doi:10.1111/jog.13569 J. Obstet. Gynaecol. Res.

2018

Maternal anemia during pregnancy and slightly higher risk

of asthma in male offspring

Maijakaisa Harju1, Juha Pekkanen2,3, Seppo Heinonen4 and Leea Keski-Nisula1,3,5

1
Department of Obstetrics and Gynecology, Kuopio University Hospital, 3Living Environment and Health Unit, National
Institute for Health and Welfare, 5Institute of Clinical Medicine, School of Medicine, University of Eastern Finland, Kuopio,
2
Department of Public Health, University of Helsinki and 4Department of Obstetrics and Gynecology, Helsinki University
Hospital, Helsinki, Finland

Abstract
Aim: We aimed to determine whether maternal hemoglobin levels or anemia during pregnancy are associ-
ated with the development of asthma among offspring.
Methods: Data were retrieved from the birth register database of Kuopio University Hospital between 1989
and 2007 (n = 38 381). Hemoglobin levels were measured during three trimesters of pregnancy and anemia
was defined according to the World Health Organization criteria. The prevalence of asthma was determined
from the register of reimbursement for medication for asthma at the Finnish Social Security Institution. Cox
proportional hazard regression analysis was performed to evaluate the possible associations between prena-
tal factors and development of asthma ever.
Results: A total of 8198 (21.4%) women had anemia at some stage of pregnancy. Mild maternal anemia dur-
ing the first trimester was associated with an increased risk of asthma among male offspring (adjusted haz-
ard ratio, 1.46; 95% confidence interval, 1.11–1.94) compared with those with normal maternal hemoglobin
levels. This finding remained significant also after applying the Bonferroni correction.
Conclusion: Male offspring with maternal anemia during the first trimester of pregnancy had significantly
more asthma ever than the offspring of women with normal hemoglobin levels during pregnancy. These
findings were not strong but suggest possible sex-specific effects of maternal health on prenatal program-
ming and future risk of asthma.
Key words: anemia, asthma, children, hemoglobin, maternal, pregnancy.

Introduction offspring have concentrated on maternal diet and

Maternal well-being, diet, and nutritional status
before and during pregnancy are all intrauterine
exposures that effect fetal development and further
lifelong health. In recent years there have been
numerous reports on the significance of these prenatal
factors as regards health and disease later in life.1–3
As asthma is the most common chronic disease dur-
ing childhood, it has been eagerly evaluated in this
context. Most recent studies involving evaluation of
prenatal risks in the development of asthma among
complications during pregnancy, mode of delivery,
prematurity, and birthweight.4–7 Maternal anemia,
hemoglobin levels, and iron status during pregnancy
have been sparsely evaluated. To our best knowledge,
only three studies thus far have studied the subject.
Two reports showed significant association between
maternal anemia or deficient iron status during preg-
nancy and increased risk for asthma, wheezing, and
decreased lung function during childhood.8,9 How-
ever, in the first study, the prevalence of asthma at
the age of 6 years was exceptionally high (17.2%) and

Received: April 19 2017.

Accepted: November 7 2017.
Correspondence: Dr Leea Keski-Nisula, Department of Obstetrics and Gynecology, Kuopio University Hospital, PL 100, 70029 KYS,
Finland. Email: leea.keski-nisula@kuh.fi

© 2018 Japan Society of Obstetrics and Gynecology 1

M. Harju et al.
diagnosis was based on maternal report.8 In the sec-
ond study, maternal deficient iron status was deter-
mined in just 157 women, even though the follow-up
of children was 10 years.9 The third study was a lon-
gitudinal population-based cohort study including
over 6000 mother–child pairs and it showed signifi-
cant association between maternal anemia in early
pregnancy and physician-diagnosed asthma at the
age of 6 years (parent-reported) in a crude model;
however, after multiple adjustments, the significant
association was lost.10
Thus far, no study has evaluated the association
between development of asthma among offspring and
maternal anemia during pregnancy in a large epide-
miological dataset; in fact, only parent-reported
asthma has been studied, even though hemoglobin
levels are routinely measured during pregnancy in
most developed countries worldwide and asthma is
the most common chronic disease during childhood.
In contrast, there have been numerous studies with
detected associations between maternal anemia dur-
ing pregnancy and the risk of schizophrenia, intellec-
tual disability, and hematological malignancies later
among offspring.11–17
In developed countries, maternal anemia or low
hemoglobin levels during pregnancy most frequently
mirror iron deficiency during pregnancy.18 Further,
maternal anemia itself exposes women to a higher
risk of infections during pregnancy and other perina-
tal complications. Similarly, anemic children have
higher risk of infections, and early respiratory infec-
tions are associated adversely with future lung function
and respiratory health.19 However, Nielsen and associ-
ates recently reported from their large Danish register
study separate and combined effects of maternal infec-
tion and anemia in the risk of development of schizo-
phrenia among offspring. According to their results,
both factors had additive but not interactive effects, and
thus were related to the independent risk factors for the
development of schizophrenia among offspring.17
The significance of maternal anemia or iron defi-
ciency in the future respiratory health of offspring has
not been well established. We have previously stud-
ied the effect of other prenatal exposures, such as
maternal or paternal smoking, infertility, and gesta-
tional age, in the development of asthma among off-
spring in our one-hospital-based birth register
data.20–22 In Finland, hemoglobin levels are routinely
followed during pregnancy and their results are read-
ily available for research. Therefore, we evaluated in
one-hospital-based birth register data covering 38 381
2 © 2018 Japan Society of Obstetrics and Gynecology
women with their live-born singleton children,
whether maternal hemoglobin levels during preg-
nancy and further anemia were related to the future
risk of asthma ever among offspring.
Methods
This study was restricted to birth register data con-
cerning all women who delivered a live singleton on
or after 22 completed weeks of gestation at Kuopio
University Hospital between 1989 and 2007, covering
a total of 40 879 pregnancies. A priori, we had
excluded all multifetal pregnancies (n = 1679), all chil-
dren that were stillborn (n = 156), and neonatal
deaths that occurred during hospital stay after birth
(n = 176). We further excluded 2498 women with no
recorded hemoglobin levels during pregnancy. After
these exclusions, 38 381 women with singleton live
births remained for the analysis.
Information on maternal characteristics during
pregnancy, such as parity, hemoglobin levels, and
smoking, and maternal pre-pregnancy weight and
more specific health issues were obtained from self-
administered questionnaires at 20 weeks of preg-
nancy, complemented later by nurse and midwife
interviews and check-ups at visits to maternity clinics
or labor wards at Kuopio University Hospital. The
data were collected prospectively during pregnancy
before delivery in the Birth Register of Kuopio Uni-
versity Hospital, which is approved by the Institu-
tional Review Board. All child-bearing women gave
informed consent as regards a possible future register
study at the time of data collection.
Birth register data were linked with data in the reg-
ister for reimbursement for medication for asthma
(KELA, Kansaneläkelaitos, Social security coverage
for Finnish residents). In Finland, patients can apply
for compensation for the costs of medication for sev-
eral chronic diseases from the Social Security Institu-
tion, but they need to present a doctor’s certificate.
For asthma, the certificate generally needs to be writ-
ten by a specialist and the disease needs to fulfill strict
criteria given by the institution. All such cases of
asthma are registered. Further, the certificate is usu-
ally temporary at first and the need for medication is
checked annually by doctors. In cases of continuous
need for medication, a permanent certificate is usually
allocated after teenage years. Before entitlement to
special reimbursement, asthmatic children must have
had regular medication for at least 6 months.

Our primary outcome was asthma at any time of
life, which was identified among children by way of
any reimbursement concerning asthma medication.
For subanalysis, we further evaluated different types
of asthma outcomes among 6–19-year-old offspring
(N = 28 467) on the basis of: (i) whether children had
reimbursement transiently before the age of 6 years
and not later (early-onset transient asthma); and
(ii) whether children had ongoing asthma reimburse-
ment at the age of 6 years or later (early-onset persis-
tent or late-onset asthma).
In Finland, more than 99% of pregnant women
book into antenatal care and are seen at intervals at
maternity units, normal care entailing an average of
16 visits during study years. At these visits, maternal
hemoglobin levels are routinely measured by nurses
in each trimester and recorded on individual mater-
nity cards. In this study population, 88.9% of women
had hemoglobin assayed in the first trimester, 92.8%
in the second trimester, and 86.0% in the third trimes-
ter. Moreover, 75.3% of women had hemoglobin
recorded during all three trimesters, 17.0% during
two trimesters, and 7.7% had hemoglobin measured
during just one trimester. First, maternal hemoglobin
levels were evaluated as quintiles in each of the three
trimesters. Second, the levels were evaluated as ane-
mic according to World Health Organization (WHO)
standards: a normal hemoglobin level was defined as
being ≥110 g/L, mild anemia was a hemoglobin level
of 90–109 g/L, moderate anemia was a hemoglobin
level of 70–89 g/L, and severe anemia was a hemo-
globin level of <70 g/L. A high hemoglobin level was
classified as a value ≥145 g/L during gestation. Gesta-
tional age was estimated on the basis of the last men-
strual period or on ultrasonography during the first
trimester of pregnancy. Data on iron supplement use
were not ascertained in this analysis.
The distribution of maternal hemoglobin values
and the presence of anemia during pregnancy as well
as confounding factors were examined by the pres-
ence or absence of asthma. Follow-up of children
Table 1 Maternal hemoglobin levels and anemia during the three trimesters of pregnancy
Median Hb, g/L
First trimester 130
Second trimester 119
Third trimester 120
Anemia during one trimester
Anemia during two trimesters
Anemia during all three trimesters
†Including only women with Hb levels measured during all three trimesters (N = 28 918). Hb, hemoglobin; SD, standard deviation.
© 2018 Japan Society of Obstetrics and Gynecology
Maternal anemia and children’s asthma
started from birth and ended with the onset of asthma
or at the end of follow-up (31 December 2008). A Cox
proportional hazards model was used to investigate
the relations between the presence of asthma and the
adjusted effects of various predictors of asthma,
including maternal hemoglobin levels or anemia. In
the analyses, the possible risks or confounding factors
regarding the presence of asthma were child’s sex,
maternal smoking during pregnancy (no vs yes),
maternal weight before pregnancy (in quartiles: ≤56,
57–62, 63–70, and ≥71 kg), birthweight (in quartiles:
≤3200, 3201–3600, 3601–3900, and ≥3901 g), gesta-
tional age at birth (≤32, 33–36, 37–40, and ≥41 weeks),
maternal parity at delivery (0, 1, and ≥2), maternal
asthma at the time of pregnancy (no vs yes), and
recorded vaginal bleeding during pregnancy (no, yes,
and not known). All variables were entered simulta-
neously into the Cox hazard proportional model and
were treated as categorical variables. Subanalysis was
done separately in accordance to child’s sex. The cut-
off level of significance was set at 0.05. We further
applied Bonferroni corrections with significant
findings.
Results
Maternal mean hemoglobin levels (with standard
deviations [SD], minimum, and maximum) during
different trimesters of pregnancy are presented in
Table 1. In total, 8198 (21.4%) women had anemia
(hemoglobin levels <110 g/L) during at least one tri-
mester of pregnancy: 906 out of 34 116 (2.7%) had
been anemic during the first trimester, 5000 out of
35 629 (14.0%) had been anemic during the second tri-
mester, and 4240 out of 33 000 (12.8%) had been ane-
mic during the third trimester (Table 1). Moderate
and severe anemia was detected in 146 (0.4%) women.
Among anemic women who were measured at least
three times during pregnancy, 1603 (23.6%) had
SD Min–Max Anemia (<110 g/L) n/N (%)
10.7 55–198 906/34 116 (2.7)
9.4 52–186 5000/35 629 (14.0)
9.8 66–196 4240/33 000 (12.8)
5180/28 918† (16.8)
1397/28 918† (3.6)
206/28 918† (0.7)
3
M. Harju et al.

anemia during two or three trimesters and 5180
(76.4%) had anemia during just one trimester.
Out of 38 381 live-born children, 2475 (6.4%) had
asthma, with a mean age of 5.3 years (SD, 4.0; range,
0–19 years) at the onset of medical cost reimburse-
ment (follow-up time of cases included in analysis).
At the time of data collection, a total of 1101 children
(2.9%) had current ongoing reimbursement, with a
mean age of 8 years (range, 1–19 years). In contrast,
the mean duration of follow-up of healthy control
children was 9.7 (SD, 5.6) years.
No significant associations were noted between the
presence of asthma among offspring and maternal
hemoglobin levels during the three trimesters of preg-
nancy (as quintiles; data not shown). However, as
regards all three trimesters, children of mothers in the
highest quintile of hemoglobin levels had the lowest
incidence of asthma (6.0–6.4%), and, on the other
hand, children of mothers in the lowest quintile of
hemoglobin levels most frequently had asthma
(6.9–7.2%). In stratified analysis, this association was
significant in male offspring during the second and
third trimesters (Table 2). After applying the Bonfer-
roni correction, the association in the second trimester
remained significant (P < 0.042).
Second, we evaluated the severity of anemia with
the development of asthma ever. Mild maternal ane-
mia in the first trimester of pregnancy was associated
significantly with a 1.46-fold higher risk (95% confi-
dence interval [CI], 1.11–1.94; P < 0.008) of any kind
of asthma in male offspring compared with children
of non-anemic mothers (Table 3). After adjustment by
means of Bonferroni correction analysis, the signifi-
cant association remained (significance at P < 0.042).
In accordance, risk of asthma among male offspring
was highest in the second and third trimesters among
mildly anemic women; however, this association was
not statistically significant (P = 0.108 and P = 0.119).
Further, male offspring with maternal anemia (hemo-
globin level <110 g/L) at any time during pregnancy
had significantly more asthma ever compared with
male offspring of mothers with higher hemoglobin
levels during pregnancy (adjusted hazard ratio [aHR],
1.15; 95%CI, 1.02–1.30; P < 0.027). The cumulative
incidence of asthma among male offspring is shown
in Figure 1. Such an association was not detected in
female offspring (aHR, 1.04; 95%CI, 0.90–1.21;
P = 0.597). The mean follow-up times in children of
anemic and non-anemic mothers were 10.0 (SD 5.2)
and 9.8 (5.7) years, respectively.

Table 2 Maternal hemoglobin levels during the three trimesters of pregnancy and asthma ever among offspring sepa-
rately by sex
Hemoglobin g/L Male offspring Female offspring
Asthma ever, n/N (%) aHR† (95%CI) Asthma ever, n/N (%) aHR† (95%CI)
First trimester
First quintile (–121) 319/3750 (8.5) 1 221/3766 (5.9) 1
Second quintile (122–127) 281/3516 (8.0) 0.96 (0.82–1.13) 194/3464 (5.6) 0.98 (0.81–1.19)
Third quintile (128–132) 247/3310 (7.5) 0.90 (0.76–1.06) 172/3131 (5.5) 0.98 (0.80–1.19)
Fourth quintile (133–138) 278/3306 (8.4) 1.04 (0.88–1.22) 163/3143 (5.2) 0.95 (0.78–1.17)
Fifth quintile (139–) 261/3516 (7.4) 0.94 (0.80–1.11) 168/3214 (5.2) 0.99 (0.81–1.22)
P-value 0.489 0.993
Second trimester
First quintile (–111) 311/3596 (8.6) 1 213/3674 (5.8) 1
Second quintile (112–117) 376/4278 (8.8) 1.01 (0.87–1.17) 211/4103 (5.1) 0.89 (0.74–1.09)
Third quintile (118–121) 248/3314 (7.5) 0.86 (0.73–1.01) 183/3184 (5.7) 0.97 (0.80–1.19)
Fourth quintile (122–127) 264/3638 (7.3) 0.83 (0.71–0.98) 172/3435 (5.0) 0.88 (0.72–1.08)
Fifth quintile (128–) 229/3361 (6.8) 0.81 (0.68–0.97) 155/3046 (5.1) 0.94 (0.76–1.16)
P-value 0.014 0.687
Third trimester
First quintile (–112) 303/3537 (8.6) 1 193/3620 (5.3) 1
Second quintile (113–118) 306/3809 (8.0) 0.93 (0.79–1.09) 204/3623 (5.6) 1.05 (0.86–1.28)
Third quintile (119–122) 223/2818 (7.9) 0.90 (0.75–1.07) 146/2730 (5.3) 0.99 (0.80–1.23)
Fourth quintile (123–128) 263/3532 (7.4) 0.84 (0.72–1.00) 172/3298 (5.2) 0.97 (0.79–1.19)
Fifth quintile (129–) 228/3096 (7.4) 0.84 (0.71–1.00) 147/2937 (5.0) 0.95 (0.77–1.18)
P-value 0.238 0.907
Bold indicates P < 0.05. †Adjusted for maternal parity, maternal prepregnancy weight, maternal asthma and smoking during pregnancy,
gestational age at birth, birthweight, and bleeding during pregnancy. aHR, adjusted hazard ratio; CI, confidence interval.

4 © 2018 Japan Society of Obstetrics and Gynecology

 Table 3 Severity of maternal anemia and high hemoglobin levels during the three trimesters and asthma ever among offspring
N total (%) Asthma ever, aHR† Male aHR† Female aHR†
n (%) (95%CI) asthma ever, (95%CI) asthma ever, (95%CI)
n/N (%) n/N (%)
First trimester (g/L)
High hemoglobin (≥145) 2779 (8.1) 187 (6.7) 1.07 (0.92–1.25) 116/1506 (7.7) 1.04 (0.86–1.26) 71/1273 (5.6) 1.10 (0.86–1.40)
Normal (110–144) 30 431 (89.2) 2039 (6.7) 1 1217/15 443 (7.9) 1 822/14 988 (5.5) 1
Mild anemia (90–109) 880 (2.6) 76 (8.6) 1.24 (0.99–1.56) 51/437 (11.7) 1.46 (1.11–1.94) 25/443 (5.6) 0.96 (0.65–1.43)
Moderate and severe 26 (0.1) 2 (7.7) 0.95 (0.24–3.83) 2/12 (16.7) 1.81 (0.45–7.25) 0/14 (0) 00 (0)

© 2018 Japan Society of Obstetrics and Gynecology

anemia (≤89)
P-values 0.259 0.051 0.890
Second trimester (g/L)
High hemoglobin (≥145) 240 (0.7) 16 (6.7) 1.08 (0.66–1.77) 10/133 (7.5) 0.99 (0.53–1.85) 6/107 (5.6) 1.18 (0.53–2.64)
Normal (110–144) 30 389 (85.3) 1981 (6.5) 1 1208/ 15 640 (7.7) 1 773/14 749 (5.2) 1
Mild anemia (90–109) 4933 (13.8) 360 (7.3) 1.11 (0.99–1.24) 207/2380 (8.7) 1.13 (0.97–1.31) 153/2553 (6.0) 1.13 (0.95–1.34)
Moderate and severe 67 (0.2) 5 (7.2) 1.06 (0.44–2.55) 3/34 (8.8) 1.07 (0.35–3.33) 2/33 (6.1) 1.06 (0.27–4.26)
anemia (≤89)
P-values 0.352 0.457 0.593
Third trimester (g/L)
High hemoglobin (≥145) 250 (0.8) 14 (5.6) 0.89 (0.52–1.50) 8/121 (6.6) 0.69 (0.43–1.74) 6/129 (4.7) 0.95 (0.42–2.11)
Normal (110–144) 28 510 (86.4) 1875 (6.6) 1 1142/14 631 (7.8) 1 733/13 879 (5.3) 1
Mild anemia (90–109) 4145 (12.6) 291 (7.0) 1.09 (0.96–1.24) 171/1994 (8.6) 1.14 (0.97–1.34) 120/2151 (5.6) 1.08 (0.89–1.31)
Moderate and severe 95 (0.3) 5 (5.3) 0.79 (0.33–1.91) 2/46 (4.3) 0.55 (0.14–2.21) 3/49 (6.1) 1.18 (0.38–3.68)
anemia (≤89)
P-values 0.485 0.338 0.875
Bold indicates P < 0.05. †Adjusted for sex, maternal parity, maternal prepregnancy weight, maternal asthma and smoking during pregnancy, gestational age at birth, birth-
weight, and bleeding during pregnancy. aHR, adjusted hazard ratio; CI, confidence interval.
Maternal anemia and children’s asthma

5
M. Harju et al.
Incidence of asthma among male offspring
Maternal anemia during
pregnancy
Cumulative incidence (%)
Age (years)
We further evaluated the different types of asthma
among 6–19-year-old children (n = 28 467). No signif-
icant associations were detected between early-onset
transient, early-onset persistent, or late-onset asthma
versus maternal hemoglobin levels in the three trimes-
ters of pregnancy in the total study population
(Table 4).
Discussion
According to data from a large birth register, we have
shown here that maternal hemoglobin levels during
pregnancy tended to be inversely related to the future
risk of asthma among offspring. As regards the sec-
ond trimester, children of mothers in the highest quin-
tile of hemoglobin levels significantly had the lowest
prevalence of asthma, and, on the other hand, chil-
dren of mothers in the lowest quintile of hemoglobin
levels most frequently had asthma. A similar ten-
dency was detected also in the first trimester. This dif-
ference was not strong and was detected more often
in male offspring. Consistent with this, mild maternal
anemia in the first trimester was associated signifi-
cantly with asthma at any time of life among male off-
spring. Possibly due to physiologic hemodilution,
which occurs after midgestation, this was detected
6 © 2018 Japan Society of Obstetrics and Gynecology
No anemia
Figure 1 Cumulative inci-
dence of asthma among
male offspring in mothers
with and without anemia
during pregnancy.
only in the first trimester. Our results confirm earlier
studies showing associations between maternal ane-
mia or deficient iron status during pregnancy and
asthma and wheezing among offspring;8,9 however,
our results show that this association was more sex-
specific and significantly detected only in male
offspring.
Maternal hemoglobin concentrations during preg-
nancy would mirror, in general, social characteristics
or maternal nutritional status. It is well known that
severe anemia is directly associated with maternal
mortality and morbidity during pregnancy,23,24 but it
also may have effects on the fetus.24,25 In our preg-
nant population, severe and moderate anemia were
rare; only 0.4% of our pregnant women had hemoglo-
bin levels ≤89 g/L during some stage of pregnancy.
The effects of milder forms of anemia in terms of
maternal or fetal health during pregnancy are not yet
well studied.25–27 Lower hemoglobin levels and nutri-
tional status during early pregnancy may predispose
women to a higher risk of infections and fetuses to
the suboptimal intrauterine environment with
decreased oxygen availability that can alter placental
function and lung development.28–30 In this study, we
adjusted for maternal pre-pregnancy weight, maternal
asthma, parity, and smoking during pregnancy.
Maternal asthma was the highest risk factor for the
 Maternal anemia and children’s asthma

Table 4 Maternal hemoglobin level during three trimesters of pregnancy and its relation to the different types of asthma
among 6–19-year-old offspring
Hemoglobin g/L Early-onset aHR‡ Early-onset aHR‡ (95%CI)
transient asthma, (95%CI) persistent
n/N† (%) or late-onset
asthma, n/N† (%)
First trimester
First quintile (–121) 70/5919 (1.2) 1 437/6286 (7.0) 1
Second quintile (122–127) 47/5260 (0.9) 0.80 (0.55–1.17) 387/5600 (6.9) 0.82 (0.86–1.14)
Third quintile (128–132) 47/4755 (1.0) 0.85 (0.58–1.24) 334/5042 (6.6) 0.94 (0.81–1.09)
Fourth quintile (133–138) 53/4577 (1.2) 0.94 (0.65–1.36) 348/4872 (7.1) 1.02 (0.88–1.18)
Fifth quintile (139–) 57/4511 (1.3) 0.95 (0.66–1.37) 325/4779 (6.8) 0.95 (0.82–1.11)
P-value 0.800 0.817
Second trimester
First quintile (–111) 69/5512 (1.3) 1 404/5847 (6.9) 1
Second quintile (112–117) 62/6285 (1.0) 0.81 (0.57–1.15) 477/6700 (7.1) 1.02 (0.89–1.18)
Third quintile (118–121) 60/4885 (1.2) 1.06 (0.74–1.51) 347/5172 (6.7) 0.96 (0.83–1.11)
Fourth quintile (122–127) 46/5124 (0.9) 0.74 (0.50–1.09) 346/5424 (6.4) 0.91 (0.78–1.06)
Fifth quintile (128–) 42/4173 (1.0) 0.71 (0.48–1.06) 304/4435 (6.9) 0.97 (0.83–1.13)
P-value 0.171 0.562
Third trimester
First quintile (–112) 62/5582 (1.1) 1 400/5920 (6.8) 1
Second quintile (113–118) 57/5770 (1.0) 0.97 (0.67–1.39) 414/6127 (6.8) 0.99 (0.86–1.14)
Third quintile (119–122) 39/4331 (0.9) 0.89 (0.59–1.34) 307/4599 (6.7) 0.97 (0.83–1.13)
Fourth quintile (123–128) 42/5169 (0.8) 0.85 (0.57–1.27) 356/5483 (6.5) 0.94 (0.81–1.09)
Fifth quintile (129–) 46/4394 (1.0) 1.11 (0.75–1.65) 306/4654 (6.6) 0.96 (0.82–1.12)
P-value 0.765 0.928
†Children with other types of asthma excluded. ‡Adjusted for maternal parity, maternal prepregnancy weight, maternal asthma and
smoking during pregnancy, gestational age at birth, birthweight, and bleeding during pregnancy. aHR, adjusted hazard ratio; CI confi-
dence interval.

development of asthma among offspring (aHR,
2.87–2.94). Interestingly, Triche and associates
reported that maternal anemia played a more signifi-
cant role in the development of asthma among chil-
dren born to asthmatic mothers.8 In this study,
maternal anemia was associated with the increased
risk of asthma among male offspring regardless of
maternal asthma status (aHR, 1.19–1.49). Neverthe-
less, it is obvious that these adjustments do not
exclude all nutritional and environmental effects that
may have an association with maternal hemoglobin
levels or a role in the development of long-term dis-
eases, such as asthma, among offspring.
Various complications during pregnancy, for exam-
ple vaginal bleeding, preterm delivery, and pre-
eclampsia, have also been associated with an
increased risk of asthma among offspring.7,31,32 We
included earlier occurrences of vaginal bleeding and
the duration of gestation at delivery in multivariable
analysis, and even after these inclusions, the signifi-
cant association between maternal hemoglobin levels
during the first trimester versus asthma among male
offspring remained significant. There are several other
maternal chronic diseases that may have effects on
the maternal hemoglobin levels and risk of anemia
during pregnancy. As we did not include pre-
eclampsia or maternal chronic conditions in this anal-
ysis, we cannot exclude their possible role in the
development of asthma among offspring. However,
pre-eclampsia has been associated merely with high
maternal hemoglobin levels during pregnancy.33,34 It
is unlikely that pre-eclampsia could explain the
detected significant association between the risk of
asthma among offspring and low maternal hemoglo-
bin levels and anemia during pregnancy.
One of the most interesting and surprising findings
in this study was that we showed an association
between maternal anemia and low hemoglobin levels
with asthma merely among male offspring. Sexual
dimorphism has become a new area of interest to
study maternal environmental effects in fetal develop-
ment and later health. It is likely that the maternal
and fetal metabolic environment, including hormones,
contributes to the sex-specific development of the pla-
centa. Differences in placental function are regulated
by epigenetic mechanisms, which are driven by differ-
ent hormone milieu.35 In clinical point, there are
known sex-specific differences in early fetal and

© 2018 Japan Society of Obstetrics and Gynecology 7

M. Harju et al.
neonatal life as regards morbidity and mortality.
Mothers with a male fetus are more likely to experi-
ence pregnancy and delivery complications, such as
preterm delivery, low-birthweight infants, and emer-
gency cesarean deliveries, and male neonates them-
selves also have higher risks of early neonatal
respiratory and neurologic morbidity compared with
female neonates.36–40 Although there are plenty of
reports concerning sexual dimorphism during gesta-
tion and possible diversity based on different hor-
monal profile and its effects, the evidence on
mechanisms is sparse and the research area has
remained poorly understood.
Some limitations of our approach should be
acknowledged. First, the detected association between
maternal hemoglobin levels or anemia and later
asthma among male offspring was not strong even
though our database was large, comprising over
38 000 singleton mother–child pairs. Second, the num-
ber of women with moderate or severe anemia
(≤89 g/L) was low, hampering evaluation of severe
anemia in this setting. Third, the diagnosis of anemia
in different trimesters of pregnancy is affected by the
duration of gestation, as low hemoglobin levels are
more frequently observed in the last two trimesters
and they may be just an indicator of an expanded
maternal plasma volume. We used WHO standards
for anemia,41 but the analyses were also carried out
using an alternative cut-off value of 100 g/L, with
similar results (data not shown). Fourth, we did not
report the use of iron supplementation in this study,
but during the study period (1989–2007) it was rou-
tine practice in most maternity outpatient clinics in
Finland among cases with relatively low hemoglobin
levels (approx. <120–125 g/L). Finally, we did not
exclude subjects with hereditary hemoglobinopathies,
such as thalassemia or sickle cell anemia. However,
the incidence of such cases in the Finnish population
is extremely low, occurring in less than 0.001% of
pregnant women.
In conclusion, according to a large epidemiological
birth register database, we found that maternal ane-
mia and low hemoglobin levels during pregnancy
were associated with a subsequent risk of asthma
among male offspring. The detected association was
not strong, although it was statistically significant.
These findings support the significance of maternal
health as regards prenatal programming in a sex-
specific manner during the fetal period and further as
regards the development of long-term diseases, such
as asthma, among offspring. However, future studies
8 © 2018 Japan Society of Obstetrics and Gynecology
are warranted to confirm these findings and to better
explore the diversity of sex in prenatal programming.
Disclosure
None declared.
References
1. McMillen IC, Muhlhausler BS, Duffield JA, Yuen BSJ. Prena-
tal programming of postnatal obesity: Fetal nutrition and
the regulation of leptin synthesis and secretion before birth.
Proc Nutr Soc 2004; 63: 405–412.
2. Seckl JR, Holmes MC. Mechanisms of disease: Glucocorti-
coids, their placental metabolism and fetal ’programming’ of
adult pathophysiology. Nat Clin Pract Endocrinol Metab 2007;
3: 479–488.
3. Bertram CE, Hanson MA. Prenatal programming of postna-
tal endocrine responses by glucocorticoids. Reproduction
2002; 124: 459–467.
4. Kindlund K, Thomsen SF, Stensballe LG et al. Birth weight
and risk of asthma in 3-9-year-old twins: Exploring the fetal
origins hypothesis. Thorax 2010; 65: 146–149.
5. Keski-Nisula L, Katila M, Remes S et al. Intrauterine bacte-
rial growth at birth and risk of asthma and allergic sensitiza-
tion among offspring at 15-17 years. J Allergy Clin Immunol
2009; 123: 1305–1311.
6. Keski-Nisula L, Harju M, Jarvelin MR, Pekkanen J. Vacuum-
assisted delivery is associated with late-onset asthma.
Allergy 2009; 64: 1530–1538.
7. Kumar R, Yu Y, Story RE et al. Prematurity, chorioamnioni-
tis, and the development of recurrent wheezing: A prospec-
tive birth cohort study. J Allergy Clin Immunol 2008; 121:
878–884.
8. Triche EW, Lundsberg LS, Wickner PG, Belanger K,
Leaderer BP, Bracken MB. Association of maternal anemia
with increased wheeze and asthma in children. Ann Allergy
Asthma Immunol 2011; 106: 131–139.
9. Nwaru BI, Hayes H, Gambling L et al. An exploratory study
of the associations between maternal iron status in preg-
nancy and childhood wheeze and atopy. Br J Nutr 2014; 112:
2018–2027.
10. Tromp II, Gaillard R, Kiefte-de Jong JC et al. Maternal hemo-
globin levels during pregnancy and asthma in childhood:
The Generation R Study. Ann Allergy Asthma Immunol 2014;
112: 263–265.
11. Insel BJ, Schaefer CA, McKeague IW, Susser ES, Brown AS.
Maternal iron deficiency and the risk of schizophrenia in off-
spring. Arch Gen Psychiatry 2008; 65: 1136–1144.
12. Petridou E, Trichopoulos D, Kalapothaki V et al. The risk
profile of childhood leukaemia in Greece: A nationwide
case-control study. Br J Cancer 1997; 76: 1241–1247.
13. Roman E, Simpson J, Ansell P, Lightfoot T, Mitchell C,
Eden TOB. Perinatal and reproductive factors: A report on
haematological malignancies from the UKCCS. Eur J Cancer
2005; 41: 749–759.
14. Roman E, Ansell P, Bull D. Leukaemia and non-Hodgkin’s
lymphoma in children and young adults: Are prenatal and

neonatal factors important determinants of disease? Br J
Cancer 1997; 76: 406–415.
15. Leonard H, de Klerk N, Bourke J, Bower C. Maternal health
in pregnancy and intellectual disability in the offspring: A
population-based study. Ann Epidemiol 2006; 16: 448–454.
16. Drassinower D, Laery JA, Friedman AM, Levin HI,
Obican SG, Ananth CV. The effect of maternal haematocrit
on offspring IQ at 4 and 7 years of age: A secondary analy-
sis. BJOG 2016; 123: 2087–2093.
17. Nielsen PR, Meyer U, Mortensen PB. Individual and combined
effects of maternal anemia and prenatal infection on risk for
schizophrenia in offspring. Schizophr Res 2016; 172: 35–40.
18. Kassebaum NJ, GBD 2013 Anemia Collaborators. The global
burden of anemia. Hematol Oncol Clin North Am 2016; 30:
247–308.
19. Kouzouna A, Gilchrist FJ, Ball V et al. A systematic review
of early life factors which adversely affect subsequent lung
function. Paediatr Respir Rev 2016; 20: 67–75.
20. Harju M, Keski-Nisula L, Raatikainen K, Pekkanen J,
Heinonen S. Maternal fecundity and asthma among off-
spring: Is the risk programmed preconceptionally? Retro-
spective observational study. Fertil Steril 2013; 99: 761–767.
21. Harju M, Keski-Nisula L, Georgiadis L, Räisänen S, Gissler M,
Heinonen S. The burden of childhood asthma and late pre-
term and early term births. J Pediatr 2014; 164: 295–299.
22. Harju M, Keski-Nisula L, Georgiadis L, Heinonen S. Parental
smoking and cessation during pregnancy and the risk of
childhood asthma. BMC Public Health 2016; 16: 428.
23. Yip R. Significance of an abnormally low or high hemoglo-
bin concentration during pregnancy: Special consideration
of iron nutrition. Am J Clin Nutr 2000; 72: 272S–279S.
24. Geelhoed D, Agadzi F, Visser L et al. Maternal and fetal out-
come after severe anemia in pregnancy in rural Ghana. Acta
Obstet Gynecol Scand 2006; 85: 49–55.
25. Sifakis S, Pharmakides G. Anemia in pregnancy. Ann N Y
Acad Sci 2000; 900: 125–136.
26. Lao TT, Pun TC. Anaemia in pregnancy: Is the current defi-
nition meaningful? Eur J Obstet Gynecol Reprod Biol 1996; 68:
53–58.
27. Allen LH. Anemia and iron deficiency: Effects on pregnancy
outcome. Am J Clin Nutr 2000; 71: 1280S–1284S.
28. Das I, Saha K, Mukhopadhyay D et al. Impact of iron defi-
ciency anemia on cell-mediated and humoral immunity in chil-
dren: A case control study. J Nat Sci Biol Med 2014; 5: 158–163.
© 2018 Japan Society of Obstetrics and Gynecology
Maternal anemia and children’s asthma
29. Nairz M, Haschka D, Demetz E, Weiss G. Iron at the inter-
face of immunity and infection. Front Pharmacol 2014;
16: 152.
30. Sehgal S, Bhatnagar S, Pallavi SK. Provocative ideas on
human placental biology: A prerequisite for prevention and
treatment of neonatal health challenges. Am J Reprod Immu-
nol 2017; 77: e12656.
31. Nafstad P, Magnus P, Jaakkola JJ. Risk of childhood asthma
and allergic rhinitis in relation to pregnancy complications. J
Allergy Clin Immunol 2000; 106: 867–873.
32. Strachan DP, Butland BK, Anderson HR. Incidence and
prognosis of asthma and wheezing illness from early child-
hood to age 33 in a national British cohort. BMJ 1996; 312:
1195–1199.
33. Amburgey OA, Ing E, Badger GJ, Bernstein IM. Maternal
hemoglobin concentration and its association with birth
weight in newborns of mothers with preeclampsia. J Matern
Fetal Neonatal Med 2009; 22: 740–744.
34. Phaloprakarn C, Tangjitgamol S. Impact of high maternal
hemoglobin at first antenatal visit on pregnancy outcomes:
A cohort study. J Perinat Med 2008; 36: 115–119.
35. Sundrani DP, Roy SS, Jadhav AT, Joshi SR. Sex-specific dif-
ferences and developmental programming for diseases in
later life. Reprod Fertil Dev 2017; 29: 2085–2099.
36. Melamed N, Yogev Y, Glezerman M. Effect of fetal sex on
pregnancy outcome in twin pregnancies. Obstet Gynecol
2009; 114: 1085–1092.
37. Tan H, Wen SW, Walker M et al. The association between
fetal sex and preterm birth in twin pregnancies. Obstet Gyne-
col 2004; 103: 327–332.
38. Agarwal U, Anastasakis E, Kadir RA. The effect of fetal sex
on the outcome of labour induction. J Obstet Gynaecol 2009;
29: 711–713.
39. Dailey TL, Jayakrishnan A, Phipps M, Raker CA, Chien EK.
The contribution of maternal race/ethnicity and fetal sex to
prematurity in twins. Am J Obstet Gynecol 2009; 201:
e61–e66.
40. Spinillo A, Montanari L, Gardella B, Roccio M, Stronati M,
Fazzi E. Infant sex, obstetric risk factors, and 2-year neuro-
developmental outcome among preterm infants. Dev Med
Child Neurol 2009; 51: 518–525.
41. World Health Organization. Iron Deficiency Anaemia: Assess-
ment, Prevention, and Control – A Guide for Programme Man-
agers. Geneva: World Health Organization, 2001.
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