Vous êtes sur la page 1sur 5

European Journal of Obstetrics & Gynecology and Reproductive Biology 206 (2016) 4852

Contents lists available at ScienceDirect

European Journal of Obstetrics & Gynecology and


Reproductive Biology
journal homepage: www.elsevier.com/locate/ejogrb

Placental weight in pregnancies with high or low hemoglobin


concentrations
Sandra Larsena,b,* , Elisabeth Krefting Bjellanda , Camilla Haavaldsena , Anne Eskilda,b
a
b

Department of Obstetrics and Gynecology, Akershus University Hospital, Lrenskog, Norway


Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Norway

A R T I C L E I N F O

A B S T R A C T

Article history:
Received 11 May 2016
Accepted 19 August 2016

Objectives: To study the associations of maternal hemoglobin concentrations with placental weight and
placental to birthweight ratio.
Study design: In this retrospective cohort study, we included all singleton pregnancies during the years
19982013 at a large public hospital in Norway (n = 57 062). We compared mean placental weight and
placental to birthweight ratio according to maternal hemoglobin concentrations: <9 g/dl, 913.5 g/dl or
>13.5 g/dl. The associations of maternal hemoglobin concentrations with placental weight and placental
to birthweight ratio were estimated by linear regression analyses, and adjustments were made for
gestational age at birth, preeclampsia, parity, maternal age, diabetes, body mass index, smoking,
offspring sex and year of birth.
Results: In pregnancies with maternal hemoglobin concentrations <9 g/dl, mean placental weight was
701.2 g (SD 160.6 g), followed by 678.1 g (SD 150.2 g) for hemoglobin concentrations 913.5 g/dl and
655.5 g (SD 147.7 g) for hemoglobin concentrations >13.5 g/dl (ANOVA, p < 0.001). Mean placental to
birthweight ratio was highest in pregnancies with maternal hemoglobin concentrations <9 g/dl (0.203
(SD 0.036)). We found no difference in mean placental to birthweight ratio for maternal hemoglobin
concentrations 913.5 g/dl (0.193 (SD 0.040)) and >13.5 g/dl (0.193 (SD 0.043)). Adjustments for our study
factors did not alter the estimates notably.
Conclusions: Placental weight decreased with increasing maternal hemoglobin concentrations. The high
placental to birthweight ratio with low maternal hemoglobin concentrations suggests differences in
placental growth relative to fetal growth across maternal hemoglobin concentrations.
2016 Elsevier Ireland Ltd. All rights reserved.

Keywords:
Anemia
Birthweight
Hemoglobin concentrations
Placental weight
Pregnancy

Introduction
Anemia is common in pregnant women, and low maternal
hemoglobin concentrations have been associated with increased
risk of giving birth to offspring with low birthweight [13]. Also
high maternal hemoglobin concentrations have been associated
with low offspring birthweight [35].
A well-functioning placenta is important for fetal growth. As
opposed to the relation with birthweight, low maternal hemoglobin concentrations seem to be associated with high placental
weight [68], but the evidence is conicting [911]. Few studies
have compared placental weight in pregnancies with low
hemoglobin concentrations to pregnancies with high hemoglobin
concentrations [1215]. In two of these studies, placental weight

* Corresponding author at: Department of Obstetrics and Gynecology, Akershus


University Hospital, Sykehusveien 25, 1478 Lrenskog, Norway.
E-mail address: Sandra.Larsen@ahus.no (S. Larsen).
http://dx.doi.org/10.1016/j.ejogrb.2016.08.039
0301-2115/ 2016 Elsevier Ireland Ltd. All rights reserved.

decreased signicantly by increasing maternal hemoglobin concentrations [14,15].


Placental weight relative to birthweight has previously been
used as an indicator of placental function, and both high and
low placental to birthweight ratio have been associated with
adverse pregnancy outcomes [16,17]. Knowledge about the
association of hemoglobin concentrations with placental to
birthweight ratio could provide insight to consequences of
aberrant maternal hemoglobin concentrations in pregnancy.
Some studies report high placental to birthweight ratio in
pregnancies with low hemoglobin concentrations [14,18,19],
whereas other studies found no such association [15,20]. One
study found that placental to birthweight ratio decreased
signicantly by increasing hemoglobin concentrations [14].
Since previous studies report conicting results, new and larger
studies are needed.
Therefore, we compared placental weight and placental to
birthweight ratio according to low, normal or high maternal
hemoglobin concentrations in 57 062 pregnancies in Norway.

S. Larsen et al. / European Journal of Obstetrics & Gynecology and Reproductive Biology 206 (2016) 4852

Materials and methods


In this retrospective cohort study, we included all singleton
pregnancies from gestational week 26 at Akershus University
Hospital in Norway during the years 19982013 (n = 60 826).
Akershus University Hospital is a large public hospital located close
to Oslo, the capital of Norway, and the catchment area includes
almost half a million people living in urban or rural areas. Almost
all pregnant women who live in the catchment area give birth at
this hospital and antenatal and obstetric care is free of charge.
We used data from the electronic patient delivery records to
which information about the pregnancy, the delivery and the
offspring is entered shortly after delivery. We excluded 1392 women with missing information on hemoglobin concentrations in
pregnancy. Also, we excluded 449 pregnancies with offspring
birthweight less than 250 grams (g) or above 6500 g, and
1923 pregnancies with placental weight less than 25 g or above
2500 g since we considered these values to be outlying and thus
erroneously recorded. Hence, a total of 57 062 pregnancies could
be included in statistical analysis.
Our outcome measures were placental weight and placental to
birthweight ratio. The placentas were weighed with membranes
and umbilical cord attached within one hour after birth, according
to Norwegian standards. Birthweight was based on routine
weighing of the newborn shortly after birth. Weight was measured
in grams, and the placental to birthweight ratio was calculated as
placental weight/birthweight. Hence, a high placental to birthweight ratio indicates a high placental weight relative to birthweight.
Maternal hemoglobin concentrations were measured in the
rst and in the second trimester according to Norwegian guidelines for antenatal care. Almost all women who give birth in
Norway attend the public antenatal program, and results from
antenatal clinical examinations are routinely recorded in
standardized antenatal patient journals. Maternal hemoglobin
concentrations during pregnancy were reported as <9 grams/
deciliter (g/dl) (yes or no) or >13.5 g/dl (yes or no). Thus, women
without such values had hemoglobin concentrations at 913.5 g/dl

49

during pregnancy. We categorized maternal hemoglobin concentrations as: <9 g/dl, 913.5 g/dl or >13.5 g/dl.
Other study factors included in our data analyses were:
gestational age at birth, preeclampsia, parity, maternal age (years),
diabetes, body mass index (BMI), smoking, offspring sex and year
of birth. Gestational age at birth was based on term date estimated
at routine fetal ultrasonographic examination in gestational weeks
1719. Preeclampsia (yes/no) was dened as presence of blood
pressure 140/90 mmHg in addition to proteinuria (protein
dipstick 1+ or >0.3 g/24 h) after 20 weeks of gestation. Parity
was coded: 0 or 1 previous deliveries. Maternal diabetes (yes/no)
included diabetes type 1, diabetes type 2 and gestational diabetes.
Maternal BMI was calculated as weight (kg)/height (m)2 at
admission to the delivery ward, and was categorized as <25,
2529, 3035, >35 kg/m2 or missing. Occasional or daily smokers
were dened as being smokers and smoking was categorized as
yes, no or missing.
We calculated mean placental weight and placental to birthweight ratio for each category of maternal hemoglobin concentrations (<9 g/dl, 913.5 g/dl and >13.5 g/dl). Differences in means
were tested by applying one-way ANOVA with Bonferronicorrection. The associations of hemoglobin concentrations with
placental weight and placental to birthweight ratio were estimated
as crude and adjusted unstandardized regression coefcients (B)
with 95% condence interval (CI) by applying linear regression
analyses. Hemoglobin concentrations 913.5 g/dl were used as the
reference group. The unstandardized regression coefcient (B) can
be interpreted as the estimated change in placental weight (grams)
by change in category of hemoglobin concentrations. Adjustments
were made for the study factors presented above. We performed
sensitivity analyses in subsamples of pregnancies without
preeclampsia and pregnancies with term delivery (gestational
week 37).
All statistical analyses were conducted by using the IBM SPSS
Statistics Version 22.0, (IBM Corp., Armonk, NY, USA).
Our study was approved by the Data Protectorate at Akershus
University Hospital (License number 11-018/July 2011).

Table 1
Distributions of study factors according to maternal hemoglobin concentrations.
n (%)

Hemoglobin concentrations
<9 g/dl
679 (1.2)

913.5 g/dl
54 849 (96.1)

>13.5 g/dl
1534 (2.7)

Mean placental weight, g (SD)


Mean birthweight, g (SD)
Mean placental to birthweight ratio, g (SD)
Mean gestational age at birth, days (SD)
Mean maternal age, years (SD)
Nulliparous, n (%)
Preeclampsia, n (%)
Maternal diabetes, n (%)

701.2 (160.6)
3473.2 (589.5)
0.203 (0.036)
277.3 (13.5)
29.5 (6.4)
206 (30.6)
48 (7.1)
18 (2.7)

678.1 (150.2)
3531.9 (572.9)
0.193 (0.040)
278.3 (13.4)
30.3 (5.1)
19 747 (36.1)
1758 (3.2)
657 (1.2)

655.5 (147.7)
3444.1 (646.1)
0.193 (0.043)
278.1 (15.4)
30.1 (4.8)
608 (40.1)
148 (9.8)
23 (1.5)

Maternal BMI (kg/m2), n (%)


<25
2530
3035
>35
Missing

111 (16.5)
228 (33.9)
103 (15.3)
37 (5.5)
194 (28.8)

6424 (11.7)
19 406 (35.5)
11766 (21.5)
5002 (9.1)
12 109 (22.1)

167 (11.0)
518 (34.2)
347 (22.9)
213 (14.1)
271 (17.9)

Offspring sex, n (%)


Boy
Girl

320 (47.5)
353 (52.5)

27 951 (51.1)
26 757 (48.9)

858 (56.6)
658 (43.4)

Smoking, n (%)
No
Yes
Missing

530 (78.8)
83 (12.3)
60 (8.9)

40 536 (74.1)
7874 (14.4)
6298 (11.5)

1110 (73.2)
254 (16.8)
152 (10.0)

50

S. Larsen et al. / European Journal of Obstetrics & Gynecology and Reproductive Biology 206 (2016) 4852

Table 2
Estimated differences in placental weight (grams) according to maternal hemoglobin concentrations among 57 062 pregnancies.
n (%)

Hemoglobin concentrations
679 (1.2)
<9.0 g/dl
9.013.5 g/dl
54 849 (96.1)
>13.5 g/dl
1534 (2.7)

Mean (SD)

702.0 (160.9)
678.2 (150.3)
655.8 (147.9)

Differences in placental weight


Crude B

95% CI

Adjusted Ba

95% CI

Adjusted Bb

95% CI

23.1*
0.0
22.6*

11.734.5

26.9*
0.0
20.8*

15.837.9

26.9*
0.0
20.2*

16.237.6

30.3 to

15.0

28.2 to

13.4

27.4 to

13.0

Differences in grams are presented as unstandardized B-coefcients estimated by linear regression analyses. Abbreviations: CI, condence interval; SD, standard deviation.
*
p < 0.001. All p-values are two-sided.
a
Adjustments made for gestational age at birth and preeclampsia.
b
Adjustments made for gestational age at birth, preeclampsia, parity, maternal age, diabetes, body mass index, smoking, offspring sex and year of birth.

Among the 57 062 pregnancies, 1.2% of the women had


hemoglobin concentrations <9 g/dl, 96.1% had hemoglobin concentrations 913.5 g/dl, and 2.7% of the women had hemoglobin
concentrations >13.5 g/dl (Table 1).
Mean birthweight was lower in pregnancies with maternal
hemoglobin concentrations <9 g/dl and >13.5 g/dl compared to
pregnancies with hemoglobin concentrations 913.5 g/dl (ANOVA,
p < 0.001) (Table 1).
Mean placental weight was highest in pregnancies with
maternal hemoglobin concentrations <9 g/dl, and placental
weight decreased by increasing maternal hemoglobin concentrations. In pregnancies with hemoglobin concentrations <9 g/dl,
mean placental weight was 701.2 g (SD 160.6 g), followed by 678.1 g
(SD 150.2 g) for hemoglobin concentrations 913.5 g/dl, and
655.5 g (SD 147.7 g) for hemoglobin concentrations >13.5 g/dl
(ANOVA, p < 0.001) (Table 1). The crude estimated difference in
mean placental weight between pregnancies with hemoglobin
concentrations <9 g/dl and >13.5 g/dl was 45.7 g (Table 2, Fig. 1a).
Mean placental to birthweight ratio was highest in pregnancies
with maternal hemoglobin concentrations <9 g/dl (0.203
(0.036 SD)). We found no difference in mean placental to
birthweight ratio between pregnancies with hemoglobin concentrations 913.5 g/dl and >13.5 g/dl (0.193 (SD 0.040) and 0.193 (SD
0.043), respectively) (Table 3, Fig. 1b).
Adjustments for gestational age at birth, gestational age at
birth, preeclampsia, parity, maternal age, diabetes, body mass
index, smoking, offspring sex and year of birth did not alter any of
the above estimates notably (Tables 2 and 3). Also, the associations
remained almost unchanged in separate analyses of pregnancies
without preeclampsia and of pregnancies with term delivery
(gestational week 37) (data not shown).
Comment

Hemoglobin concentrations during pregnancy were pre-categorized, and we had no information about the exact hemoglobin
values. Neither did we have information on the causes of high or
low maternal hemoglobin concentrations. We have little reason to
believe that systematic errors in measurements or in reporting of
hemoglobin concentrations have biased our estimates, since
maternal hemoglobin concentrations were measured prior to
the measurement of placental weight and birthweight. Placental
weight and birthweight were measured by standardized procedures shortly after delivery.
An increasing number of women from non-western countries
gave birth at our hospital during our study period. Unfortunately,
we had no information about the womens country of birth. We
included year of offspring birth in the data analyses to adjust for
any changes in the composition of our study sample or in data
collection that may have occurred during our study period.

a)
40.0
30.0
Weight differences (grams)

Results

20.0
10.0
0.0
-10.0
-20.0
-30.0
-40.0
<9

9-13.5
Hemoglobin concentrations

>13.5

b)
0.016

0.012
Differences in ratio

In this study of 57 062 pregnancies, placental weight was highest


in pregnancies with low maternal hemoglobin concentrations and
decreased with increasing hemoglobin concentrations. Placental
weight relative to birthweight was higher in pregnancies with low
maternal hemoglobin concentrations as compared to pregnancies
with normal or high hemoglobin concentrations. This nding
suggests differences in placental growth relative to fetal growth
across maternal hemoglobin concentrations.
Our study included all singleton pregnancies at a large public
hospital in Norway during the years 19982013, and almost all
women in the catchment area give birth at this hospital. A skewed
selection of the study sample is therefore unlikely. Furthermore,
the large study sample provides statistical precision. In Norway,
the standard of living is high. The health and nutritional status of
women in reproductive age are generally good compared to many
other countries in the world. Therefore, our results may not be
universally generalized.

0.008

0.004

0.000

-0.004
<9

9-13.5
Hemoglobin concentrations

>13.5

Fig. 1. Crude differences in placental weight (a) and placental to birthweight ratio
(b) with 95% condence interval according to maternal hemoglobin concentrations
among 57 062 pregnancies. Maternal hemoglobin concentrations 913.5 g/dl was
used as reference.

S. Larsen et al. / European Journal of Obstetrics & Gynecology and Reproductive Biology 206 (2016) 4852

51

Table 3
Estimated differences in placental to birthweight ratio according to maternal hemoglobin concentrations among 57 062 pregnancies.
n (%)

Hemoglobin concentrations
679 (1.2)
<9.0 g/dl
9.013.5 g/dl
54 849 (96.1)
>13.5 g/dl
1534 (2.7)

Mean (SD)

0.203 (0.037)
0.193 (0.040)
0.193 (0.043)

Differences in placental to birthweight ratio


Crude B

95% CI

Adjusted Ba

95% CI

Adjusted Bb

95% CI

0.010*
0.000
0.000

0.0070.013

0.009*
0.000
0.001

0.006012

0.008*
0.000
0.000

0.0050.011

0.002 to 0.002

0.003 to 0.001

0.000 to 0.001

Differences in grams are presented as unstandardized B-coefcients estimated by linear regression analyses. Abbreviations: CI, condence interval; SD, standard deviation.
*
p < 0.001. All p-values are two-sided.
a
Adjustments made for gestational age at birth and preeclampsia.
b
Adjustments made for gestational age at birth, preeclampsia, parity, maternal age, diabetes, body mass index, smoking, offspring sex and year of birth.

Previous studies on the associations of low maternal hemoglobin concentrations with placental weight and placental to birthweight ratio have shown conicting results. Two large studies
reported low hemoglobin concentrations to be associated high
placental weight [6,7]. Other studies, including less than
1000 pregnancies, suggest that low hemoglobin concentrations
are associated with low placental weight [911]. Further, low
hemoglobin concentrations have been associated with high
placental to birthweight ratio [7,14,18,19], but no association with
placental to birthweight ratio have also been reported [15,20].
Few studies have included information about low and high
hemoglobin concentrations within the same study sample [1215],
and most of these studies were performed over two decades ago
with relatively small study samples. Similarly to our ndings, these
studies suggest lower placental weight in pregnancies with high
hemoglobin concentrations compared to pregnancies with low
hemoglobin concentrations [12,14,15]. Only one study found that
placental to birthweight ratio decreased signicantly by increasing
hemoglobin concentrations [14].
We found high placental weight but low birthweight in
pregnancies with low hemoglobin concentrations. Thus, in these
pregnancies the placental to birthweight ratio was high. If the
growths of the placenta and fetus were proportional across
maternal hemoglobin concentrations, one would expect similar
placental to birthweight ratio in pregnancies with low, normal and
high hemoglobin concentrations. Placental growth was relatively
more pronounced than fetal growth at low maternal hemoglobin
concentrations.
Low hemoglobin concentrations may result in decreased
oxygenation of tissue. In pregnancy, low hemoglobin concentrations may therefore increase the risk of uteroplacental hypoxia.
Hypoxia could cause sub-optimal fetal growth [21]. In the placenta,
however, it is possible that biological compensatory mechanisms
exist to enhance fetal oxygen supply. Increased angiogenesis is a
known response to hypoxia [22], and increased vascularization of
the placenta has been reported in pregnancies with low
hemoglobin concentrations [23]. It is conceivable that development of new vessels in the placenta, as a response to hypoxia, can
explain the placental enlargement in pregnancies with low
hemoglobin concentrations. Placental enlargement has also been
reported in pregnant women who live on high altitudes and
thereby have decreased availability of oxygen [24]. An alternative
explanation for the higher placental weight in pregnancies with
low hemoglobin concentrations is that only pregnancies with
optimal potential for placental growth are successful. It is possible
that women with low hemoglobin concentrations have higher risk
of miscarriage, and that in pregnancies with low hemoglobin
concentrations and large placentas are overrepresented at birth as
a result of positive selection.
As opposed to low hemoglobin concentrations, we found that
high hemoglobin concentrations were associated with low
placental weight and low birthweight. Thus, placental and fetal

growths were proportional at high maternal hemoglobin concentrations. High hemoglobin concentrations may cause hyperviscosity of the blood, vascular occlusion and capillary congestion.
Therefore, high hemoglobin concentrations may result in reduced
availability of oxygen in the intervillous space and thereby suboptimal placental and fetal growth [25]. In addition, it cannot be
ruled out that high hemoglobin concentrations impair early
placental development and thereby placental growth later in
pregnancy. High hemoglobin concentrations may be a consequence of a maternal condition that inuences placental growth,
such as preeclampsia. We found the same results, however, in
separate analyses of pregnancies without preeclampsia.
In this study of more than 57 000 pregnancies in Norway,
placental weight decreased with increasing maternal hemoglobin
concentrations. Placental to birthweight ratio was highest in
pregnancies with low hemoglobin concentrations. This nding
suggests differences in placental growth relative to fetal growth
across maternal hemoglobin concentrations.
Acknowledgements
The authors thank Samantha Salvesen Adams for help with data
management and statistical analyses. We received funding from
the South-Eastern Norway Regional Health Authority, which had
no role in the planning process, data collection, analyses or writing
the manuscript, nor in the decision to submit the manuscript for
publication.
References
[1] Haider BA, Olon I, Wang M, Spiegelman D, Ezzati M, Fawzi WW. Anemia,
prenatal iron use, and risk of adverse pregnancy outcomes: systematic review
and meta-analysis. BMJ 2013;346:f3443.
[2] Ren A, Wang J, Ye RW, Li S, Liu JM, Li Z. Low rst-trimester hemoglobin and low
birth weight, preterm delivery and small for gestational age newborns. Int J
Gynaecol Obstet 2007;98:1248.
[3] Murphy JF, ORiordan J, Newcombe RG, Coles EC, Pearson JF. Relation of haemoglobin levels in rst and second trimesters to outcome of pregnancy. Lancet
1986;1:9924.
[4] Scanlon KS, Yip R, Schieve LA, Cogswell ME. High and low hemoglobin levels
during pregnancy: differential risks for preterm birth and small for gestational
age. Obstet Gynecol 2000;96:7418.
[5] Steer P, Alam MA, Wadsworth J, Welch A. Relation between maternal
haemoglobin concentration and birth weight in different ethnic groups. BMJ
1995;310(6978):48991.
[6] Baptiste-Roberts K, Salaa CM, Nicholson WK, Dugan A, Wang NY, Bracanti FL.
Maternal risk factors for abnormal placental growth: the national collaborative perinatal project. BMC Pregnancy Childbirth 2008;8:44.
[7] McNamara H, Hutcheon JA, Platt RW, Benjamin A, Kramer MS. Risk factors for
high and low placental weight. Paediatr Perinat Epidemiol 2014;28:97105.
[8] Beischer NA, Sivasamboo R, Vohra S, Silpisornkosal S, Reid S. Placental
hypertrophy in severe anemia. J Obstet Gynaecol Br Commonw 1970;77:398
409.
[9] Mahajan S, Aalinkeel R, Shah P, Singh S, Koshupillai N. Nutritional anemia
dysregulates endocrine control of fetal growth. Br J Nutr 2008;100:40817.
[10] Marwah P, Singla PN, Krishna M, Agarwal KN. Effect of pregnancy anemia on
cellular growth in the human placenta. Acta Paediatr Scand 1979;68:899901.
[11] Singla PN, Chand S, Khanna S, Agarwal KN. Effect of maternal anemia on the
placenta and newborn infant. Acta Paediatr Scand 1978;67:6458.

52

S. Larsen et al. / European Journal of Obstetrics & Gynecology and Reproductive Biology 206 (2016) 4852

[12] Gaillard R, Eilers PH, Yassine S, Hofman A, Steegers EA, Jaddoe VW. Risk factors
and consequences of maternal anemia and elevated haemoglobin levels in
pregnancy: a population-based prospective cohort study. Paediatr Perinat
Epidemiol 2014;28:21326.
[13] Nordenvall M, Sandstedt B. Placental lesions and maternal hemoglobin levels.
A comparative investigation. Acta Obstet Gynecol Scand 1990;69(2):
12733.
[14] Godfrey KM, Redman CWG, Barker DJP, Osmond C. The effect of maternal
anemia and iron deciency on the ratio of fetal weight to placental weight.
BJOG 1991;98:88691.
[15] Sagen N, Nilsen ST, Kim HC, Bergsj P, Roller O. Maternal hemoglobin
concentration is closely related to birth weight in normal pregnancies. Acta
Obstet Gynecol Scand 1984;63(3):2458.
[16] Shehata F, Levin I, Shrim A, Ata B, Weisz B, Gamzu R, Almog B. Placenta/
birthweight ratio and perinatal outcome: a retrospective cohort analysis. BJOG
2011;118:7417.
[17] Haavaldsen C, Samuelsen SO, Eskild A. Fetal death and placental weight/
birthweight ratio: a population study. Acta Obstet Gynecol Scand
2013;92:58390.

[18] Lao TT, Wong WM. Placental ratio-its relationship with mild maternal anemia.
Placenta 1997;18:5936.
[19] Williams LA, Evans SF, Newnham JP. Prospective cohort study of factors
inuencing the relative weight of the placenta and the newborn infant. BMJ
1997;314:18648.
[20] Perry IJ, Beevers DG, Whincup PH, Bareford D. Predictors of ratio of placental
weight to fetal weight in multiethnic community. BMJ 1995;310:4369.
[21] Hutter D, Kingdom J, Jaeggi E. Causes and mechanisms of intrauterine hypoxia
and its impact on the fetal cardiovascular system: a review. Int J Pediatr
2010;2010:401323.
[22] Wang K, Jiang YZ, Chen DB, Zheng J. Hypoxia enhances FGF2- and VEGFstimulated human placental artery endothelial cell proliferation: roles of
MEK1/2/ERK1/2 and PI3K/AKT1 pathways. Placenta 2009;30:104551.
[23] Kadyrov M, Kosanke G, Kingdom J, Kaufmann P. Increased fetoplacental
angiogenesis during rst trimester in anemic women. Lancet 1998;352:1747
9.
[24] Zamudio S. The placenta at high altitude. High Alt Med Biol 2003;4(2):17191.
[25] Koller O, Sandvei R, Sagen N. High hemoglobin levels during pregnancy and
fetal risk. Int J Gynaecol Obstet 1980;18:536.