >1 toxin,^24,26,28 which when absorbed by the fetus can work singly or in a concerted fashion to produce adverse fetal effects.

Epidemics of MeHg poisoning in Japan, Iraq, and Russia from ingestion of fish and contaminated grain demonstrated that neurotoxicity occurs in the developing fetus^11-17,29 In the whale-eating community of the Faroe Islands, subtle neurologic deficits in infants and children have been reported in a large long-term study even without symptoms in the mother^28,29 In the Seychelle Island study, where fish contain the same level of Hg as fish found in the United States, no adverse neurodevelopmental effects were noted in 779 children followed for 29 months despite the presence of detectable Hg of <50 to >300 ppb in 32 brains of autopsied infants who died of unrelated causes.^30,31

Evidence of fetal exposure in mothers with no known Hg exposure in the literature are based on paired maternal and cord blood measurements. The maternal mean values ranged from 1.15 ppb to 25 ppb with corresponding higher mean cord blood levels (Table 4).

The simultaneous exposure to environmental inorganic Hg through inhalation and/or to organic Hg through dietary intake among pregnant women in Tagum serves as an excellent natural laboratory for the study of Hg transfer from maternal blood to breast milk, and to cord blood, neonatal hair, and meconium. The levels that we obtained in this setting were considerably higher than the levels reported in the literature in mothers with no known Hg exposure (Table 4). We also sought out to determine if Hg in meconium may serve as a better representation of the fetus' true Hg load.

All 78 mothers had no signs of neurologic impairment. Both the prevalence of detectable Hg and the concentrations in the maternal compartment were lower than in the fetal compartments. The human fetus with a developing brain at its most vulnerable stage, carries a heavier tissue burden at exposure levels that do not produce overt clinical reactions in the mother. It is also remarkable that no Hg was detected in he maternal blood of the 36 infants with Hg in meconium. The mother of the infant with the highest cord blood level of 130 ppb had no Hg in her blood. Therefore determinations on the mothers' blood will significantly underestimate the extent and degree of fetal exposure.

Although cord blood Hg levels showed a correlation with maternal blood levels the cord blood concentration of Hg was higher than in maternal blood. This may be secondary to the oxidation of Hg into polar compounds by the placenta, which prevents its reentry into maternal circulation.^6,13

There was no correlation in the prevalence of detectable Hg in meconium and cord. There was 1 infant of a 21-year-old G1P1 mother who had stayed in Tagum for >5 years with a high Hg level of 200 ppb in meconium. This infant had no measurable level in cord blood. The GA was 41^5/7 weeks, HC was 31 cm (<5th percentile), weight 2.7 kg (25th percentile).²² Another infant, born of a 23-year-old G1P1 mother who lived in Tagum for <5 years had a Hg meconium level of 200 ppb with no detectable Hg in cord blood. GA was 42^6/7 weeks, HC was 34 cm (<10^th percentile), weight was 3800 g (95th percentile).²²

The prevalence of Hg was much higher in meconium (46% vs 16.7%; P < .0495) than cord blood and there was no significant correlation between the prevalence of Hg in meconium and cord blood. This finding is not surprising, because toxins in the blood are in a constant, dynamic phase of metabolism, tissue distribution and excretion; thus, blood levels may not represent the true degree of exposure to the toxin. On the other hand, meconium is a repository of many xenobiotic substances that the fetus has been exposed to in utero.^32-34 These agents are deposited in meconium through bile secretion and/or fetal swallowing of amniotic fluid via the fetal urine and accumulate in meconium, starting from the 12th week of gestation, when meconium is first formed through fetal swallowing, until birth. Fetal exposure to various xenobiotic agents have therefore been demonstrated through meconium analysis.^35-39 On the other hand, there were instances in one study, wherein cord blood was positive for Hg but negative in meconium. This may be related to the manner of meconium sampling. In this study, meconium was collected from only 1 diaper and it is likely that the sampled meconium was negative for Hg. The presence of drug or toxins in meconium is related to the timing of exposure of the fetus to the drug.⁴⁰ If the exposure was episodic, then drug deposition in meconium will be sporadic and not every meconium sample can test positively for the drug. For this reason, it is advisable to collect and pool meconium from several diapers to obtain a sample that is representative of a longer period of exposure. Another explanation for the absence of Hg in cord blood of infants with high levels of Hg in meconium is the saturation of the Hg transport system existing in the hemochorial placenta.⁴¹

The effect of Hg on HC was evidenced by a positive relationship between levels of Hg in cord blood and a smaller HC (Table 3). The same trend is seen in the quadrant analysis of HC of the full-term infants included in the study and Hg levels in meconium (Fig 2). A similar study with a larger sample size clearly established this relationship.²⁴ The significance of a small HC associated with Hg remains to be ascertained by future neurodevelopmental evaluation. Most reports show that signs and symptoms even when toxicity is severe, start from 6 weeks to 3 months.¹¹ A subsequent prospective cohort study will be performed.

MSAF was significantly associated with Hg levels (P = .0064), which may indicate a certain degree of fetal compromise.

We cannot adequately explain the inverse relationship between the concentration of Hg in meconium and the duration of maternal residence in the polluted area. However, the mothers who stayed longer in Tagum had a significantly higher number of pregnancies than those who stayed for a shorter duration. It is likely that in the multigravid mother, her finite pool of Hg would have been distributed to a greater number of fetuses, thus accounting for the lower concentration of Hg in these mothers. The role of amino acids^42,43 and protective interactive elements like selenium, zinc,⁴⁴ and vitamin E^25,47 may also be operative.

In contrast to studies in older children and adults that hair is a reliable index of exposure to Hg,^{1,12,20,25,35} this study shows a negative correlation of prevalence of Hg in hair and Hg levels in cord blood and meconium which suggests that the factors other than concentration alone may be responsible for Hg deposition in newborn hair.

Studies on Hg levels in breast milk are very few, and have been in mothers exposed solely to organic Hg from fish or agricultural products.²⁹ All of the breast milk levels were lower than the maternal levels. In contrast, our study shows a tendency to higher levels in breast milk than maternal blood levels (Table 1), probably attributable to the remarkable ease in transmembrane transfer of Hg° to which these mothers were simultaneously exposed.

Although additional Hg burden to the infant may result from breastfeeding,⁴⁶ the study by Grandjean⁴⁸ in 1995 on the milestone development in infants exposed to MeHg from human milk showed that breastfeeding confers an advantage to the infant in terms of neurobehavioral development, thereby compensating for the increase in MeHg exposure as detected through measurements of hair Hg levels. Milestone criteria were reached earlier in breastfed babies despite the higher hair concentrations at 12 months.

	CONCLUSION

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In summary, the absence of Hg in the maternal compartments is not indicative of the absence of Hg in the fetus. Exposure of the mother to Hg results in higher levels of Hg in cord blood and meconium compared with maternal blood levels indicating a lack of placental protection to the infant and with trapping of Hg on the fetal side. This has to be considered when setting limits of exposure for pregnant women. Hg in pooled meconium should be determined in addition to cord blood to obtain a better estimate of fetal exposure. There were indications that those found positive for Hg in cord blood and meconium had smaller HC and a greater chance of having MSAF. Adverse effects may not be evident at birth but subclinical toxicity of the fetus is a possibility. Therefore, long-term developmental and neurobehavioral assessments are needed.

	ACKNOWLEDGMENT

This study was funded by Astra Fund for Clinical Research and Continuing Medical Education Research Grant.

	FOOTNOTES

Received for publication Jul 15, 1999; accepted Apr 7, 2000.

Reprint requests to (G.B.R.) Neonatology Division, Philippine Children's Medical Center, Quezon Avenue, Quezon City, 1100 Philippines. E-mail: neo{at}hiss.pcmc.org.ph or jramirez{at}skyinet.net

	ABBREVIATIONS

Hg, mercury; Hg°, mercury vapor; MeHg, methyl mercury; ppb, parts per billion; PROM, premature rupture of membranes; MSAF, meconium-stained amniotic fluid; AAS, atomic absorption spectrophotometry/spectrometer; HC, head circumference; GA, gestational age; GP, gravida, para.

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