Maternal and Umbilical Cord Blood Lead Levels and pregnancy outcomes: A Hospital Based Enquiry
.........................................................................................................................
Asma A. Al- Jawadi *†
Zina W. A. Al-Mola**†
Raghad A. Al- Jomard***†
*Professor of Public Health & Preventive Medicine. Department of Community Medicine, College of Medicine, University of Mosul, Mosul, Iraq
** Community Medicine Specialists, Ninevah Directorate of Health, Mosul, Iraq.
E. mail: bannder@yahoo.com
***Assistant researcher, Environmental Health Education & Resources Unit, College of Medicine, Mosul, Iraq.
E. mail: Raghad0@yahoo.com
† Equal contribution.

Corresspondence to:
Asma A. Al- Jawadi
E mail: asmaa_aljawadi@yahoo.com

As far as the exposure to environmental elements is concerned, attention has been directed to study the exposure to lead, and since its health effects may begin during exposure in uterus, the study of
maternal exposure is of significance^[1].

Potential sources of lead exposure may vary, both within and between countries, however, lead gets into the body through water, food, and air^[2].

The blood lead levels (BLLs) of concern for young children, pregnant women, and nursing mothers is 10 microgram per decilitre of blood (µg / dl). For adults, a BLLs of 25 µg / dl is considered to be
elevated^[3,4].

The Center for Disease Control and Prevention (CDC) has grouped blood lead values into three ranges:
(1) low (1 - 10 µg / dl)
(2) moderate (11 - 20 µg / dl)
(3) high (20 - 38 µg / dl)^[5].

Needleman and Landrigan in 2004 stated that, there is no demonstrated safe concentration of lead in blood, adverse health effects can occur at BLLs as low as 2.5 µg / dl^[6].

Great attention has been directed to study maternal and children BLLs since pregnant women and young children are the most sensitive populations to the lead exposure from various sources, as
the absorption of lead from the gastro-intestinal tract is higher in children and pregnant women than adults and the developing nervous system in children is thought to be far more vulnerable to the toxic effects of lead than mature brain^[7].

During pregnancy stores of lead deposited in bones over a lifetime may be mobilized and transferred to the more bio-available compartment of the maternal circulation with potential toxic effects on the fetus and mother^[8]. This possibility of bone resorption during pregnancy is alarming in view of recent studies linking even lower levels of lead exposure with deficits in neurobehavioral function
in infants^[9]. The early 3rd trimester of pregnancy may constitute a critical period for subsequent intellectual child development during which lead exposure can produce lasting and possibly permanent effects^[9,10]. Neuro-developmental effects from prenatal and early childhood exposures have been observed at a relatively low level of lead and it may be the most sensitive end point for its toxicity^[11].

The period of fetal growth is often the stage of development at which an organism is most sensitive to toxic agents. However, fetal exposure cannot be directly measured during pregnancy in human
research studies. Maternal measurements are the only exposure indices ethically available^[12].

Lead is one of the most significant reproductive toxicant. It is associated with impaired infertility. Additionly, reduction in secondary sex ratio (ratio of live-born males to live-born females) may be associated with lead exposure, because male conceptus may be more susceptible to environmental stressors affecting mothers^[13] Maternal BLLs were also associated with increase of systolic and
diastolic blood pressure as well as increased risk of 3rd trimester hypertension^[14].

The effects of lead on fetal growth, intrauterine development, and postnatal status have long been of concern in occupational and environmental medicine. Lead in large amounts has been shown to be feto-toxic in humans. Prenatal lead exposure likely increases the risk of preterm delivery and is inconsistently associated with reduced APGAR score at delivery, birth weight, head circumference, and recumbent length^[15], Moreover Borja-Aburto et al. concluded that low, moderate and high levels produced limited evidence of an association with spontaneous abortion^[16].

The present study is the first report of a cross - sectional analysis of heavy and trace metal (lead) in maternal and newborns' blood at time of delivery in Mosul city. Its main concern is monitoring the
association of maternal blood lead levels (MBLLs) with pregnancy outcomes among the study sample.

Prior to data collection official permission was obtained from Ninevah Health Office and Maternity Hospital Administrators who were to be involved in this work. Written consent was taken from
participants prior to the interview and blood sample collection. The present study was conducted in Mosul city, the Center of Ninevah Governorate. For the purpose of data collection three maternity hospitals were selected on the basis of having the largest number of births each month and their accessibility to the whole population living in this region. These hospitals include Al-Batool which is on the right bank of Mosul city. It was established in 1973 and it contains 179 beds. It has the largest number of births per month.

Al-Khansaa Maternity Hospital was established in 1986 and has 121 beds. In Al-Atheer Maternity and Pediatric Hospital, the maternity section was established in 2000 and it includes 40 beds. These two maternity hospitals are on the left bank of Mosul city.

To achieve the aim of the present study a cross-sectional study design was adopted among women who attended the delivery units in the three hospitals mentioned above. Data were obtained directly
from mothers themselves through a detailed questionnaire form before delivery.

In this study a sample of 370 maternal mothers was adopted, which forms 10% of the average monthly attendants in the three maternity hospitals. Out of this number 350 maternal - fetus pairs were involved. Mothers were informed about the nature and the aim of the present work, and they agreed to participate in the study and signed a letter of informed consent .

Participants were to have the following inclusion criteria:

(1) Mother's age 15 - 49 years old.
(2) Mosul city resident for more than 3 years.
(3) Have a full term single viable pregnancy.
(4) Have no gestational diabetes or seizure.
(5) Have no psychiatric illness.
(6) Delivered by normal vaginal delivery without any intervention.

Especially designed questionnaires were used to collect the information from participants. It was tested and proved to have a good validity (82.3%) and reliability (86.3%). The form included information related to socio-demographic characteristics, potential lead related variables, life style related behaviour, reproductive history, medical and drug use histories.

Birth weight was measured immediately after birth using an ordinary balance machine which was available in the maternity hospitals and recorded to the nearest 0.1 kilograms. This machine was checked each morning and standardized. Neonatse weighing less than 2.5 Kg were considered as a low birth weight baby^[17].
Head circumference was measured using non stretchable tape (from the most prominent area of the frontal bone above the eyebrows to the most prominent area of the occipital bone in the midline, returning to the starting point) and recorded to nearest 0.5 cm. The normal head circumference average was 35 cm^[18].
APGAR score was determined immediately after birth and 5 minutes later. APGAR score more than 7 was considered a normal neonate^[18].

Blood pressure (BP) for each participant was measured before delivery in the sitting position with a cuff that is large enough for the subject's arm. Pregnant women are considered hypertensive if one
measurement of diastolic BP is 110 mmHg or more, or with diastolic BP more than 90 mmHg on two occasions four hours apart^[19].
Haemoglobin (Hb) level was obtained from the case sheet of the mother. Pregnant women with Hb level less than 11g / dl were considered as a case of anaemia^[12].

Maternal blood samples were taken from pregnant women just before delivery. The venipuncture site was properly wiped clean with alcohol wipes already supplied with the system, for each woman and 5 ml of blood was drawn into a lead free K3 EDTA tube.

Five ml of umbilical cord blood was taken immediately after birth from each newborn, into a lead free K3 EDTA tube. Analysis of blood lead was performed at the Environmental Health Education and
Resources Unit of Mosul Medical College on a batch of 6 - 7 days, using LEAD CARE (Blood Lead Testing System) and LEAD CARE (Blood Lead Testing Kits) from (ESA, Inc.; USA).

Data collection was conducted between May and October 2007.
As all the target hospitals agreed to participate in the present study, a special timetable for visits was arranged for the purpose of data collection. Each maternity hospital was visited 1 - 2 times/week from 8.00am till 1.00pm.

The information regarding each woman was transferred into code sheets and data entry was done using Computer Pentium IV and statistical analysis was done using SPSS package version 13.

The following statistical methods were used for the analysis of data:

1. Standard statistical methods were used to determine the mean, standard deviation (SD), number, and percentage.
   
2. Student t test and analysis of variance (ANOVA) were used to determine the presence or absence of any association between lead content of blood and each of the determinant factors. P value of <0.05 was considered to be significant throughout the present study.
   
3. Linear regression analysis, i.e. Pearson correlation coefficient (r) was performed to find degree of association between MBLLs and UBLLs.
   
4. chi - square ( _²) test was used to test for the presence or absence of significant association between elevated MBLLs and pregnancy outcomes. Odd ratio (OR) and the corresponding 95% confidence interval (CI) were also computed.
   

Overall, out of 370 women adopted 350 reached the participation rate which equals to 94.59%. All participants accepted the interview and gave blood samples.

Mean MBLLs at delivery was 4.03 ± 2.97 µg/dl and ranged from 0.5 to 22.3 µg/dl. Only 5% of the study sample had BLL > 10 µg/dl. The mean lead concentration in the umbilical cord was 3.05 ± 2.67 µg/dl, the range was 0.30 - 23.10µg/dl.

Figure (1) portrays a significant positive correlation between MBLLs and umbilical blood lead levels (UBLLs) (r = 0.92, P = 0.001). UBLLs is approximately equal to 92% of the MBLLs. On average,
UBLLs was lower than MBLLs by 0.97µg/dl.

Figure (3): Graphic representation of the correlation between UBLLs and MBLLs

Table (1) exhibits the significant potential lead related to maternal variables. These are maternal age (p=0.000), occupation (p=0.000), year of house building (p=0.000), exposure to chipping paint (p=0.002), parity (p=0.002), physical activity (p=0.000) history of pica (p=0.000), smoking (p=0.001), calcium and iron supplements intake during the current pregnancy (p=0.000). Other variables such as residence, presence of house near traffic jammed areas, presence of electrical generator at house, type of transportation used to place of work, history of abortion and stillbirths, cosmetics use, coffee and tea consumption, history of hyperemesis, chronic diseases and acute diseases during the current pregnancy played no significant role.

Table (2) clarifies the effect of MBLLs on the development of hypertension and anaemia among the studied women during the current pregnancy. Pregnant women with BLLs > 10 µg/dl are more at risk of developing hypertension than those with BLLs < 10 µg/dl (OR = 6.84, P = 0.000). Although there is an evident risk of anaemia development among women with high BLLs (OR=2.73), this risk does not reach a significant level.

Table (3) presents the distribution of neonatal characteristics among women with different blood lead categories. Overall, the mean birth weight was 3.058 ± 0.515 kg, and the mean head circumference was 35.12 ± 0.838 cm. Babies born to mothers with high BLLs (> 10 µg/dl) are more at risk of developing low birth weight and small head circumference than those born to mothers with low BLLs (OR = 43.54, 3.16 respectively), (P = 0.000, 0.013 respectively). While high BLLs are not considered a risk factor for developing low APGAR score.

There is a considerable interest in the measurement of blood lead concentration in communities as evidence has been brought forward to support the relationships between the body burden of lead
and various health problems^[9].

Lead exposure does not only directly affect health, but also allows the accumulation of lead in tissue as bone. Millions of women at child bearing age have substantial bone lead stores due to lead exposure as children. During pregnancy, the mobilization of bone lead increases, apparently as the bone is resorbed to produce fetal skeleton^[20,21].

The survey of targeted population at special risk for either lead exposure or toxic health effects can provide improved, cost-effective means for eventual control of exposure. Prenatal lead exposure is of concern because it may have an effect on cognitive development and may increase delinquent and antisocial behaviours when the child gets older and it may also reduce neonatal weight gain. In addition to fetal risk, lead may be a risk to mother by causing an increase in blood pressure^[22].

One of the important sources of lead exposure for fetus and infants is maternal blood. It was reported that 45 - 70 % of lead in the blood of reproductive age women originated from long-term tissue stores. This suggests that the blood and tissue levels of lead in women determine the body burden of lead in their offspring^[23].

Mosul is a densely populated city. It is the second largest city in Iraq. As other cities in this country, it is facing several environmental health problems with an increased burden from environmental lead
pollution. This pollution may come from various sources such as old cars, electrical generators which are widely distributed in the city, and the presence of a large number of old houses which can be translated into increased BLLs in the general population^[24].

There is an ongoing debate over the appropriate cut-off point of blood lead concentration of concern in infants and young children. Consequently, it was lowered by CDC from 60 µg / dl in 1960 to 25µg / dl and then to the currently used value of 10 µg / dl in 1991. Two factors brought this reduction: improved investigational strategies and reduced background lead levels due to removal of lead from
gasoline^[25]. Several studies showed that even low doses of exposure (Blood lead level less than 10 µg / dl), of environmental lead continues to be a biological and social toxicant^[22].

However, Needleman and Landrigan recommended that time has come to lower the CDC recommended cut-off for blood lead in pregnant women and infants to 5 µg / dl.^[6]

To achieve the aim of the present study, a cross sectional study design was carried out with advantages carefully balanced against the disadvantages.

Among the well known advantages of cross-sectional studies are^[26]:

1. The study describes the distribution of the items under study i.e. MBLLs and its burden on the community.
   
2. The study is useful in determining association between variables of interest and thereby gives a hint at formulating a hypothesis for the causation of elevated maternal and UBLLs.
   

An important point that gives strength to the present study is the large, diverse and city wide representative sample of pregnant women in the study population. When considering the findings of the present study, limitations should be taken in account which include:

1. A causal association which is one of the important disadvantages of cross sectional study; if it cannot be determined findings can provide directions for more future studies.
   
2. The extent of over-reporting or under-reporting of the factors that related to elevated MBLLs cannot be determined.
   

As the present study is one of the first to examine lead levels in pregnant women and their infants in the city, data derived from such a study could be used as a baseline indicator for future programs. It is important to have a high confidence of data derived from this survey.

The present study showed a high maternal response rate (95%) and maternity hospital participation rate (100%). During the study period, a total of 350 mothers were examined. This sample size was
higher than was expected. This is partly due to high maternal response rate and the large number of women who attended these three maternity hospitals for delivery.

The mean lead concentration of maternal blood in this study was 4.03 ± 2.98 µg / dl with a range of (0.5 - 22.3 µg / dl), which is lower than reported in Al - Naemi et al. study carried out in 2007 (5.26 ±
3.33 µg / dl) in the same venue^[27]. The mean BLL reported by Al - Naemi et al. was for 306 non-pregnant mothers at childbearing age who were taken randomly from women coming to the Primary Health Care Center (PHCC) for their children's vaccination^[27].

This discrepancy could be explained by two hypotheses:

1. The sample of the current study is hospital based and probably could not be considered as representative. While the sample of Al - Naemi et al. included females of a childbearing age who attended Al - Hadbaa PHCC. This center has a wide catchment area mostly of moderate and low socio-economic status women^[27].
   
2. Al - Naemi in his work used finger stick samples which may yield higher false measurements than venous blood samples used in the present study probably due to outside lead contamination^[28].

The present study revealed that 5% of the examined women have BLLs > 10 µg / dl, a higher figure (8.5%) was reported by the study of Mosul city^[27]. The Mousul study covered non pregnant women at childbearing age, while the present study was conducted among pregnant women. Since blood volume increases in pregnancy by as much as 30 - 40%^[29], the relatively lower BLLs in pregnant women could be due to this dilution effect.

Blood lead level in Iraq is not routinely measured in any health facility, therefore there is limited data about the prevalence of high BLL either in general population nr in disadvantaged groups like
pregnant women and infants. Lanphear et al. said that although a blood lead level of greater than 10 µg / dl is generally accepted as the threshold for concern, levels of less than 10 µg / dl have been
associated with undesirable outcomes in human fetuses^[30].

The primary biomarker of prenatal lead exposure is the concentration of lead in whole blood samples either from maternal venous blood or from umbilical cord blood at the time of delivery^[31].

The mean lead concentration in the umbilical cord recorded by this study was 3.05 ± 2.67 µg/dl with a range of (0.30 - 23.10 µg/dl).
This mean was higher than that reported by Kirel et al. in Turkey who recorded a mean UBLL value of (1.65 ± 1.4 µg / dl). This difference may be due to small sample size in the Kirel study (n = 120)^[32]. Also it is worth noting that unleaded gasoline which is widely used in this country, may lead to a sub-statistical low level of exposure to lead.

A study carried out by Satin et al. in California observed a higher mean UBLL value (4.9 ± 3.9 µg / dl). In this study the sample was collected from women of low socio-economic status who delivered at targeted hospitals. In such setting low socio-economic status mothers are associated with increased lead exposure, which usually comes from occupation, soil, and residential paint^[33].

In the present work lead concentration in the umbilical cord is significantly correlated with, and lower than, the concentration of maternal venous blood (r = 0.92, P = 0.001). This finding is consistent with the findings of other studies^[34]. In fact, in this study the UBLLs are approximately 92% of levels found in maternal blood. This finding supports the conclusion that the placenta is not a very effective biological barrier and it does not hinder much of the lead transport^[35].

Lead freely crosses the placenta, consequently gestational lead is not only harmful to women but also to the developing fetus^[36].

Birth weight is a strong predictor of survival and of development outcomes in childhood including growth, morbidity, and cognitive performance [9]. Kaul et al. mentioned that there is an inverse relation between maternal lead burden and birth weight in the offspring of women with relatively low blood lead^[37].

In the current study, it was observed that neonates born to women with BLLs > 10 µg / dl had an increasing risk of having low birthweight babies (OR = 43.54, P = 0.000).

The public health significance of this finding is notable, because early growth problems have health and social consequences. It has been shown that the early impaired growth is associated with decreased intellectual and physical performance, such as work capacity, and school achievement^[39].

Gonzalez - Cossio et al. stated that lead may impair birth weight through an effect on prenatal bone growth itself, in such a way that the attained weight at birth may be negatively affected^[38]. Also Sanin et al. said that the mechanism behind lead effects on growth seem to involve action at different sites. Lead may interfere with vitamin D metabolism or with the calcium role as a cellular messenger in its endocrine functions^[38].

Schnaas et al. mentioned that increased MBLL was associated with decreased birth weight, and lower birth weight was associated with poor postnatal intellectual development, which is the modeled effect of MBLL on children six to ten years later. Also an intelligence quotient (IQ) could be mediated through lead effect on birth weight, since the third trimester of pregnancy constitutes a critical period for fetal growth and subsequent intellectual child development, during which lead exposure can produce long lasting and possibly permanent effects. In addition there is no threshold for the adverse consequences of lead^[9].

Rahman and Hakeem found no association of MBLLs with fetal growth either in terms of birth weight or in birth length^[40]. A small sample size (n = 73) which is not large enough to pick up these associations and racial differences in the effect of lead may explain this apparent lack of association.

A study by Hernandez - Avila et al. evaluated the effect of MBLLs on head circumference of newborn and one month old infants. They concluded that high MBLLs were significantly related to risk of a low head circumference score^[41]. The present work also demonstrated that mothers with high BLL (>10 µg / dl) are at risk of having newborns with low head circumference score (OR = 3.16, P = 0.013). However, Rahman and Hakeem did not confirm this result [40] .

The present study revealed that only 5.3% of newborns have an APGAR score less than 7. These were newborns to mothers with high BLLs (>10 µg / dl). Despite that, however, no association was
demonstrated between MBLLs and APGAR score. Sowers et al. conducted a study among 705 women aged 14 - 34 years which showed that maternal blood lead concentration and its changes were not associated with reduced APGAR score^[42].

The findings of this study demonstrated that high MBLLs were significantly related to risk of development of hypertension during pregnancy (OR = 6.84, P = 0.000). This result is similar to the result obtained by Rothenberg et al. who reported an association between blood lead and blood pressure during pregnancy by a cohort study conducted among 1932 pregnant women in South Central Los Angeles. Because of this given association that BLLs during pregnancy present an increased risk to both mother and fetus, effort should be directed to screen women at childbearing age for high BLLs, to reduce further exposure^[43].

Gulson et al. mentioned that bone lead concentration accumulated over a lifetime of exposure, and some part of blood lead during pregnancy is derived from bone lead. The relationship between blood lead and blood pressure is mediated by the contribution of bone lead to blood lead. The action of bone-lead mediated blood lead on blood pressure is direct, as lead entering the bloodstream from bone will enter through the serum or plasma, before being rapidly distributed to other body tissues, including erythrocytes, which hold 99% or more of total blood lead. Lead in the serum may contain the portion of lead in circulation that is bioactive (i.e. available to enter other organs and produce biological effects)^[44].

Elevated lead in bone continuously feeds the serum lead compartment, placing a larger amount of bio-available lead into tissues and organs that affect blood pressure^[43].

The particular target tissue for an effect of lead on blood pressure has not yet been established, but several biological mechanisms have been suggested. The two major modes of action identified are direct effect on end-arterial smooth muscle mediated through distributed calcium metabolism; and effects on the rennin - angiotensin axis. In addition, lead may interact with vaso-active agents^[45].

The present study showed that 234 out of 350 pregnant women (66.86%) were anaemic. Although iron has been shown to be important in lead absorption, in this study no association between
haemoglobin level and concentration of lead in pregnant women was found. This finding is most likely due to the difficulty of measuring iron deficiency anaemia in a population undergoing the physiological
changes associated with pregnancy^[29].

Wright et al. said that iron-mediated biochemical and physiological processes are modified by lead toxicity; adverse effects of lead on the haematological system appears to be more severe among
iron deficient subjects^[47].

Hu et al. carried out a survey among members of the construction trade in Boston, and concluded that bone lead levels are associated with decreased hematocrit and haemoglobin levels despite the presence of low BLLs^[46]. This conclusion may reflect a substantial effect of bone stores on hematopoiesis and it suggests that bone lead may be a more important biological marker of ongoing
chronic toxicity than BLLs.

The present study provides, for the first time in the country, data on maternal and UBLLs with clear evidence association between high MBLLs and low birth weight neonates with small head
circumference. The following points should be carefully considered in Mosul city :

1. Efforts should be made to reduce BLLs of reproductive age women to minimize transfer of MBLL to fetus and nursing infant. Screening of women at childbearing age for elevated BLLs is needed.
   
2. General education on measures to reduce lead exposure may be useful for parents. This includes information on potential risk factors for lead exposure and specific prevention strategies that should be tailored for the family and for the community in which care is provided.
   
3. Future research is needed to evaluate the BLLs among women in child bearing age, since little is known about the cycling of blood lead through generations and means to reduce the lead burden on women's body's at child bearing age, measurement of MBLLs throughout the pregnancy, and direct measure of family socio-economic status or the care giving environment.
   

We are grateful to the staff of the maternity hospitals & to all mothers for their kind cooperation, which made this work possible.

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