SERUM MAGNESIUM

LEVEL AND MATERNOFETAL OUTCOME IN

PREGNANT NIGERIAN WOMEN

A DISSERTATION SUBMITTED TO THE NATIONAL

POSTGRADUATE MEDICAL COLLEGE IN PARTIAL

FULFILLMENT OF THE REQUIREMENTS FOR THE PART

II FELLOWSHIP EXAMINATION OF THE COLLEGE

FACULTY OF OBSTETRICS AND GYNAECOLOGY

BY

ENARUNA, NOSAKHARE OSASERE

MB.BS (BENIN)

2011

ii

CERTIFICATION

We hereby certify that DR. ENARUNA NOSAKHARE OSASERE of the

Department of Obstetrics and Gynaecology, University of Benin Teaching Hospital,

Benin City carried out this study under our supervision.

SUPERVISORS:

PROF. E.E. OKPERE

MBBS, FRCOG, FMCOG, FWACS, FICS

Consultant Obstetrician and Gynaecologist

Department of Obstetrics and Gynaecology

University of Benin Teaching Hospital

Benin City.

DR. A.B.A. ANDE,

B.Sc (Hons), MB.CHB, FWACS, FICS, MPH

Consultant Obstetrician and Gynaecologist,

Department of Obstetrics and Gynaecology,

University of Benin Teaching Hospital,

Benin City.

DR. M.E. AZIKEN,

MB.BS (Ibadan) FWACS, FMCOG, FICS, MPH, DMAS (India)

Consultant Obstetrician and Gynaecologist,

Department of Obstetrics and Gynaecology,

University of Benin Teaching Hospital,

Benin City.

HEAD OF DEPARTMENT:

DR. M.E. AZIKEN,

MB.BS (Ibadan) FWACS, FMCOG, FICS, MPH, DMAS (India)

Consultant Obstetrician and Gynaecologist,

Department of Obstetrics a nd Gynaecology,

University of Benin Teaching Hospital,Benin City.

iii

DECLARATION

This research is original and to the best of my knowledge and belief, it contains

no material previously published or written by another person nor material which to a

substantial extent has been accepted for the award of any other degree or diploma of

the university or other institution of higher learning, except where due acknowledgement

has been made in the text.

DR. ENARUNA NOSAKHARE OSASERE.

MBBS (BENIN)

iv

ACKNOWLEDGEMENTS

In gratitude I submit to Almighty God who made it possible from the very

beginning. He showed me answers in situations that seemed insurmountable.

To my dear wife I owe immeasurable thanks for her love, patience and support.

I would like to thank my parents and siblings for their belief in me.

I would also like to thank all my friends, especially Dr Maduka Roy and Dr

Osaikhuwuomwan James.

I would like to especially thank all the professors and consultants of the

Department of Obstetrics and Gynaecology, UBTH, for helping me realize this dream. In

particular, my sincere gratitude goes to Prof EE Okpere, Dr ABA Ande and Dr ME

Aziken for supervising my work. I cannot thank Dr (Mrs) AP Osemwenkha enough for

being there for me. And I would like to thank again Dr ME Aziken for being both a

teacher and a friend.

Many thanks go to all resident doctors and house officers in the Department of

Obstetrics and Gynaecology, especifically Dr Akpata, Dr Uwagboe and Dr Dunsin for

their contribution to this project.

Special thanks go to my collaborators in the Department of Clinical Chemistry,

UBTH, notably the Head of Department, Dr O Idemudia, Mr. E P Okosun as well as Mr

P Aikoriogie who assisted me in carrying out the laboratory assays. I would also like to

express my sincere gratitude to Mr. Titus for his role in the secretarial work and data

analysis.

And finally, to all the patients who allowed me share in their stories and

contributed to this work, I remain grateful.

v

TABLE OF CONTENTS

SERUM MAGNESIUM ........................................................................................... i

LEVEL AND MATERNOFETAL OUTCOME IN PREGNANT NIGERIAN WOMEN

............................................................................................................................... i

A DISSERTATION SUBMITTED TO THE NATIONAL POSTGRADUATE MEDICAL

COLLEGE IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE PART II

FELLOWSHIP EXAMINATION OF THE COLLEGE .............................................. i

FACULTY OF OBSTETRICS AND GYNAECOLOGY ............................................ i

BY .......................................................................................................................... i

ENARUNA, NOSAKHARE OSASERE ................................................................... i

MB.BS (BENIN) ...................................................................................................... i

2011 ....................................................................................................................... i

DECLARATION .................................................................................................... iii

LIST OF ABBREVIATIONS AND SYMBOLS

AIDS — Acquired immune deficiency syndrome

ATP — Adenosine triphosphate

DM — Diabetes mellitus

DNA — Deoxyribonucleic acid

EGTA — Ethylene glycol tetra-acetic acid

GA — Gestational age

GPC — General practice clinic

IUFD — Intrauterine fetal death

HIV — Human immune deficiency virus

RDA — Recommended daily allowance

RNA — Ribonucleic acid

SCBU — Special care baby unit

SD — Standard deviation

vi

SPSS — Statistical Package for Social Sciences

UBTH — University of Benin Teaching Hospital

Mg2+ — Magnesium ion

MgSO4 — Magnesium sulphate

mEq — Milliequivalent

L — Litre

ml — Millilitre

dl — decilitre

mg — Milligram

% — Percentage

< — Less than

> — Greater than

= — Equal to

vii

ABSTRACT

Background: Magnesium plays a critical role in metabolism especially with respect to

carbohydrate, protein and energy syntheses, and it is known to decline in pregnancy. A

suggested role for magnesium deficiency in the genesis of preeclampsia, gestational diabetes,

intrauterine growth restriction, muscle cramps and preterm delivery has prompted studies with

conflicting evidence. Assessing the prevailing serum magnesium levels in our locale and

identifying maternal characteristics linked to a diagnosis of hypomagnesaemia will serve to

reduce possible morbidity and/or mortality due to associated maternal disease conditions like

preeclampsia and preterm delivery.

Objectives: The primary objective of this study was to determine the level of serum magnesium

at which hypomagnesaemia could be diagnosed, while secondary objectives attempted to

define maternal and fetal outcome due to hypomagnesaemia.

Methodology: An initial pilot study was done to document the mean serum magnesium level for

the population of patients attending UBTH. The main study was a prospective cohort study of

antenatal women recruited in the second trimester and followed up till delivery and one week

postpartum. Serum magnesium estimates were done with samples collected at recruitment and

thereafter, at delivery. The magnesium levels determined were used to divide the subjects into

two groups of hypomagnesaemic and normomagnesaemic patients. Their sociodemographic

and clinical characteristics were used to generate a database for analysis.

Results: Serum magnesium levels were higher in the non-pregnant subjects than the pregnant

women in the pilot study. The prevalence of magnesium deficiency in the main study was

16.25%. Hypomagnesaemia was more likely in teenagers (P=0.00), women of higher parities

and lower social class (P=0.00), and was significantly correlated with the occurrence of

preeclampsia (P=0.01), leg cramps (P=0.01) and preterm birth (P=0.03).

Conclusion: Hypomagnesaemia in pregnancy is associated with a higher risk of preeclampsia,

leg cramps and preterm delivery. Direct interventional strategies such as magnesium

supplementation or consumption of magnesium-rich vegetables, legume seeds, beans and nuts,

should be recommended to improve maternal and perinatal health.

1

INTRODUCTION

Magnesium is the fourth most prevalent cation (Mg2+) in the body and is found

predominantly in bone but also substantially in muscle and neuronal tissue. Magnesium

deficiency is not readily detectable since less than 1% of the total body magnesium is

found in the plasma and red blood cells1,2; moreover, ionized magnesium assays are

non-routine and extremely expensive3. The recommended dietary allowance (RDA) for

magnesium is 350mg per day for a male adult and 280mg per day for a female1. The

magnesium requirement is increased during pregnancy and lactation to 360-400mg

daily1.

Studies done in the United States of America to estimate the magnesium intake

during pregnancy reported a consistently lower intake than recommended, with a range

of 35-58% of the recommended dietary allowance (RDA). Lower income women were

noted to have lower magnesium intake, and prescribing prenatal supplements provided

better magnesium balance4-8. Magnesium nutritional status can be influenced by a

number of factors, but the easiest to correct is magnesium intake9.

Magnesium is vital for many biochemical processes, activating over 300 enzyme

systems including those involved in carbohydrate metabolism, protein synthesis,

oxidative phosphorylation and the synthesis of ATP, DNA and RNA1,2. Magnesium

regulation depends on renal excretion. The excretion capacity of the kidney ranges

widely depending on the plasma Mg2+ concentration. The generally accepted normal

range for total serum magnesium is 0.75-1.0mmol/L1 (1.5-2.0mEq/L). This level is

regulated by the contributions of dietary intake, mobilization of body stores and renal

excretion 1.

2

Magnesium levels have been shown to decline during pregnancy10,11, reaching

their lowest point at the end of the first trimester11. This decline may be due to factors

such as higher nutritional demands in pregnancy, inadequate intake in the diet, and

volume expansion in pregnancy. Other forms have been linked to magnesium depletion

related to a dysregulation of magnesium status such as poor absorption and excessive

urinary loss. Gestational magnesium deficiency is able to induce maternal, fetal,

neonatal and paediatric consequences which may last throughout life. Magnesium

deficiency has been associated with disordered glucose metabolism, vascular disorders

and electrolyte disturbances, especially of potassium1,2. From animal studies, evidence

suggests that hypomagnesaemia has marked effects on the processes of parturition,

postpartum uterine involution and on fetal growth and development12. It has also been

reported that magnesium deficiency during pregnancy may be associated with the

sudden infant death syndrome13.

Magnesium deficiency causes uterine artery spasm and this has been linked to

placental insufficiency, which leads to the development of preeclampsia and fetal

growth restriction1. Many researchers have associated magnesium lack with preterm

labour and an increased incidence of leg cramps and constipation during

pregnancy13,14, necessitating the use of oral magnesium supplementation for weeks or

months until delivery in some centres15.

The possible role of magnesium deficiency in the genesis of preeclampsia,

gestational diabetes, insulin resistance and preterm labour continues to be the subject

of considerable debate. It is noteworthy that most of the existing data on this

insufficiently investigated subject emanate from outside sub-Saharan Africa. The

3

question that remains unanswered is ‘do these data reflect the situation in our

environment?’ Considering the fact that Africans experience more poverty and other

social deprivation compared to citizens of most industrialized countries where these

studies are done, the need to establish what the situation is in our pregnant women who

face more risk of inadequate diet, vis a vis the implication for maternal and fetal health,

cannot be overemphasized.

Furthermore, available evidence suggests that most of the outcome measures

considered in these studies viz. preterm labour, preeclampsia, gestational diabetes and

intrauterine growth restriction either occur more in our environment or appear to be

more severe compared to developed nations16-20. The maternal and perinatal mortality

and morbidity due to these conditions remain significant in this part of the world.

Therefore, the frequency of magnesium deficiency in pregnancy and the role of

hypomagnesaemia in the development of adverse outcomes in pregnancies form the

basis for this study.

4

LITERATURE REVIEW

Metabolism of magnesium in pregnancy

Coons and Blunt were among the earliest investigators in the United States to

study the magnesium balances of pregnant women who used milk of magnesia as

laxative21. They found no interference with calcium retention, even in women on

magnesium intakes as high as 810mg/day. Towards the end of pregnancy, they noticed

there was a tendency toward more and larger negative magnesium balances, even

when the women were on daily magnesium intakes of 400mg. Johnson and Phillips

studied 47 pregnant women residing in the United States and found that their daily

magnesium intake was less than the recommended daily allowance22. They

documented that the lower magnesium intakes correlated with lower birth weights.

Most green leafy vegetables, legume seeds, peas, beans and nuts are rich in

magnesium, as are some shellfish, spices, and soya flour. In contrast, many highly

refined flours, tubers, fruits, and most oils and fats contribute little to dietary magnesium.

Corn flour, cassava and polished rice have extremely low magnesium content23.

Absorption of magnesium can vary greatly depending on magnesium intake. Studies

show that absorption is low when intake is high, and vice versa23. Magnesium

absorption appears to be greatest within the duodenum and ileum and occurs by both

passive and active processes24. The kidney has a very significant role in magnesium

homeostasis. Active reabsorption of magnesium takes place in the loop of Henle, in the

proximal convoluted tubules, and this is influenced by both the urinary sodium and

probably the acid-base balance25. Excess magnesium is eliminated by the kidneys.

5

Effect of Pregnancy on Magnesium Level

When the dietary intake of magnesium is not sufficient to meet the demands of

pregnancy, the maternal stores are mobilized and magnesium deficiency can develop.

The rates of magnesium deficiency in pregnancy have been determined by some

researchers as between 25.6% and 44%26,27. Although under most circumstances the

body maintains plasma magnesium levels within narrow limits, the pregnant woman

tends to develop lower than normal magnesium levels, even in the absence of

preeclampsia.

The first reports of blood magnesium levels during pregnancy were in the 1920s.

Krebs and Briggs reported a range of 1.7-2.2mEq/L among 17 women in their eighth to

fortieth weeks of pregnancy28. Bogart and Plass reported that the average magnesium

value of 2.0mEq/L at the outset fell to an average of 1.7mEq/L by the end of pregnancy

compared to non-pregnant women29. In the same light, Hall reported that the normal

pregnant woman tended to have serum magnesium levels that remained at the lower

limit for the non-pregnant range of 1.69-2.0mEq/L, with the broadest range of 1.6-

2.1mEq/L in the second trimester30. Olatubosun et al also reported an average serum

magnesium level of 1.03mg/dl (0.87mEq/L) in the 8th month of pregnancy, dropping

from a non-pregnant average of 1.47mg/dl10 (1.24mEq/L). Reduced serum magnesium

in pregnancy may be due to haemodilution of pregnancy, poor absorption or excessive

urinary loss from increased glomerular filtration rate, but experimental and clinical data

continue to highlight the importance of low magnesium intake in pregnancy.

6

Effect of Magnesium on Pregnancy and the Foetus

Human pregnancy is characterized by several cardiovascular changes, among

them a 40% blood volume expansion. It is possible that alterations in magnesium

metabolism may be responsible for some of the physiological changes seen during

pregnancy and many diseases related to cardiovascular abnormalities. There is a

growing body of evidence that a compromised magnesium status may be involved in

several disorders that can occur during pregnancy, such as hypertension31-34,

premature delivery35,36, intrauterine growth restriction37-39 and muscle cramping15,40-42.

Hence, Resnick stated in an editorial that a link between magnesium, diabetes and

hypertension seems established beyond a reasonable doubt43.

Some biologic mechanisms have been proposed to explain the physiologic

effects of magnesium in hypertension, diabetes and hyperlipidemia3. First, magnesium

deficiency causes a dysregulation of the Na-Mg exchanger, resulting in higher

intracellular sodium and higher blood pressure. Second, a relatively low magnesium

level creates an intracellular imbalance between calcium and magnesium, which results

in increased vascular tone in the smooth muscle of the artery and therefore increased

blood pressure. Third, magnesium deficiency causes insulin resistance, which in turn

causes hyperinsulinemia, resulting in hypertension, diabetes, and hyperlipidemia.

HYPERTENSION AND PREECLAMPSIA The possibility that magnesium

deficiency might contribute to preeclampsia has long been recognized. Studies in ewes

with pregnancy-induced hypertension demonstrated higher arterial pressure and lower

fetal weights in sheep fed on a magnesium-deficient diet44. Kisters et al studied the

plasma and intracellular magnesium concentrations in pre-eclamptic and normal

7

pregnant women45. They found that plasma magnesium concentrations were not

significantly different, but these showed a greater scatter in the pre-eclamptic women.

Both groups, however, showed lower red cell magnesium concentrations than normal

non-pregnant values, and the pre-eclamptic group had a significantly lower red cell

magnesium concentration than the normal pregnant women. They thus suggested that

this decrease in intracellular magnesium might contribute to the vascular lesions of pre-

eclampsia.

Similarly, Standley and colleagues in another study demonstrated that all

subjects who eventually developed preeclampsia showed a decrease in ionized

magnesium (Mg2+) concentration with increasing gestational age46. However, this

finding has not been consistent from the work of other researchers who concluded that

magnesium deficiency had no causative role to play in the genesis of pre-eclampsia47-

48. Despite this conflicting data, many authorities suggest offering magnesium

supplementation to any pregnant woman who becomes magnesium-deficient, especially

in diabetic mothers as magnesium deficiency is common in diabetics and may also

worsen the pathology of the disease1,49,50.

In a meta-analysis of randomized clinical trials, Jee et al reviewed twenty studies

with a total of 1,220 participants. They noted that magnesium supplementation resulted

in a small overall reduction in systolic blood pressure of 0.6 mmHg (P=0.051), and a

small overall reduction in diastolic blood pressure of 0.8 mmHg (P=0.142). The authors

concluded that their meta-analysis detected a dose-dependent reduction in blood

pressure from magnesium supplementation, but stated that adequately powered trials

with sufficiently high doses of magnesium supplementation are needed to confirm this

8

relationship51. In a similar clinical trial conducted by Hatzistavri et al, a total of 48

patients with mild uncomplicated hypertension were studied to investigate the effect of

oral magnesium supplementation on 24-h blood pressure and intracellular ion status.

Twenty-four of the subjects were assigned to 600mg of pidolate magnesium daily in

addition to lifestyle modification for a 12-week period, and the other 24 patients who

were matched for age and sex were given only lifestyle recommendations. Their results

showed that in the magnesium group, small but significant reductions in the mean 24-h

systolic and diastolic blood pressures occurred (P=0.001 and P=0.002 respectively).

The authors thus concluded that oral magnesium supplementation is associated with

small but consistent ambulatory blood pressure reduction in patients with mild

hypertension52.

GESTATIONAL DIABETES Magnesium deficiency is known to cause insulin

resistance, which in turn causes hyperinsulinaemia, resulting in hypertension, diabetes

and hyperlipidaemia2,53. In a general population, hypomagnesaemia may affect 6.9%,

while amongst diabetic patients the prevalence is higher at 25%54-57.The clinical

correlation of decreased plasma magnesium and diabetes was first proposed by

Londono and Rosenbloom in 197158 .This inverse relationship between glycaemic

control and magnesium level has been attributed to increased magnesium urinary

losses. McNair et al observed that in the presence of hypomagnesaemia, plasma

magnesium levels were inversely correlated with fasting blood glucose values and

urinary magnesium59. Their conclusion was that net tubular re-absorption of magnesium

was decreased in severe hyperglycemia.

9

The work by Bardicef et al strengthened the evidence that gestational diabetic

women had significantly lower intracellular free magnesium values compared with non-

pregnant and normal pregnant individuals60. This relationship between poor metabolic

control and impaired magnesium balance was confirmed by Fugii et al when they

analysed magnesium in plasma, erythrocytes and urine of diabetic patients61. Simental-

Mendia and colleagues in Mexico gave an interesting explanation for the

hyperinsulinaemia exhibited by patients with hypomagnesaemia. They showed that the

decrease in insulin sensitivity in pregnancy is not appropriately compensated by beta-

cell function in individuals with hypomagnesaemia62, suggesting that hypomagnesaemia

could be linked to poor beta-cell compensation. Hypomagnesaemia occurs in poorly

controlled diabetic pregnancies and may contribute to the hypomagnesaemia of infants

of such mothers63.

SPONTANEOUS ABORTION Hypomagnesaemia has been demonstrated to be

significantly common in women who have experienced spontaneous abortions64,65. The

greater the number of abortions, the greater the degree of magnesium deficiency

detected. Whether the uterine hypercontractility, considered part of the preeclamptic

syndrome and found as a complication of pregnancy among women with latent tetany of

marginal hypomagnesaemia is related to the hypomagnesaemia of recurrent aborters,

remains to be proven66. Balazs and colleagues in Hungary examined the relationship

between spontaneous abortion and magnesium intake. They found that magnesium

intake was not sufficient in their subjects who had a spontaneous abortion rate of

12.6%. In their study, early supplementation of magnesium started before 9 weeks

gestation significantly reduced the risk of spontaneous abortion (P=0.001)67. In another

10

randomized controlled trial involving 128 women, 38 were healthy non-pregnant women,

40 were healthy women in the first trimester and the remaining 50 were women who

had symptoms of threatened abortion in the first trimester. The investigators found that

the symptoms of threatened miscarriage were related to decreased concentrations of

phosphorus, magnesium and total protein and albumin68. Rusu et al studied the

relationship between serum magnesium levels and response of the uterus to oxytocin

stimulation. Their conclusion was that with falling serum magnesium levels, the uterine

reactivity to oxytocin tended to increase69. And this link may also explain the role of

magnesium in the genesis and possible treatment of preterm delivery.

PRETERM LABOUR Magnesium has been used since the late 1970s to treat

preterm labour, especially in the United States70. A possible mechanism of action of

magnesium in preterm labour attenuation is by competing with intracellular calcium at its

binding sites, thereby decreasing muscle contractility and stabilizing the membrane

potential. There is evidence that magnesium inhibits myometrial contraction as

effectively as beta-agonists, doing this with a better profile of side effects71,72. In a study

of 568 women given magnesium aspartate or placebo from 16 weeks’ gestation or

earlier, the magnesium group had fewer hospital admissions, less frequent preterm

labour and fewer neonatal intensive care unit admissions51. However, some publications

have argued against the use of magnesium for treating preterm labour. Grimes and

Nanda indicated that magnesium sulphate is ineffective as a tocolytic, potentially

harmful to infants and unpleasant for women, while Simhan and Caritis in their review

discredited the use of magnesium sulphate as a tocolytic citing absence of efficacy and

a possible increase in side effects, particularly fetal death73,74.

11

LEG CRAMPS IN PREGNANCY While some studies have shown a useful role

for magnesium in the treatment of pregnancy-induced leg cramps, others have not been

very complimentary. Dahle and colleagues worked with seventy-three women who had

leg cramps in a prospective double-blind, randomized trial. Their initial serum

magnesium levels and diurnal magnesium excretions were determined, following which

they had oral magnesium or placebo given for 3 weeks. The patients were re-

interviewed and laboratory analyses performed. In the results, the serum magnesium

levels were noted to be at or below the reference limit, but oral magnesium substitution

was associated with a significant decrease in leg cramps distress41. Another double-

blind, randomized controlled trial designed to assess the role of oral magnesium

substitution using 360mg magnesium lactate or citrate daily failed to demonstrate any

significant difference in the frequency and intensity of leg cramps reported by the

patients over a 2-week period, though there were more dropouts in the placebo group75.

Young and Jewell in a Cochrane review later concluded that if a woman found cramps

troublesome in pregnancy, the best evidence was for magnesium lactate or citrate taken

as 5mmol in the morning and 10mmol in the evening42.

POSTPARTUM UTERINE CRAMPS The severity of postpartum uterine cramps

has also been related to the drop in serum magnesium after delivery. A double-blind

study in which one group was given magnesium therapy after delivery (500mg

magnesium lactate 4 times a day) or placebo resulted in a significant increase in

magnesium level in the magnesium-treated group, a change that was associated with

improvement in uterine discomfort compared to the placebo-treated group76. In the work

by Meier and colleagues, two groups of women were studied for at least 4 weeks until

12

delivery with the magnesium group given between 15mmol and 30mmol magnesium

aspartate per day. The results of the study showed that there was less report of

postpartum cramps and less need for spasmolytic in the magnesium group15.

FETAL GROWTH AND WELLBEING The foetus is said to be a strict parasite to

the mother, but on this matter of magnesium the fetal stores are generally a marker of

what is available in the mother. There is evidence that the mineral contents of foetuses

and neonates have a wide range at any given age, possibly reflecting maternal stores

and intake, and placental integrity; and infants born preterm have considerably less of

these minerals than do full-term infants77,78. Theoretically, the calcium and N-methyl-D-

Aspartate antagonism of magnesium could protect the developing brain from hypoxia.

FineSmith et al found that magnesium protected exposed neonates against developing

cystic periventricular leukomalacia79, but Canterino and colleagues found no benefit80.

Recently, however, two meta-analyses suggested that magnesium administration to

women at risk of delivery before 34 weeks of gestation reduced the risk of cerebral

palsy81,82, and one study concluded that the neuro-protective role for antenatal

magnesium sulphate (MgSO4) therapy given to women at risk of preterm birth for the

preterm foetus is now established.

Justification for the Study

In our environment, there are not many studies focusing on the role of

magnesium in the genesis of preeclampsia, gestational diabetes, and preterm labour or

adverse fetal outcome. Interestingly, these conditions together contribute significantly to

the high maternal and perinatal mortality and morbidity experienced in this part of the

world. Most of the existing data on levels of serum magnesium in pregnancy and their

13

role in adverse pregnancy outcome were done many years ago and were mainly done

among Caucasians. Where evidence is available from studies done among blacks these

are usually African-Americans who may not truly represent the situation in black

Africans living in Africa! The paucity of local studies in this area serves as an attraction

considering the consequences of late diagnosis, inadequate clinical management and

the unfortunate poor health-seeking behavior of the population with great impact on the

associated morbidity and mortality of these diseases.

Magnesium levels are not routinely assayed in pregnant women. This means that

those who are deficient may not be detected, and therefore, are not likely to benefit from

treatment. In order to assess if our pregnant women have significant levels of

hypomagnesaemia studies have to be generated, so that possible risk factors can be

outlined to guide practice and identify pregnant women who may benefit from screening

and possible correction of hypomagnesaemia. These considerations justify the need for

a study to determine the serum magnesium levels of our pregnant women, assess the

frequency of magnesium deficiency, and correlate pregnancy outcomes with levels of

serum magnesium with a view to establishing relevant associated factors in our

environment. And these further highlight the importance of this study, the findings of

which will contribute to an increased understanding of pregnancies complicated by

hypomagnesaemia, while setting the stage for a new vista of interventional research to

improve maternal and fetal outcome in our women.

As it is being advocated in other areas of public health interest, preventive

medicine remains the key to improving the health status of our women. Should

magnesium deficiency be found to be common in pregnancy, and a link is established

14

with serious conditions like preeclampsia, gestational diabetes and intrauterine fetal

death, then a recommendation for routine magnesium substitution will become

necessary to reduce their toll on the health of our mothers and their babies.

15

OBJECTIVES

The primary objective of this study will be to determine the levels of serum

magnesium in pregnant women in Benin City.

Secondary objectives:

1 To determine the levels of serum magnesium in abnormal range.

2 To determine the influence of low serum level of magnesium on pregnancy

outcome.

16

STUDY HYPOTHESIS (ALTERNATE)

Low levels of serum magnesium are common in pregnancies, and affected

pregnancies may be at higher risk of adverse materno-fetal outcome compared to

women with normal serum magnesium levels.

17

METHODOLOGY

SETTING: This study was conducted at the Obstetrics and Gynaecology Department of

the UBTH, Benin City. The hospital is a major referral centre in the south-south of

Nigeria. Patients attending antenatal care here come from neighbouring states of Delta,

Ondo, Ekiti, Kogi as well as from other health facilities within Edo State. Within the

hospital, the major portal of entry for pregnant women is the general practice clinic

(GPC) from where they are referred to the antenatal clinic for booking. Some patients

are also referred from other departments within the hospital when they are discovered

to be pregnant by their primary care doctors.

On the average, between 75 and 120 patients are booked for antenatal care

every week in the hospital, while follow up attendance rate is between 250 and 300

patients per week. The delivery rate in the hospital in the last few years has been about

2,700 per year, which gives an average monthly delivery rate of 225.

Magnesium assay was carried out in the Department of Clinical Chemistry of the

hospital.

STUDY DESIGN: This was a prospective cohort study of patients attending antenatal

care at the University of Benin Teaching Hospital (UBTH). The subjects were healthy

pregnant women with uncomplicated pregnancies at the time of enrollment. These

patients had their blood drawn for serum magnesium measurement at enrollment, and

thereafter, at delivery. Subsequently, they were followed up till delivery and discharge

from hospital, or up to one week post-delivery.

18

A pilot study was carried out to determine the normal levels of serum magnesium

in patients attending UBTH. Subjects for the pilot study were selected at the GPC which

is likely to comprise of a mix of patients of varying background, as this is an outpatient

unit of the hospital. All consecutive patients who met the criteria for inclusion in the

study were recruited until the required numbers of enrollees were achieved. The pilot

group consisted of both pregnant and non-pregnant women so as to define a mean

serum magnesium level for the population of patients attending UBTH. The pregnant

women were selected from all three trimesters. There were 60 pregnant and 60 non-

pregnant subjects representing 75% of the projected sample size in the study proper. A

single blood sample was taken from each subject to determine serum magnesium level.

SELECTION OF SUBJECTS AND CLINICAL MANAGEMENT: The subjects in the

main study were patients who had antenatal care in UBTH and delivered during the

study period. All patients who met the criteria for inclusion were counseled and given a

consent form, and those who elected to participate in the study were enrolled until the

sample size was achieved. Due counseling on the nature of the study, the amount of

blood to be drawn, the details of the subsequent follow up, and the time of termination

of the study for each patient was given. The women were told that participation was

voluntary and that they were free to withdraw at any time. They were also told that their

decision to participate or not participate in the study will not affect their care. Their

written consent was obtained if they decided to join the study. (Appendix III)

Evaluation of the patients commenced between 24 and 26 weeks gestation. This

period was chosen because most existing data are in agreement that serum

magnesium levels in pregnancy decreased before the third trimester11,29,30, while others

19

emphasize a fall in the third trimester10. This suggests that the effects due to changes in

serum magnesium levels in pregnancy may be most marked in the later part of

pregnancy.

The 160 participants were recruited over two weeks, and were then followed up

till delivery and one week postpartum. Routine antenatal care was given unless

complications arose. Routine antenatal investigations and drugs were prescribed. All

complications in pregnancy and outcome of delivery were then noted. The participants

were advised to avoid taking magnesium supplements.

In particular, all patients were assessed for occurrence of leg cramps in

pregnancy, and after delivery, the presence of and need to treat uterine cramps were

evaluated. Following delivery, the mothers were followed up in the lying-in ward along

with the babies. For the babies admitted to the special care baby unit (SCBU), their

follow up was done in conjunction with my colleagues in the neonatal unit.

The subjects were divided into two groups at the end of the study following the

determination of their serum magnesium levels at recruitment. This was necessary to

avoid the ethical issues concerning withholding treatment should any of the patients

have a laboratory report of hypomagnesaemia as determined by the standards of the

study. The study thus comprised: Group A with those who had serum magnesium levels

less than 2 standard deviations (SD) below the mean of the pilot study; and Group B

were patients with serum magnesium levels from 2SD below the mean to above the

mean. Hypomagnesaemia was defined as less than 2SD below the mean serum

magnesium derived from the pilot study.

20

SAMPLE SIZE DETERMINATION

In evaluating pregnancies with respect to hypomagnesaemia, a previous study showed

that hypomagnesaemia occurred in 44% of a pregnant rural Indian population27. I

attempted to detect a 50% decrease in pregnant Nigerian women in the current study

who were largely urban dwellers. Accepting a statistical power of 80%, confidence

interval of 90%, with the level of significance set at 0.05, and up to 10% of the

participants expected to drop out, the required sample size was calculated from this

formula:

n = 1 x 2 x (Zα + Zβ)2 x P x (1 – P) 83

1 – f (P0 – P1)2

Where n = minimum sample size

P0 = rate of hypomagnesaemia in pregnancy in previous study

P0 = 44% = 0.44

P1= Proportion of pregnant Nigerian women expected to have

hypomagnesaemia.

I accepted a 50% decrease in the reported rate so that

P1 = 0.44 – (0.44 x 0.5) = 0.22

Zα = determined from a statistical table based on the value of the level of significance

and for this study we set α at 0.05. Therefore, Zα = 1.96

Zβ = determined from a statistical table based on the acceptable power of comparison

between 2 groups. For this study, we used a power of 80% (0.80). Therefore, Zβ = 0.84

21

f = proportion of study participants who are expected to drop out. For this study f = 10%

(0.1)

P = P0 + P1 = 0.44 + 0.22 = 0.33

2 2

Therefore, the minimum sample size required for each study group will be:

n = 1 x 2 x (1.96 + 0.84)2 x 0.33 x (1 – 0.33)

1 – 0.1 (0.44 – 0.22)2

n = 79.5, which is approximately 80.

Therefore, a total of 160 patients were recruited for this study.

SPECIMEN COLLECTION AND LABORATORY PROCEDURES

Five milliliters of venous blood was drawn from each patient at enrollment and

subsequently at delivery for assay of serum magnesium. The blood was collected in a

20ml plain plastic container and immediately transferred to the clinical chemistry

laboratory where serum was separated by centrifugation at 2000rpm following clot

retraction. The separated serum was then frozen at -800C until the time for analysis.

Analysis was done by a direct method (calmagite method) in the clinical

chemistry laboratory using the kit (by TECO DIAGNOSTICS, CALIFORNIA, USA) which

defines adult reference range as 1.3 - 2.5 mEq/L84. The kit consists of magnesium

buffer reagent, magnesium colour reagent and magnesium standard (which has a

concentration of 2mEq per litre).

Principle of the Assay Method: Magnesium forms a coloured complex with

calmagite in alkaline medium to produce a red complex that can be measured

spectrophotometrically at 530nm. Ethylene glycol tetra-acetic acid(EGTA) in the buffer

22

reagent serves to complex and prevent calcium interference, while the surfactant in the

colour reagent eliminates the effect of protein. The intensity of the colour produced is

proportional to the magnesium concentration.

Procedure: The working reagent was prepared by mixing ten (10) volumes of the

colour reagent with one (1) volume of the buffer reagent in a disposable plastic

container. The procedure involved dispensing 1ml of the working reagent into test tubes

labeled as ‘blank’, ‘standard’, ‘control’, and ‘test’. Thereafter, 0.01ml of the patient’s

serum was added to the test tube labeled “test” and gently mixed. The standard, blank

and control were similarly constituted and all mixtures were then incubated for 5

minutes at room temperature. After incubation, the spectrophotometer was zeroed with

the blank at 530nm (range: 500-550nm), and thereafter, the absorbances (Abs) of the

samples were read and recorded. The concentration of magnesium was derived from

the formula:

Abs of Test Concentration of the Standard (2mEq/L)

Abs of Standard

Reference range for the test kit is 1.3-2.5mEq/L.

The triplicate mean was taken for each sample.

Sensitivity and Coefficient of Variation: The sensitivity of the test was

determined by serial dilution of the standard (with a known concentration of 2mEq/L) to

detect at which dilution the level of magnesium will no longer be recordable. Serial

dilution was done until the level of the lowest detectable concentration of 0.225mEq/l at

1:8 was derived. The limit of linearity for the test is 4.0mEq/L84.

23

Precision studies84 done using this magnesium assay method revealed that the

intraobserver coefficient of variation at a mean of 1.7±0.1mg/dl and 3.7±0.1mg/dl were

5.7% and 6.0% respectively. Similarly, the interobserver coefficient of variation at a

mean of 1.7±0.1mg/dl was 5.7%.

OUTCOME MEASURES

Primary outcome measure was the rate of hypomagnesaemia in pregnancy. The

hypomagnesaemic and normomagnesaemic groups were also compared for maternal

socio-demographic characteristics, maternal and neonatal outcomes such as frequency

of preeclampsia/pregnancy induced hypertension, intrauterine growth restriction,

gestational diabetes mellitus, preterm labour, stillbirth rate, leg cramps, postpartum

uterine cramps, birth asphyxia, low birth weight, special care baby unit (SCBU)

admission and early neonatal death.

INCLUSION CRITERIA

All healthy patients of gestational age between 24 weeks and 26 weeks attending

antenatal care in UBTH during the study period were eligible. For all participants,

sociodemographic data including age, parity, occupation and level of education of the

patient and her spouse, estimated gestational age, as well as relevant clinical

parameters were entered into a data extraction sheet (Appendix I), and used to

generate a database. The social classes of the women were determined from Olusanya

et al classification, making use of the educational status of the woman and her

husband’s occupation85. (Appendix II)

24

EXCLUSION CRITERIA

Patients with the following conditions were excluded from the study:

peptic ulcer disease patients placed regularly on magnesium-containing antacids,

multiple pregnancy,

pre-gestational diabetes,

chronic hypertension,

chronic renal disease,

sickle cell anaemia,

intrauterine growth restriction,

retroviral infection or acquired immune-deficiency syndrome (AIDS).

ETHICAL CONSIDERATION

Ethical approval for this work was obtained from the Research Ethics Committee of the

University of Benin Teaching Hospital (Appendix V). All participants were adequately

counseled and their written consent obtained before enrollment into the study. The

study was open to all women attending antenatal clinic who met the inclusion criteria.

No particular group, tribe or religion was selectively chosen to participate in the study.

The participants benefitted from the close observation they received in the course of the

study, and no extra cost or additional visit was required of the participants.

DATA MANAGEMENT

All results were entered into a proforma (Appendix I) and analysis was done with

a personal computer using the SPSS for Windows version 15.0. Categorical variables

are expressed as absolute numbers and percentages and significant differences were

determined using the Chi square test or Fisher exact test where appropriate, while

25

continuous variables are presented as means with standard deviations and significant

differences were determined with the Student t test. The level of significance was set as

p<0.05.

FUNDING

This study was funded by the researcher with assistance from the head of clinical

chemistry department of UBTH.

LIMITATIONS

An important limitation of this study is that it is teaching hospital-based, and so

may have been open to only a select group in the population, viz. the elites of the

society.

It has been recognized that the use of ion-selective electrode is the best way to

assess serum magnesium. In this study, a direct (Calmagite) method was used as it is

less expensive and easily available. However, the use of Atomic Absorption

Spectroscopy is a better method of determining magnesium levels.

Many researchers also express concern that serum magnesium levels as

determined in this study may not necessarily reflect the ionized magnesium status.

And the use of frozen samples might have introduced some variability in the

assay of serum magnesium compared with immediate determination using freshly

centrifuged blood samples.

26

RESULTS

There were 120 subjects in the pilot group, made up of 60 pregnant women with

20 from each of 1st, 2nd, and 3rd trimesters, and 60 non-pregnant women. The mean

age, parity and body mass index of the pregnant and non-pregnant subjects were not

significantly different. The mean serum magnesium for the pilot group was

2.01±0.49mEq/L; SE 0.039, 95% CI 1.93--2.09(Table 1; Figure 1). The mean serum

value for the pregnant population in the pilot study was less than that of the non-

pregnant women. Whereas the mean for the non-pregnant women was

2.46±0.43mEq/L, in the pregnant population, the mean declined steadily from a value of

1.93±0.57mEq/L in the first trimester, through 1.73±0.29mEq/L in the second trimester

to1.45±0.18mEq/L in the third trimester, which showed a decreasing trend in serum

magnesium level as gestational age increased (Table 1). In the main study,

hypomagnesaemia was defined as any serum magnesium level lower than (Mean

minus 2SD in mEq/L) of the pilot study (that is less than 1.03mEq/L).

In the main study, 160 participants were recruited. All 160 participants remained

in the study till delivery. Table 2 shows the level of hypomagnesaemia in the main study

population. The mean serum magnesium level at recruitment was 1.54±0.46mEq/L,

while at delivery it was 1.37±0.45mEq/L (P=0.00). The frequency of hypomagnesaemia

in this study was 16.25% with 26 out of the 160 patients having serum magnesium

levels less than 1.03mEq/L at recruitment. The frequency however increased at delivery

to 40 out of the 160 subjects (25%), though this difference in proportion was not

statistically significant (P=0.07). Ten out of the 14 patients who subsequently had their

serum magnesium level decreased at delivery had developed preeclampsia in the

27

course of pregnancy. There were 10 other patients with preeclampsia whose serum

magnesium levels remained normal. Fourteen patients were taking self-prescribed

multivitamin in the whole group. Despite this, 8 of them had hypomagnesaemia.

Table 3 depicts the frequency of hypomagnesaemia in correlation with maternal

socio-demographic characteristics. The age of the subjects ranged from 19 years to 36

years with a mean age of 30.14±3.76 years. There were 4 patients under the age of 20

years and all of them had hypomagnesaemia (P=0.00). The other age group with

significant level of hypomagnesaemia was 30-39 years with a frequency of 20.75%

(P=0.04). Most of the patients had parity between 1 and 4 which contributed 67.5%,

while the nulliparas made up the remaining 32.5%. There were more cases of

hypomagnesaemia among paras 1 to 4, but this observation was not statistically

significant (P=0.11). With respect to social class, most (48.8%) of the patients were in

social class 1, and they also made the highest number of patients with

hypomagnesaemia (P=0.03). There were 8 patients in social class 4 and all 8 had

magnesium deficiency (P=0.00). The prevalence of obesity in the group was 21.3% and

none of the obese women had hypomagnesaemia (P=0.00). Most cases of

hypomagnesaemia were in the overweight category but this relationship was not

statistically significant (P=0.28).

Table 4 shows the maternal adverse outcome related to hypomagnesaemia. The

development of preeclampsia was significantly higher in the hypomagnesaemic group

where 10 out of 26 (38.5%) patients were involved compared with 20 out of 134 patients

in the normomagnesaemic group (P=0.01). There were no cases of glucose intolerance

in the patients. Intrauterine fetal death was not encountered in this study. Most (94.7%)

28

of the patients who had symphysiofundal height smaller than date at the time of delivery

were in the normomagnesaemic group (P=0.02). The level of preterm birth was

generally low in this study. All the subjects in this study delivered after 34 weeks

gestation. There were 8 (30.8%) out of 26 patients in the hypomagnesaemic group who

delivered before 37 weeks while out of a total of 134 patients in the normomagnesaemic

group, 16 (11.9%) patients delivered preterm. This difference was statistically significant

(P=0.03).

The occurrence of leg cramps was significantly more in the hypomagnesaemic

group compared with patients who had higher serum magnesium levels (P=0.01). The

presence of postpartum uterine cramps was not related to the prevalence of

hypomagnesaemia in this study. There were 34 subjects who reported postpartum

uterine cramps, but only 2 of these had low serum magnesium levels (P=0.18)

Table 5 shows the rate of adverse perinatal outcome in this study. Adverse

perinatal events were generally rare. There were 12 cases of low birth weight babies

with 2 (7.7%) of them born to mothers who had low magnesium levels, but this did not

reach statistical significance (P=1.00). There were 20 babies with birth asphyxia in this

study out of which 4 were from hypomagnesaemic women, but the difference was not

statistically significant (P=0.75). Of the 8 babies admitted to the SCBU for moderate

birth asphyxia none were in the hypomagnesaemic group (P=0.43). All 8 babies were

transferred to their mothers within 96 hours of admission. There was no record of early

neonatal death as all the babies were discharged home with their mothers.

29

Table 1: Baseline serum magnesium levels amongst pregnant and non-pregnant

women in UBTH.

Trimester of pregnancy Serum magnesium concentration (mEq/L)

mean SD SE 95% CI

Non-Pregnant

First Trimester

Second Trimester

Third Trimester

P-value

2.46

1.93

1.73

1.45

0.00

0.43

0.57

0.29

0.19

0.013

0.065

0.042

0.055

1.90 – 1.95

1.59 – 1.87

1.36 – 1.53

2.35 – 2.57

SD – Standard Deviation

SE – Standard Error of the Mean

CI – Confidence Interval

30

Figure 1: Dot plot of serum magnesium levels of pilot study

31

Table 2: Frequency of maternal hypomagnesaemia at enrollment and delivery

Gp A(n=26)

frequency(%)

Gp B(n=134)

frequency(%)

P value

Enrollment 26(16.25) 134(83.75) 0.07

Delivery

40(25)

124(75)

Values are given as number (percent)

32

Table 3: Maternal socio-demographic characteristics in relation to hypomagnesaemia

Characteristic Frequency (%) P-value

Gp A(n=26) Gp B(n=134)

Age(years)

<20

20-29

30-39

4(15.38)

0(0)

22(84.62)

0(0)

50(37.31)

84(62.69)

0.00

Parity

0

1-4

12(46.15)

14(53.85)

40(29.85)

94(70.15)

0.11

Body Mass Index(BMI)

Kg/M2

Normal

Overweight

Obese

Social class83

1

2

3

4

10(38.47)

16(61.53)

0(0)

18(69.23)

0(0)

0(0)

8(30.77)

36(26.87)

64(47.76)

34(25.37)

60(44.78)

42(31.34)

32(23.88)

0(0)

0.00

0.00

33

Table 4: Adverse maternal outcome

Variable Gp A(n=26)

frequency(%)

Gp B(n=134)

frequency(%)

P value

Hypertension/Preeclampsia 10(38.46) 20(14.93) 0.01

Leg cramps 18(69.23) 34(25.37) 0.01

Preterm labour

Postpartum cramps

8(30.77)

2(7.69)

16(11.94)

32(23.88)

0.03

0.18

Values are given as number (percent).

34

Table 5: Adverse perinatal outcome

Characteristic Gp A(n=26)

frequency(%)

Gp B(n=134)

frequency(%)

P value

Low birth weight 0(0) 12(8.96) 1.00

Birth asphyxia 0(0) 20(14.93) 0.75

SCBU admission 0(0) 8(5.97) 0.43

Abbreviation: SCBU, special care baby unit.

Values are given as number (percent).

35

DISCUSSION

The pilot study conducted to establish a baseline serum magnesium level for the

patients attending UBTH revealed that the serum magnesium level was significantly

lower in the pregnant population compared to the non-pregnant women. In addition, a

tendency toward reducing serum levels as pregnancy advanced was observed. It has

been established in many studies that serum magnesium values are reduced during

pregnancy10,11,39,40. This observation is attributable to the increasing need for

magnesium in the mother and baby as pregnancy advances, and it may be amplified by

the consistent reports by previous workers that magnesium intakes in pregnancy fell

short of the recommended daily allowance4-8.

Also in the pilot study, the fall in serum magnesium value was most marked

between the first and second trimesters. Similar observations have been made by

previous workers11,39,40, while others emphasized a fall in the third trimester10.

Suggested reasons for the low levels of magnesium in pregnancy include inadequate

intake, increased metabolic demand of pregnancy especially as gestation advanced,

physiological haemodilution in pregnancy, and increasing parity1,9,37,43,84.

The main study revealed that 16.25% of our pregnant women had deficiency of

magnesium as revealed by the serum level at recruitment (24-26weeks). The definition

of normal serum magnesium for the population was as determined in the initial pilot

study. Hence this prevalence may be different from figures reported by other

investigators working in different populations. Pathak et al reported 43.6%37 amongst

rural Indian women in a community-based cross-sectional study, while a previous

hospital-based pilot study involving urban Indian dwellers reported magnesium

36

deficiency in 4.6%85 of all pregnant women included in the study. Another reason for this

difference may be the period in pregnancy included in the study. This study evaluated

pregnant women at the end of their 2nd trimester, which is similar to the work by Pathak

et al who recruited women from their 28th week of pregnancy37, and this can explain the

high levels of magnesium deficiency reported in both studies; though the prevalence in

the present study was lower probably due to the involvement of largely urban dwellers

in a teaching hospital setting. Again the documented magnesium deficiency in 4.6% of

pregnant women by Kapil et al is low but this observation can be explained by their

inclusion of pregnant women from as early as 12 weeks gestation.

In this study, being a teenager was significantly associated with magnesium

deficiency, and to a lesser degree, the age group 30-39 years was also correlated with

hypomagnesaemia. This may explain the similarity with the findings of Pathak et al who

had 75 % of their study subjects in the age group 18-22 years37. This study also

revealed a higher frequency of magnesium deficiency in the group of paras 1-4 but this

association was not statistically significant. This is, however, closely related to the

finding by Pathak et al that there was a decrease in serum magnesium with increase in

parity37. In their study, pregnant women with parity 2 or more had a significantly lower

serum magnesium level (1.77±0.35mg/dl) compared to nulliparous pregnant women

(2.01±0.57mg/dl); and further logistic regression analysis showed that women with a

parity 2 or more were at a 2.59 times higher risk of magnesium deficiency (P=0.002)

compared to the nulliparous pregnant women. To explain this relationship some

investigators have proposed that frequent cycles of reproduction exert a significant

stress that leads to a greater risk of malnutrition in pregnant women86.

37

Social class 4 was significantly correlated with the occurrence of magnesium

deficiency in the main study. This is similar to previous reports that lower income

women had lower magnesium intake 4-8, which results in a higher negative magnesium

balance, hence the association of low socio-economic status with magnesium

deficiency. Low socio-economic status has also been associated with preterm

labour/delivery, intrauterine growth restriction and low birth weight, which have all been

linked to hypomagnesaemia25-29. It is likely that low social class imposes a status of

inadequate magnesium intake in the diet because of a low consumption of green leafy

vegetables, legumes, nut, peas and soya flour.

The use of multivitamin supplements by a small group of the participants in this

study was not associated with a better serum magnesium status. In contrast, previous

studies have shown improvement in magnesium balance when patients are put on

adequate magnesium supplements with a better clinical outcome46,48,49,64. It is

noteworthy that in this study the patients who were taking additional multivitamin drugs

did not aim to take magnesium supplements, and should magnesium be present in their

multivitamin the content is likely to be negligible. This may explain the lack of

association observed in this study, as the use of additional multivitamin did not appear

to improve the magnesium balance in these subjects.

The occurrence of preeclampsia was significantly associated with

hypomagnesaemia in the main study. Several investigators in the past have also

reported a link between magnesium depletion and hypertension in pregnancy in both

animal and human studies21-24,41. This link is attributed to vascular muscle spasm in the

uterus which is thought to be produced by magnesium deficiency1. Standley and

38

colleagues in their study demonstrated that all subjects who eventually developed

preeclampsia showed a decrease in ionised Mg2+ concentration with increasing

gestational age43. In the present study, 10 patients with hypomagnesaemia at

recruitment developed preeclampsia. Another 10 patients who had normomagnesaemia

at enrollment and eventually developed preeclampsia, showed low serum magnesium

levels at the time of diagnosis. The remaining 10 patients had normal mean serum

magnesium level at the time of diagnosis; however, they showed a decrease from a

mean of 1.41±0.41mEq/L at recruitment to 1.22±0.08mEq/L at delivery, and this is in

agreement with the report of Standley and colleagues43. This is likely part of the reason

for the decrease in mean serum magnesium level to 1.37±0.45mEq/L in labour from

1.54±0.46mEq/L at enrollment. This relationship between hypertension and magnesium

lack has led some researchers to advocate for the use of supplemental magnesium to

reduce the risk of developing hypertension48,49.

Patients who had low magnesium levels in this study were more likely to report

leg cramps. This finding is in agreement with reports of several other studies15,30-32.

Dahle and colleagues in a prospective double-blind, randomized trial interviewed a

group of women before and after supplementation with magnesium, and their results

showed that oral magnesium substitution was associated with a significant decrease in

leg cramps distress31. Similarly, a Cochrane review by Young and Jewell also supported

evidence for magnesium lactate or citrate in the treatment of muscle cramps in

pregnancy73.

The risk of having preterm birth was significantly higher for women with

magnesium deficiency in this study. This finding agrees with previous studies which

39

noted that women with magnesium deficiency tended to deliver prematurely, hence the

application of magnesium sulphate in the treatment of preterm labour67. There have also

been several reports of improved outcome in patients given magnesium supplements

with evidence of reduced preterm births, fewer hospital admissions and reduced

neonatal intensive care admission rates for the babies46. Symphysiofundal height

discrepancy during pregnancy did not predict hypomagnesaemia in this study.

The literature supports a possible role for magnesium deficiency in the causation

of postpartum uterine cramps. In contrast, our findings in the present study did not show

any correlation between magnesium lack and the occurrence of postpartum uterine

cramps. This may be so because those studies reporting an association were

interventional and involved the use of supplemental magnesium salts without a

documentation of deficiency. And this makes it difficult to say what level of deficiency is

critical for uterine cramps to be significant. It is also possible that other factors may be

involved in the determination of what the patient considers to be significant uterine

cramps necessitating reporting, such as previous experience during breastfeeding,

parity, age, mode of delivery and emotional state.

With respect to perinatal outcome, the findings of this study did not show any

relationship between magnesium lack and the rates of low birth weight, birth asphyxia or

special care baby unit admission contrary to the previous reports of some other workers

12,46. However, the findings in the present study are not surprising considering the fact

that all the babies were delivered after the 34th week of gestation, and so perinatal

outcome was expectedly favourable.

40

CONCLUSION AND RECOMMENDATIONS

This study found a magnesium deficiency level of 16.25% and revealed that

pregnancy is associated with reduced serum magnesium concentration as gestation

advanced. The factors in the woman which may determine the degree of manifestation

of magnesium lack were shown in this study to include young age, high parity and low

socio-economic status. The relationship of a negative magnesium balance to

preeclampsia, preterm delivery and muscle cramps in pregnancy was confirmed in this

study. It is noteworthy that the toll on maternal health and perinatal indices from a

combination of preeclampsia and preterm delivery remains significant in our

environment.

From the findings of this study, magnesium balance needs to be improved in our

pregnant women. A viable way to reduce the prevalence of conditions caused by

magnesium lack will be the achievement of normal magnesium balances in pregnancy.

This can be attained through nutritional counselling. I recommend that the average diet

in this environment be evaluated in a nutritional study to determine the content of

magnesium. The diet with the highest amounts of magnesium can be advised for

women who are at risk of magnesium deficiency.

The assay of magnesium ion is non-routine and expensive, but total serum

magnesium which was assayed in this study will suffice, being a reliable indicator of

biologically active magnesium. Even then, it is also likely that many women who are

deficient may not show it early because less than 1% of total body magnesium is found

in the blood, so that doing a blood test may not necessarily identify a deficiency state. It

is this possibility of completely missing a magnesium-deficient patient that gives

41

credence to the use of associated factors as shown in this study. At-risk patients who

are so identified will thus benefit from either dietary advice or magnesium substitution.

The literature supports the use of magnesium supplementation in women who

are found to be magnesium-deficient. Hence, some units have adopted the policy of

routine magnesium substitution throughout pregnancy. Ascertaining the magnesium

content of our local diet may be difficult because of the diversity of our diets which relies

strongly on our socio-cultural backgrounds. A possible way to overcome this is the

supplementation of the diet with oral magnesium. From the findings of this study,

magnesium lack is likely to be pronounced in the last trimester of gestation. All patients

should therefore be supplemented with oral magnesium in their second trimester, or

magnesium-rich diet especially consisting of green leafy vegetables, legumes, nuts,

peas, soya flour or shellfish be advised at this stage of pregnancy.

I recommend that this policy of routine supplementation be directed at young,

lower income women or those with high parities commenced in the second trimester of

pregnancy, as these are women who have been shown to be at higher risk of negative

magnesium balance in this study. It is believed that prescribing drugs or diet to enhance

magnesium status at a particular time in pregnancy is likely to be accepted as a useful

intervention when it is carefully explained to the women that its use is prophylactic, just

like giving haematinics or antimalarials in pregnancy. It is also necessary to continue to

stress the need for a balanced diet during pregnancy as other micronutrients remain

vital to the metabolic needs of the woman and her baby.

On a more general note, discouragement of teenage pregnancy and delivery will

help to reduce the risk of hypomagesaemia in young mothers. Similarly, observing a

42

standard period of birth-spacing to allow the body to replenish its stores of essential

nutrients including magnesium will help to reduce the prevalence of low magnesium in

pregnancy. Furthermore, improving the socio-economic status of every woman through

education and social emancipation, as well as economic empowerment will directly

translate to giving them the means to better their magnesium balance in or out of

pregnancy.

I recommend that a population-based cross-sectional study be conducted to

strengthen the findings of this study. This is necessary because the sample size will be

larger and likely to be more representative, so that the defects arising from a hospital-

based study will be eliminated. In the same vein, nutritional surveys or interventional

studies can be embarked on to prove the efficacy or otherwise of dietary counseling or

magnesium substitution in pregnancy. Further research can be done in this area to

determine the magnesium content of our diet and thus assess the magnesium intake in

our pregnant women.

43

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52

DATA EXTRACTION SHEET

SERUM MAGNESIUM LEVELS AND MATERNOFETAL OUTCOME

Consultant Date:

(1) Name: (2) Hospital Number

(3) Self-prescribed multivitamin………………………Yes No

(4) Age: .................................................. (5) Parity: ................................................

(6) Height (meters):… (7) Weight (kg):… (8) BMI (Kg/m2)….

(9) Occupation: ....................................... (10) Level of Education: ..........................

(11) Husbands’ Occupation: ................... (12) Husbands’ Level of Education: ........

(13) Social Class: 1 / 2 / 3 / 4 / 5 .........................................

(14) Gestational Age at Recruitment …. (15) Gestational Age at Delivery….

(16) Mg at Recruitment…. (17) Mg at Delivery….

(18) Blood pressure (a): Recruitment… (b): 4wk… (c): 8wk… (d): Delivery…

(19) Urinalysis (a): Recruitment… (b): 4wk … (c): 8wk… (d): Delivery…

(20) Fundal height (a): Recruitment… (b): 4wk… (c): 8wk… (d): Delivery…

(21) Leg cramps Y/N (22) Preterm Y/N (23) IUFD Y/N (24) Postpartum cramps Y/N

(25) Neonatal outcome Alive/Stillbirth (26) Sex M/F (27) Apgar scores 1min…

(28) Birth weight… (29) SCBU Y/N (30) If Yes, Indication: …

(31) Early neonatal death Y/N

53

SCORING SYSTEM FOR SOCIAL CLASS

A. Husband’s occupation

Score: 1. Professionals, top civil servants, politicians and

businessmen.

2. Middle–level bureaucrats, technicians, skilled artisans

and well-to-do traders

3. Unskilled workers and those in general whose income

would be at or below the national minimum wage.

B. Level of education attainment

Score: 0. Education up to university level

1. Secondary or tertiary level below the university (e.g.

college of education, school of nursing etc).

2. No schooling or up to primary level only.

SOCIAL CLASS = Score A + Score B.

Courtesy: Olusanya O, Okpere E, Ezimokhai M. (West.Afr.J Med 1995; 4: 205-

212).

54

RESEARCH CONSENT FORM

Title: Serum magnesium levels and maternofetal outcome in pregnant Nigerian women

Invitation: You are being asked to join a research study. This form contains information

about the study. It is completely voluntary whether or not you join the study. If you

decide not to join this study you will continue to receive care from this hospital and your

decision will not affect the type of care you will receive.

Purpose: The purpose of this study is to know the level of a nutrient called magnesium

in pregnant women, and to estimate how many pregnant women have insufficient

amounts of the mineral so as to understand how it affects your pregnancy and baby.

Number of participants: 160 women will be enrolled in this study.

Procedures: We will test your blood to know your magnesium level by taking 1

teaspoon (5ml) of blood today. During the antenatal period, you will be checked every 4

weeks for evidence of high blood pressure, diabetes, muscle cramps and slow growth of

your baby. At delivery, we will take another teaspoon of blood to recheck your

magnesium level. During the postpartum period, you will be checked for occurrence of

uterine cramps and be followed up with your baby until discharge.

Benefits: If we find you have developed any of the conditions above, you or your baby

will be adequately treated. You and your baby could benefit in future from research done

in this study because we will learn more about magnesium levels in pregnancy.

Confidentiality: All data collections and interviews will be conducted in a private section

of the clinic. The information will be kept confidential and private.

Consent: A copy of this consent form will be provided to you.

All my questions about this study have been answered Yes No

I give approval to use collected specimens for this study Yes No

I want to participate in this study Yes No

Volunteer signature

55

Pidgin English Version of Consent Form

Title: How magnesium for blood dey affect mama and pikin wey dey for belle as woman

get pregnancy.

Invitation: I want make u join this study for this hospital. This paper wey dey for my

hand go talk about the study. Na u go choose whether or not to join this study. If you

choose not to join this study you go continue dey come for your antenatal clinic for this

hospital, and we go dey take care of u and your pikin whether u join or not.

Purpose: The reason for this study na to know how much of the mineral wey be

magnesium dey for pregnant woman body, and to know how many pregnant woman wey

their magnesium mineral small so that we go fit understand how the mineral dey affect

mama and e pikin wey dey belle.

Number of participants: Na 160 women go join the study.

Procedures: We go test your blood to know your magnesium mineral with small blood

wey go full teaspoon today. As your belle dey grow we go dey check your blood

pressure, whether sugar high, whether muscle dey pain u and if your pikin dey grow too

small. For labour, we go take another teaspoon of blood. After u born we go dey check

whether u get pain for belle and we go check your pikin until u and your pikin go house.

Benefits: If we find say u or your pikin get any of de problem, u or your pikin go get

proper treatment. U or your pikin fit enjoy for future from the result we go find becos we

go com sabi well how mineral magnesium dey for pregnancy.

Confidentiality: All the talk and blood we go take go be for private place for clinic so

that only u go know wetin we talk about. De thing u go tell us go be secret wey no other

person no know about.

Consent: I go give u one of de paper wey we write all this talk put.

I don answer all your question wey u get for mind Yes No

U give permission to take your blood for this study Yes No

U wan join de study Yes No

Volunteer signature/thumb print

56

MAGNESIUM ION CONVERSION TABLE

48mg Magnesium ion is equivalent to:

4.06mEq

2.03mmol

57