Kafulafula,
G.E., Moodley, J., Ojwang, P.J. and Kagoro, H. (2002), Leptin and
pre-eclampsia in Black African parturients. BJOG: An International
Journal of Obstetrics & Gynaecology, 109: 1256–1261.
doi: 10.1046/j.1471-0528.2002.02043.x
Author Information
1
Department of Obstetrics and Gynaecology, Nelson R. Mandela School of Medicine, University of Natal, Durban, South Africa
2
MRC/UN Pregnancy Hypertension Research Unit, Nelson R. Mandela School of Medicine, University of Natal, Durban, South Africa
3
Department of Chemical Pathology, Nelson R. Mandela School of Medicine, University of Natal, Durban, South Africa
4
Nelson R. Mandela School of Medicine, University of Natal, Durban, South Africa
**
Dr J. Moodley, Department of Obstetrics and Gynaecology, Nelson R.
Mandela School of Medicine, Private Bag 7, Congella 4013, South Africa.
Objective
To measure serum concentrations of the hormone leptin during late
pregnancy in Black African women with pre-eclampsia, healthy
normotensive pregnant women as controls and healthy normotensive
non-pregnant women; secondly, to explore the relationship between leptin
and obesity.
Design Observational, cross sectional study.
Setting
Antenatal clinics, antenatal wards, gynaecology out patient and family
planning clinics of a tertiary hospital, Durban, South Africa.
Population Pregnant and non-pregnant Black African women.
Method
Serum leptin was measured by a homologous radio-immunoassay technique.
Simple anthropometric parameters were used to explore the relationship
between leptin and obesity. In each group, leptin levels were compared
between obese (body mass index, BMI ≥ 30 kg m−2) and lean women.
Main outcome measures Serum leptin concentrations, anthropometric parameters, mean blood pressures and proteinuria.
Results
There were 68 women with pre-eclampsia, 92 healthy normotensive
pregnant women (controls) and 32 healthy normotensive non-pregnant
women. Serum leptin levels were higher in pregnant compared with
non-pregnant women [26.66 (1.96) and 25.89 (1.65) vs 17.97 (2.11) ng/mL, P= 0.02]. Weight and BMI showed the greatest correlation with leptin both in pregnant (r= 0.61 and r= 0.58, respectively) and non-pregnant women (r= 0.74 and 0.79, respectively).
There was no significant difference in the mean concentrations of
leptin between women with and those without pre-eclampsia [26.66 (1.96) vs 25.89 (1.65) ng/mL, respectively, P= 0.95].
Conclusion
Pregnancy is a hyperleptinaemic state. There is no difference in serum
leptin levels between Black African women with pre-eclampsia and healthy
normotensive pregnant women. Serum leptin concentration is largely
determined by the degree of adiposity.
Ever since the discovery of the hormone leptin, as the obese (ob) gene product1,
much has been learnt regarding its physiology and association with
several human disorders. Leptin may have a wider place in human
physiology and pathophysiology than its initial role in the maintenance
and regulation of body weight. Leptin shares structural similarities
with cytokines2. This may explain its potential role in some human diseases that have a (sterile) inflammatory basis such as pre-eclampsia3.
Obesity
is a relatively common problem in pregnancy. Its complications such as
hypertension are also commonly associated with pregnancy. Genetic and
racial factors are also known to influence the occurrence of both
obesity and hypertension. The demonstration of human placenta as a
non-adipocyte source of leptin4 implicates it in obstetric disorders of placental origin such as pre-eclampsia.
The role of leptin in the development of hypertensive disease is further suggested by several studies. Narkiewicz et al.5
recently measured serum leptin levels in men with established essential
hypertension. Although they found a positive correlation between leptin
and pulse rate, they failed to show a correlation between leptin and
blood pressure. In a study on animals, Tartaglia et al.6
demonstrated the presence of central nervous system leptin receptors
and their role in the control of circulatory function. Villarreal et al.7
studied the renal effects of leptin in rats and showed that exogenous
leptin increases sodium loss, thus suggesting that leptin may be a
potential factor in the regulation of salt excretion and indeed play an
important role in the pathophysiology of hypertension.
Women
with chronic hypertension are more likely to develop pre-eclampsia but
the possible aetiologic role of leptin has not been fully investigated8. Shek et al.9
studied the influence of leptin in the development of essential
hypertension in African-Americans. They concluded that leptin does not
seem to play an important role in the development of essential
hypertension in this racial group.
Indeed, the role of leptin in pre-eclampsia remains unresolved. Sattar et al.10 found that pre-eclampsia did not affect serum leptin levels. On the contrary, Kokot et al.11
demonstrated significantly higher levels of leptin in women with
pre-eclampsia. These conflicting findings underlie the need for further
research in the relationship between leptin and pre-eclampsia, as leptin
may play a role in the management of pre-eclampsia in future. Leptin
research has mainly involved Caucasians and very little is known about
leptin in pregnant Black African women in whom both pre-eclampsia and
obesity are common.
Our aim, in this
study, was to determine serum leptin levels in pregnant Black African
women with pre-eclampsia and obesity and to evaluate the correlation
between simple (clinical) anthropometric measurements of obesity with
serum leptin levels in pregnancy.
Institutional
ethical permission was obtained for the study and all participating
women gave informed written consent. Pregnant Black African women
receiving antenatal care at King Edward VIII Hospital, Durban, were
enrolled. They were categorised to either Group 1 (pregnant women with
pre-eclampsia) or Group 2 (pregnant normotensive healthy women,
controls). Non-pregnant healthy women were similarly enrolled from the
family planning and general gynaecology out patient clinics. These were
allocated to Group 3 (non-pregnant women). Obesity was defined as a BMI
of at least 30 kg m−2)12.
Pre-eclampsia was defined as a blood pressure of at least 140/90 mmHg
recorded at least 6 hours apart after 20 weeks of gestation with
proteinuria of 0.3 g or more in 24 hours13. The highest blood pressure reading and degree of proteinuria for each woman with pre-eclampsia were recorded.
For
all groups, basic demographic data were obtained. Women with diabetes
mellitus, multiple pregnancy, known polycystic ovary syndrome and
smokers were excluded from the study. The following anthropometric
measurements were taken: total body weight in kilograms, height in
metres and circumferences of the mid-upper arm, waist, hip and thigh in
centimetres. The mid-upper arm was taken with a plastic tape measure at a
midpoint between the olecranon and the acromion process of the right
arm. Similarly, the hip circumference was measured at the level of the
iliac crest. The waist circumference was taken at the level of the
umbilicus and thigh at the midpoint between the anterior superior iliac
spine and the medial femoral condyle. Venous blood (5 mL) was obtained
by venepuncture in heparinised containers from each woman, at 0800 hours
following an overnight fast, for leptin measurement. The blood samples
were transported on ice to the chemical pathology laboratory and
immediately centrifuged at 4 °C for 10 minutes. The plasma was stored at
−20 °C pending batch analysis.
Serum
leptin concentrations were determined in the plasma samples by
radio-immunoassay using a commercial Human Leptin RIA kit (LINCO
Research, Missouri, USA). This assay utilises radioactive 125I-labelled
human leptin antiserum to determine the concentration of human leptin
in the serum or plasma samples by a double antibody/PEG technique. The
assay has a sensitivity limit of 0.5 ng/mL and its specificity is 100%.
The BMI and mean blood pressure were calculated using the formulae: BMI = wt/h2 where wt is the pregnant body mass in kilograms and h is the height in metres; MBP = 1/3 [SBP + 2 (DBP)],
where MBP is the mean blood pressure and SBP and DBP are the systolic
and diastolic blood pressures, respectively. The waist/hip ratio was
computed. Statistical analysis was performed using the statistical
programmes Epi Info Version 6 and 2000 and Statistical Package for the
Social Sciences (SPSS). Using the same programme, the appropriate sample
sizes to detect a 5.8-ng/mL difference in leptin levels between the two
paired groups are 70 in each (pregnant) group and 30 in the
non-pregnant group (α= 0.05, β= 0.1).
One-way ANOVA was employed to test significance among the groups.
Correlation between serum leptin and the anthropometric parameters were
performed by the Pearson's test. Leptin concentration values are
presented as means (SEM). All other values are presented as means (SD)
unless otherwise stated. All statistical tests were done at α= 0.05.
One
hundred and ninety-two women were enrolled in the study: 68 in Group 1
(pre-eclamptics), 92 in Group 2 (normotensive pregnant controls) and 32
in Group 3 (non-pregnant normotensive women). The demographic parameters
between the groups were similar (Table 1).
Age, parity and gestation did not show significant correlations with
serum leptin levels. The mean proteinuria level for women with
pre-eclampsia was 0.761 [range 0.300–3.800] g in 24 hours. The mean
blood pressure was higher in Group 1 than Group 2 [116.4 (8.9) vs 89.9 (3.8) mmHg, P < 0.001]. Table 2
gives a summary of the anthropometric parameters and serum leptin
levels in the three groups. Of the anthropometric parameters, waist and
waist/hip ratio showed statistically significant difference in the three
groups. Serum leptin concentration was higher in pregnant women (Groups
1 and 2), than in non-pregnant women (Group 3) (Table 2).
Table 1. Clinical characteristics. Values are given as mean (SD).
Group 1
Group 2
Group 3
P
Group 1 = women with pre-eclampsia; Group 2 = pregnant women without pre-eclampsia (controls); Group 3 = non-pregnant women.
Age (years)
28.1 (5.5)
30.5 (5.6)
29.5 (5.1)
0.56
Parity
1.8 (1.5)
2.3 (1.5)
2.2 (1)
0.12
Gestation (weeks)
34.4 (8.3)
35.5 (4.6)
not applicable
0.44
Table 2. Anthropometric parameters and serum leptin levels in the three groups. Values are given as mean (SD).
Group 1
Group 2
Group 3
P (F test)
*Statistically significant difference.
Group
1 = women with pre-eclampsia; Group 2 = pregnant women without
pre-eclampsia (controls); Group 3 = non-pregnant women; BMI = body mass
index; MAC, WC, HC and TC are circumferences of upper arm, waist, hip
and thigh, respectively; WHR = waist/hip ratio.
Weight (kg)
88.7 (18.9)
91.1 (21.3)
85.1 (19.7)
0.16
Height (m)
1.62 (0.25)
1.57 (0.08)
1.61 (0.07)
0.26
BMI (kg m−2)
35.0 (7.5)
37.1 (8.5)
38.5 (9.7)
0.18
MAC (cm)
30.9 (4.3)
31.2 (4.8)
30.7 (5.8)
0.42
WC (cm)
104.8 (15.5)
106.9 (14.6)
83.6 (13.8)
<0.01*
HC (cm)
111.4 (12.9)
115.8 (14.5)
107.8 (11.6)
0.27
WHR
1.05 (0.09)
0.92 (0.05)
0.78 (0.08)
<0.01*
TC (cm)
58.2 (10.6)
60.4 (8.1)
56.5 (7.7)
0.34
Leptin (ng/mL)
26.66 (1.96)
25.89 (1.65)
17.97 (2.11)
0.02*
Although the mean serum leptin level was higher in women with pre-eclampsia [26.66 (1.96) ng/mL] than the control group [25.89 (1.65) ng/mL], this difference was not statistically significant (P= 0.95). The mean blood pressure and proteinuria correlated weakly with leptin (r= 0.3, P= 0.002 and r= 0.41, P= 0.001), respectively.
All
anthropometric parameters showed a positive correlation with serum
leptin concentration in all three groups and this was generally stronger
in Group 3 than Groups 1 and 2 (Table 3). BMI showed the greatest correlation in Groups 1 and 3 (r= 0.61 and r= 0.79, respectively), while in Group 2 it was greatest for weight (r= 0.58) followed by BMI and waist circumference (r= 0.56). The BMI–leptin relationships are shown in Fig. 1.
Table 3. The correlation (r) between leptin and the anthropometric parameters in the three groups.
Parameter
Pearson's correlation coefficient (r)
Group 1
Group 2
Group 3
*Statistically significant correlation.
Group
1 = women with pre-eclampsia; Group 2 = pregnant women without
pre-eclampsia (controls); Group 3 = non-pregnant women; BMI = body mass
index; MAC, WC, HC and TC are the circumferences of upper arm, waist,
hip and thigh, respectively; WHR = waist/hip ratio.
Weight
0.55*
0.58*
0.74*
BMI
0.61*
0.56*
0.79*
MAC
0.57*
0.42*
0.71*
WC
0.52*
0.56*
0.77*
HC
0.52*
0.54*
0.49*
WHR
0.04
0.12
0.71*
TC
0.34*
0.50*
0.63*
Figure 1. Scatterplot of BMI (kg m−2)
against leptin (ng/mL). Group 1 = women with pre-eclampsia; Group 2 =
pregnant women without pre-eclampsia (controls); Group 3 = non-pregnant
women.
Anthropometric parameters were higher for the obese compared with the lean women (Table 4). The waist/hip ratio was similar for obese and lean women.
Table 4.
Clinical characteristics and leptin levels of obese and
lean women in the pregnant control group. Values are given as mean (SD).
Clinical characteristics
Obese
Lean
P (Student's t test)
*Statistically significant difference.
BMI
= body mass index; MAC, WC, HC and TC are the circumferences of
mid-upper arm, waist, hip and thigh, respectively; WHR = waist/hip
ratio.
Age (years)
31.3 (4.8)
29.8 (6.2)
0.32
Parity
2.6 (1.2)
2.3 (0.9)
0.18
Gestation (weeks)
34.9 (5.1)
35.4 (4.6)
0.08
Weight (kg)
100.4 (16.5)
66.8 (8.1)
<0.001*
Height (m)
1.61 (0.2)
1.59 (0.3)
0.74
BMI (kg m−2)
40.54 (7.1)
27.3 (2.4)
<0.001*
MAC (cm)
32.48 (4.65)
26.8 (1. 98)
<0.001*
WC (cm)
113.0 (11.7)
90.7 (8.6)
<0.001*
HC (cm)
120.2 (10.4)
99.6 (7.7)
0.001*
WHR
0.94 (0.6)
0.91 (0.2)
0.72
TC (cm)
65.6 (6.0)
52.4 (3.8)
<0.001*
Leptin (ng/mL)
30.15 (1.84)
13.79 (2.15)
<0.001*
Leptin
levels in all the three groups were significantly higher for obese
compared with lean women. The correlation between the anthropometric
parameters and leptin in obese women was strongest for weight (r= 0.39) and least for mid-upper arm and waist/hip ratio (r= 0.18). In lean women, the anthropometric parameter that showed the greatest correlation with leptin was the thigh circumference (r= 0.58), and BMI in this group also correlated weakly (r= 0.24) with leptin.
In
this study, we measured the serum leptin levels in both pregnant and
non-pregnant Black African women. The results of serum leptin levels in
late pregnancy are similar to our earlier study in obese Black African
parturients14
using the same radio-immunoassay technique of leptin assay, and the
level is much higher than in non-pregnant women. The first report on the
concentration of leptin in pregnancy by Geary et al.15
found a maternal serum level of 13.4 (8.13) ng/mL. This is much lower
than our finding. The difference may be explained in two ways. Firstly,
their sample size was small (n= 20).
Secondly, they measured serum leptin at 20 weeks of gestation. This
same group of researchers found similarly lower maternal leptin levels
(11.8 ng/mL) at 10–20 weeks of gestation in a subsequent report16. It is clear from longitudinal studies that leptin levels in pregnancy increase with advancing gestation17.
Our result is, however, in keeping with other numerous studies on leptin levels in late pregnancy. Butte et al.18
found a serum leptin level of 29.8 (17.0) ng/mL in late pregnancy.
Although there are variations in the reported levels of serum leptin in
late (uncomplicated) pregnancy in other, mainly Caucasian, population
groups, most studies are consistent in finding mean serum levels between
25.2 and 38.4 ng/mL17–19.
Our finding being consistent with these reports suggests that there are
no racial differences in leptin levels in late pregnancy.
The resemblance between the trend of maternal leptin concentration17 and the pattern of maternal adipose tissue accumulation20
suggests a possible role of leptin in metabolic regulation during
pregnancy. Alternatively, the elevated leptin levels may simply be a
reflection of total accumulated fat mass in pregnancy. Indeed, the
causal–effect relationship between leptin and adipose tissue in
pregnancy is not resolved at the moment. Pregnancy hormones may well
modulate maternal serum leptin levels18.
Normal pregnancy is a state of insulin resistance. Chronic hyperinsulinaemia can induce hyperleptinaemia21.
Therefore, the hyperleptinaemia of pregnancy may be secondary to this
resistance. In a cross sectional study such as ours, it is not possible
to explore these possible explanations regarding the observed elevated
leptin levels associated with pregnancy. The placenta is an additional
source of leptin during pregnancy4.
Therefore, the association between elevated leptin and adipose tissue
in pregnancy may be casual rather than causal. However, this is rather
unlikely in view of the strong correlation between leptin and measures
of obesity, as demonstrated in this and other studies, which holds true
both in pregnancy and the non-pregnant state.
Elevated
leptin levels may either reflect the normal physiology of pregnancy or
indicate a pathophysiologic state, such as pre-eclampsia. Kratzsch et al.22
propose that the hyperleptinaemia of late pregnancy may cause
uncoupling of feeding behaviour and diminished responsiveness of leptin
receptors as fat reserves are amassed for fetal growth and lactation.
The rapid decline in leptin levels postpartum will then stimulate eating
behaviour23
suggesting that leptin may play a role in the excessive postpartum
weight gain experienced by some women. Of further interest is the
observation that abnormally low levels of leptin in the first trimester
have been associated with increased risk of spontaneous miscarriage23.
Therefore, increased knowledge in the function and regulation of leptin
in pregnancy may have an impact on the management of pre-eclampsia,
postpartum weight gain and miscarriages.
Obese
women had much higher serum leptin levels compared with the lean women
in all three groups in our study. This is in agreement with previous
studies conducted both in men and women and in pregnancy and outside
pregnancy24,25.
The association of leptin with adiposity explains the observed higher
leptin levels in the obese compared with the lean women in all the
groups. The relevance of simple anthropometric measures of obesity to
explore this association is adequately covered in our previous work14.
In pregnancy, weight and BMI showed the greatest correlation with
leptin levels. This was true for both pre-eclamptic and normotensive
women and is in keeping with previous studies18,24.
The
syndromes of pre-eclampsia and obesity share certain clinical and
metabolic characteristics. These include hyperlipidaemia, insulin
resistance and glucose intolerance26.
Thus, it may be expected that the hyperleptinaemia observed in obese
women may also be realised in women with pre-eclampsia. It is therefore
conceivable that the prediction and/or management of pre-eclampsia may
lie in leptin research. The women with pre-eclampsia in our study had
similar serum leptin level as healthy pregnant normotensive women. This
is in contrast with a report by McCarthy et al.27
who found markedly elevated serum leptin level in Caucasian women with
pre-eclampsia compared with the control group. Several reasons may
explain this difference.
Firstly, the
criteria used to define pre-eclampsia do vary. While proteinuria in our
study was defined as total protein of 300 mg or more in a 24-hour urine
collection, McCarthy et al.27
used a cut off of 500 mg or more in a 24-hour urine collection. This
might have contributed to the difference between the results in the two
studies. Secondly, the trend in serum leptin during the third trimester
is not well established. While some authors report a continuing rise,
others found that the levels plateau and yet others have found that
leptin levels actually decline just before delivery28. The mean gestation age in our study was 34.5 weeks compared with 38 weeks in the study by McCarthy et al.27.
Furthermore, they used pre-pregnancy BMI while we computed and utilised
the pregnancy BMI. This may also have contributed to the lack of
correlation between BMI and leptin levels in their study. Pre-pregnancy
BMI may not correlate with leptin as well as pregnancy BMI28. A small sample size (n= 24) in their study may also explain this lack of correlation.
Williams et al.28
found that mid-trimester pre-eclamptic women had either higher or lower
leptin levels than controls depending on whether the BMI was 25 kg m−2 and below or was above 25 kg m−2,
respectively. They concluded that the normal leptin–adiposity
relationship during pregnancy is disrupted by pre-eclampsia and that
factors other than adiposity determine leptin levels in pregnancies
complicated by pre-eclampsia. This possibility and the fact that they
measured leptin in the second trimester (we studied leptin in the third
trimester) may explain the disparity between our results and theirs.
Anim-Nyame et al.29
recently conducted a longitudinal study to determine the timing of the
elevation in serum leptin during pregnancy. Eight women went on to
develop pre-eclampsia and it was noted that in this group the
concentration of leptin was consistently higher compared with another
group of seven women who did not develop pre-eclampsia. They also noted
that from 20 weeks of gestation, leptin concentration rose gradually in
both groups up to 32 weeks. Subsequently, there was a slight decline in
the normal group as opposed to a clear increase in the pre-eclampsia
destined group. The increase occurred before clinical manifestation of
pre-eclampsia. This is an important and interesting finding. If these
results were confirmed by other studies with greater numbers, then the
clinical value of assaying serum leptin in the prediction of
pre-eclampsia would be established. Their study design and its findings
are different from ours.
However, our data are similar to those of Sattar et al.10
who found that, although the level of leptin in the third trimester was
higher than in non-pregnant controls, the levels between pre-eclamptic
and normotensive controls were similar. Despite the observed
inconsistency of both blood pressure and proteinuria in the diagnosis
and progression of pre-eclampsia, the weak correlations between mean
blood pressure and proteinuria with leptin in this study are in keeping
with these findings.
The hyperleptinaemia
of pregnancy may be due to the increased adiposity in pregnancy,
placental source of leptin, pregnancy hormone-induced modulation of
leptin synthesis/secretion or a combination of these factors. It was not
possible to explore these mechanisms in our study because of its cross
sectional design.
We did not find higher
serum leptin concentrations in women with pre-eclampsia compared with
pregnant normotensive controls. This may be due to the fact that
adiposity has the predominant influence on serum leptin levels
overriding all other factors both in and outside pregnancy. The strong
correlation, demonstrated in this study, between the various
anthropometric parameters and leptin levels both in pregnancy and
outside pregnancy appears to be consistent with this explanation.
Indeed, studies that have demonstrated hyperleptinaemia in pre-eclampsia27 are limited by small sample sizes and failure to replicate the well-established correlation between BMI and leptin.
Nonetheless,
possible explanations for this observation have been proposed.
Pre-eclampsia may be complicated by reduced renal clearance and reduced
intravascular volume. Both of these can cause hyperleptinaemia. The
other possibility of course is that leptin may be the cause (similar to
other cytokines) rather than the result of pre-eclampsia28,30. Thus, there is need to explore further the cause–effect relationship between leptin and pre-eclampsia.
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