J. Perinat. Med.

2021; 49(4): 431–438

Lotta Kemppinen, Mirjami Mattila*, Eeva Ekholm, Nanneli Pallasmaa, Ari Törmä,
Leila Varakas and Kaarin Mäkikallio

Gestational iron deficiency anemia is associated

with preterm birth, fetal growth restriction, and
postpartum infections
https://doi.org/10.1515/jpm-2020-0379 IDA, causing an additional burden on the families and the
Received August 9, 2020; accepted December 2, 2020; healthcare system.
published online December 21, 2020
Keywords: fetal growth restriction; gestational anemia;
Abstract intravenous iron supplementation; iron deficiency anemia
in pregnancy; postpartum complications; preterm birth.
Objectives: Gestational IDA has been linked to adverse
maternal and neonatal outcomes, but the impact of iron sup-
plementation on outcome measures remains unclear. Our
Introduction
objective was to assess the effects of gestational IDA on preg-
nancy outcomes and compare outcomes in pregnancies
Anemia affects approximately 50% of pregnant women
treated with either oral or intravenous iron supplementation.
globally [1]. Iron deficiency is the most common cause of
Methods: We evaluated maternal and neonatal out-
gestational anemia [2, 3]. Furthermore, 18% of pregnant
comes in 215 pregnancies complicated with gestational
women are estimated to suffer from iron deficiency without
IDA (Hb<100 g/L) and delivered in our tertiary unit be-
anemia and, thus, are at considerable risk for developing
tween January 2016 and October 2018. All pregnancies
iron-deficiency anemia (IDA) [4]. Factors affecting iron
from the same period served as a reference group
intake and absorption, such as diets lacking iron-rich food
(n=11,545). 163 anemic mothers received oral iron sup-
sources and inflammatory bowel disease, increase IDA risk
plementation, and 52 mothers received intravenous iron
[5]. WHO defines anemia in pregnancy as hemoglobin (Hb)
supplementation.
level <110 g/L [2]. The same cut-off value for gestational
Results: Gestational IDA was associated with an increased
anemia is used in Finland [6].
risk of preterm birth (10.2% vs. 6.1%, p=0.009) and fetal
Maternal anemia has been associated with an
growth restriction (FGR) (1.9% vs. 0.3%, p=0.006). The
increased risk of prematurity [7–10], low birth weight
gestational IDA group that received intravenous iron sup-
[9–11], cesarean delivery [7, 9], admission to a neonatal
plementation had a greater increase in Hb levels compared
unit [7], perinatal mortality [9, 10], and maternal death
to those who received oral medication (18.0 g/L vs. 10.0 g/
[9, 12]. Furthermore, preoperative anemia in surgical
L, p<0.001), but no statistically significant differences in
patients is generally associated with adverse surgical
maternal and neonatal outcomes were detected.
outcomes, such as infections, the need for red blood
Conclusions: Compared to the reference group, prematu-
cell transfusions, postoperative admissions to intensive
rity, FGR, postpartum infections, and extended hospital
care, and mortality [13–15]. Thus, anemic women un-
stays were more common among mothers with gestational
dergoing cesarean delivery are suggested to benefit from
preoperative iron supplementation [16]. However, the
available data regarding the cause-effect relationship
*Corresponding author: Mirjami Mattila, MD, PhD, Department of
between IDA and adverse pregnancy outcomes remain
Obstetrics and Gynecology, Turku University Hospital, U-Hospital,
Kiinamyllynkatu 4-8, 20520 Turku, Finland; and University of Turku, inconclusive [17].
Turku, Finland, Phone: +35823130317, Fax: +35823132340, In Finland, gestational IDA is primarily treated with a
E-mail: mirjami.mattila@utu.fi 100–200 mg daily dose of oral iron. In cases of severe
Lotta Kemppinen, Eeva Ekholm, Nanneli Pallasmaa, Leila Varakas anemia, as well as when Hb levels remain low despite oral
and Kaarin Mäkikallio, Department of Obstetrics and Gynecology,
iron treatment or the mother does not tolerate oral sup-
Turku University Hospital, Turku, Finland; University of Turku, Turku,
Finland
plementation, intravenous iron infusion is used, and red
Ari Törmä, University of Turku, Turku, Finland; and Department of blood cell transfusions are given to those suffering from
Clinical Laboratory, Turku University Hospital, Turku, Finland severe anemia (Hb<80 g/L). Hematologic parameters of
432 Kemppinen et al.: Iron deficiency anemia in pregnancy
IDA (i.e. Hb, transferrin receptor [TfR], and ferritin-levels)
improve significantly in women who receive either oral or
intravenous iron supplementation [18]. Nonetheless, there
are no established guidelines for the use of intravenous
iron, and the existing results regarding the clinical benefits
of intravenous iron supplementation are unclear [19].
In the present study, we hypothesized that maternal
and neonatal complications are more frequent in preg-
nancies complicated by gestational IDA than in the refer-
ence population. Specifically, we were interested in
evaluating potential differences in maternal and neonatal
outcomes between anemic groups treated with either oral
or intravenous iron supplementation.
Materials and methods
In this retrospective study, we explored the digital pregnancy register
maintained by Turku University Hospital in Turku, Finland, between
January 1, 2016 and October 31, 2018, after obtaining approval from the
Turku Clinical Research Centre (Turku CRC Approval 11/2018, T07/
017/18), to identify mothers who had singleton pregnancies and
antenatal Hb<100 g/L. Women diagnosed with thalassemia and sickle
cell anemia were excluded. In Finland, Hb levels are checked in each
trimester by the primary care givers and oral iron supplementation is
began when Hb is <110 g/L. However, if initial Hb level is <90 g/L or Hb
persists below 100 g/L with appropriate oral treatment, the mother is
referred to a perinatal unit where the need for intravenous iron sup-
plementation is assessed based on clinician’s preference. In this
study, we used Hb<100 g/L as a cut-off value since mothers with this
Hb level are advised to be referred to our unit. The patient records of
the anemic mothers were carefully evaluated and the register-
retrieved data from all the pregnancies (n=11,545) delivered in our
tertiary unit during the study period served as a reference group.
The following variables describing maternal health were
collected from the medical records: maternal age, body mass index,
pre-existing diseases, regular medication(s), possible iron supple-
mentation prescribed by a primary caregiver, alcohol consumption
and smoking during pregnancy, and obstetric history. Maternal Hb
levels before delivery and the use of iron supplementation (oral and/or
intravenous) were reviewed. The lowest pretreatment and highest
posttreatment Hb levels from venous blood samples were recorded.
Possible changes in Hb levels were determined as the difference be-
tween the last Hb measured prior to delivery and the lowest antenatal
Hb level. Iron parameters (TfR, ferritin) were recorded when available.
Pregnancy and delivery data were collected. Maternal outcome vari-
ables, including pre-eclampsia, gestational diabetes, hepatogestosis,
thromboembolism, fetal growth restriction (FGR), postpartum in-
fections, 3rd- and 4th-degree vaginal tears, and red blood cell trans-
fusions, were reviewed. Data on postpartum infections, such as
endometritis, wound infection, urinary tract infection, and sepsis
diagnosed within six weeks postpartum, were included in the study.
The length of the postpartum hospital stay was determined as the time
interval between delivery and discharge. Neonatal outcomes were
assessed by means of birth weight, Apgar scores, pH and base excess
values of the umbilical artery, and admission to the neonatal intensive
care unit (NICU).
Statistical analysis
The statistical analyses were conducted using SPSS software
(IBM® SPSS Statistics 25.0). Possible differences in categorical mea-
sures between the groups were tested using chi-square and Fisher’s
exact tests. The distribution of the continuous data was evaluated
using the Kolmogorov–Smirnov test, and the independent sample
t-test was employed if the data were normally distributed. Otherwise,
the Mann–Whitney U-test was chosen. Adjustments for maternal pa-
rameters were used in subgroup analyses, in which individualized
patient data were available. p-Values <0.05 were considered statisti-
cally significant.
Results
During the study period, 215 women with singleton preg-
nancies had gestational IDA with antenatal Hb levels
<100 g/L. The lowest Hb levels in the study group were
recorded at a median gestational age of 31 weeks, and the
study group had significantly lower Hb values than the
reference group (Table 1). Despite iron supplementation,
the last Hb level recorded prior to delivery was significantly
lower in the anemic group compared to the reference
group, although Hb levels increased (p<0.001) more in the
anemic group than in the reference group during the
pregnancy (Table 1). In the anemic group iron parameters
TfR and ferritin were available from 49 (22.8%) and 59
(27.4%) women, respectively and due to low coverage were
not included in the statistical analyses.
Maternal parameters in the studied groups are pre-
sented in Table 1. Hypertension and pregestational dia-
betes were more frequent among anemic mothers than in
the reference population, and anemic mothers were also
younger, more frequently multiparous, and consumed
alcohol during pregnancy more often than the reference
population. No significant difference in the cesarean sec-
tion rate was detected between the groups. Pregnancies
complicated by gestational IDA showed a greater incidence
of postpartum infections, such as endometritis, wound
infection, urinary tract infection, and sepsis (OR 2.86 [CI
1.79–4.59]) than the reference group, and they also
received postpartum red blood cell transfusions more
frequently (OR 2.48 [CI 1.37–4.49]). Furthermore, post-
partum hospital stays were longer in the anemic group
than the reference group.
Neonatal outcome data are displayed in Table 1, and
2. The incidences of prematurity (gestational age at de-
livery <37 weeks, OR 1.80 [CI 1.15–2.81]) and FGR (OR 5.90
[CI 2.08–16.69]) were higher in the anemic group compared
to the reference group. Furthermore, the 1- and 5-min Apgar
scores were lower in the anemic group than in the reference
 Kemppinen et al.: Iron deficiency anemia in pregnancy 433

Table : Maternal characteristics and outcomes in pregnancies complicated with iron deficiency anemia and in the reference group, including
all pregnancies delivered during the study period. The values given are mean (SD), median (range) or n (%).

Hb< g/L n= Reference group n=, p-Value

Maternal factors
Age, years  (.)  (.) <.c
Primiparous  (.%) , (.%) .c
Body mass index  (–)  (–) .
Prior cesarean delivery  (.%) , (.%) .
Hypertension  (.%)  (.%) <.c
Type I and II diabetes  (.%)  (.%) <.c
Smoking  (.%) , (.%) .
Alcohol consumption  (.%)  (.%) .c
Pregnancy
Lowest Hb, g/L . (.–.) . (.–.) <.c
Highest Hb during pregnancy  (.–.)  (.–.) <.c
Last Hb prior delivery, g/L . (.) . (.) <.c
Hb increase, g/L . (–.) . (–.) <.c
Pre-eclampsia  (.%)  (.%) .
Gestational diabetes  (.%) , (.%) .
Hepatogestosis  (.%)  (.%) .
Thromboembolia  (.%)  (.%) .
Delivery and postpartum period
Induction of labor  (.%) , (.%) .
Mode of delivery .
Vaginal delivery  (.%) , (.%)
Operative vaginal delivery  (.%) , (.%)
Cesarean section  (.%) , (.%)
Elective  (.%)  (.%) .
Emergency  (.%) , (.%)
Crash emergency  (.%)  (.%)
Hemorrhage, mL  (–,)  (–,) .
> mL  (.%)  (.%) .
> mL  (.%)  (.%) .
Postpartum infectiona  (.%)  (.%) <.c
Vaginal tears (rd–th degree)  (.%)  (.%) .
Red blood cell transfusionb  (.%)  (.%) .c
Hospital stay after delivery, days . (–) . (–) <.c
Neonatal outcome
Male  (.%)  (.%) .
Birthweight, g  (–)  (–) .
Birthweight <− SD  (.%)  (.%) .c
GA at delivery < weeks  (.%)  (.%) .c
GA at delivery – weeks  (.%)  (.%) .c
GA at delivery < weeks  (.%)  (.%) .
Fetus mortus  (.%)  (.%) .
Apgar  min . (.) . (.) .c
Apgar  min . (.) . (.) .c
Apgar  min <  (.%)  (.%) .c
Apgar  min <  (.%)  (.%) .
Umbilical artery pH . (.–.) . (.–.) .
Umbilical artery BE −. (.) −. (.) .
NICU admission  (.%)  (.%) .

Hb, hemoglobin; GA, gestational age; BE, base excess; NICU, neonatal intensive care unit. aEndometritis, urinary tract infection, wound infection
and sepsis within six postpartum weeks. bGiven during delivery or puerperium. cp<..
434 Kemppinen et al.: Iron deficiency anemia in pregnancy

Table : Maternal characteristics and outcomes in pregnancies complicated with iron deficiency anemia and treated either with oral iron
supplementation solely or with additional intravenous iron injections. The values given are mean (SD), median (range) and n (%).

Intravenous iron n= Oral iron n= p-Value

Maternal factors
Age, years  (.)  (.) .
Primiparous  (.%)  (.%) .
Body mass index  (–)  (–) .
Prior cesarean delivery  (.%)  (.%) .
Hypertension  (.%)  (.%) .
Diabetes type I and II  (.%)  (.%) ,
Smoking  (.%)  (.%) .
Alcohol consumption   (.%) .
Pregnancy
Lowest Hb during pregnancy, g/L . (.–.) . (.–.) <.d
Highest Hb during pregnancy, g/L . (;) . (.) .
Last Hb prior delivery, g/L . (.) . (.) .
Hb increase, g/La . (–.) . (–.) <.d
Pre-eclampsia  (.%)  (.%) ,
Gestational diabetes  (.%)  (.%) .
Hepatogestosis   (.%) ,
Thromboembolia  (.%)  .
Delivery and postnatal period
Induction of labor  (.%)  (%) .d
Mode of delivery .
Vaginal delivery  (.%)  (.%)
Operative vaginal delivery  (.%)  (.%)
Cesarean delivery  (.%)  (.%)
Elective  (.%)  (.%) .
Emergency  (.%)  (.%)
Crash emergency   (.%)
Hemorrhage, mL  (–,)  (–,) .
Infectionb  (.%)  (.%) .
Vaginal tears (rd–th degree)  (.%)  (.%) .
Red blood cell transfusionc  (.%)  (.%) .
Hospital stay after delivery, days . (–) . (–) .
Neonatal outcome
Male  (.%)  (.%) .d
Birthweight, g  (–)  (–) .
Birthweight <− SD  (.%)  (.%) ,
GA at delivery < weeks  (.%)  (.%) .
GA at delivery – weeks  (.%)  (.%) ,
GA at delivery < weeks  (.%)  (.%) ,
Fetus mortus  (%)  (.%) ,
Apgar  min . (.) . (.) .
Apgar  min . (.) . (.) .
Apgar  min <  (.%)  (.%) .
Apgar  min <  (.%)  (.%) .
Umbilical artery pH . (.) . (.) .
Umbilical artery BE −. (.) −. (.) .d
NICU admission  (.%)  (.%) .
NICU stay, days  (–)  (–) .

Hb, hemoglobin; GA, gestational age; BE, base excess; NICU, neonatal intensive care unit. aCalculated as the difference between last Hb
recorded prior delivery and lowest Hb recorded during pregnancy. bEndometritis, urinary tract infection, wound infection and sepsis within six
postpartum weeks. cGiven during delivery or puerperium. dp<..

control group, and 1-min Apgar scores <7 were detected
more frequently among the newborns of anemic mothers
than in the reference group (OR 1.72 [CI 1.08–2.75).
The results of our subgroup analysis on maternal and
neonatal outcomes in the groups with gestational IDA and
either oral or intravenous iron supplementation are shown in
Table 2. During the study period, all mothers were prescribed
100–200 mg oral iron supplementation daily, and 52 mothers
received additional intravenous iron supplementation (Fer-
inject® 1000 mg, single dose) at a median gestational age of 33
(range=18–39) weeks. In addition, two mothers received two
red blood cell units twice at 25–26 gestational weeks. The pre-
treatment median Hb level was 88.5 (range 65–99) g/L in
mothers who received intravenous iron supplementation.
Maternal Hb levels increased more with intravenous iron
supplementation than solely oral medication, but no signifi-
cant differences in the last Hb values recorded prior to delivery
were detected. The deliveries of the mothers receiving intra-
venous iron treatment were induced more frequently than of
those receiving oral iron supplements. The incidences of
postpartum infections did not differ significantly between oral
and intravenous iron supplementation groups, and there
were no clinically significant differences in neonatal outcome
parameters between the groups.
Discussion
According to the present study, gestational IDA manifests
more frequently among diabetic and hypertensive women,
and those with young age, previous delivery and alcohol
consumption. Anemic mothers and newborns are predis-
posed to severe complications, such as prematurity, FGR,
and maternal postpartum infections, suggesting that
attention should be paid to the treatment of anemia in
order to avoid these complications.
In our study, hypertension and pregestational diabetes
were more common among anemic mothers than the
reference group. This finding is consistent with previous
data showing that diabetic patients have a higher preva-
lence of anemia [20]. According to animal and human
studies, IDA can impair glucose homeostasis and may
negatively affect glycemic control; thus, it may also in-
crease the risk of complications initiated by metabolic
changes in diabetic patients [21]. Furthermore, HbA1c is
likely to be affected by iron deficiency and IDA with a
spurious increase in HbA1c values [22]. These findings
suggest that IDA and diabetes may involve complicated
interactions that affect pregnancy outcome. Mothers with
gestational IDA in our cohort consumed more alcohol than
controls, and IDA was also associated with younger
Kemppinen et al.: Iron deficiency anemia in pregnancy 435
maternal age, as in previously conducted studies [7].
Although alcohol consumption is generally thought to
reduce the risk of iron deficiency [23], patients who
consume alcohol may also have an iron-deficient diet,
which can further predispose them to IDA. Maternal IDA
was more common in multiparous mothers, which
may be due to depleted iron stores caused by previous
pregnancies [24].
The increased incidence of prematurity and FGR
among mothers with gestational IDA reported in this study
is in line with previous publications [7, 9–11]. Allen et al.
[25] suggested that by causing chronic tissue hypoxia,
gestational anemia increases corticotrophin-releasing
hormone (CRH) secretion. The initiation of labor is regu-
lated by CRH, and elevated levels of CRH are associated
with both preterm delivery and FGR [26]. In addition, CRH
induces cortisol production, which, in turn, is also asso-
ciated with FGR [27]. Chronic tissue hypoxia and maternal
arterial hypoxemia are also recognized as possible mech-
anisms of FGR [25]. In our gestational IDA group, preterm
deliveries at <37 weeks gestational age were twice as
common, and at 32–34 weeks, they increased to three times
more common than in the reference group. However, no
increase in the incidence of early preterm birth prior to
32 weeks was detected in the gestational IDA cohort, sug-
gesting that other mechanisms, such as infections, might
have a stronger impact on premature deliveries prior to
32 weeks. In addition, mothers with gestational IDA had
higher incidences of hypertension, diabetes, and alcohol
consumption, all of which increase the risk of premature
delivery through various interacting mechanisms. Our
findings indicate that despite treating gestational IDA ac-
cording to current guidelines, the outcomes of newborns
are affected in the group of anemic mothers with associated
comorbidities, predisposing the infants to long-term
adverse effects.
According to our subgroup analysis labor was induced
more commonly in the intravenous iron supplementation
group than in the group with oral iron supplementation,
which is consistent with previous studies reporting that
lower Hb levels and anemia related symptoms, such as
fatigue, palpitation, shortness of breath, dizziness, and
maternal exhaustion, increase the probability of labor in-
duction [9, 28, 29]. While the number of pregnancy com-
plications did not differ significantly between intravenous
and oral supplementation groups, we speculate that the
higher incidence of inductions in the intravenous iron
supplementation group may also be partly a consequence
of more severe anemia in this group: mothers with more
severe anemia were controlled more frequently and,
therefore, were more likely to be induced. We found no
436 Kemppinen et al.: Iron deficiency anemia in pregnancy
significant difference in cesarean section rates between
groups. The fairly low cesarean section rate in Finland
(16.7% in 2018) and the small sample size of our study
cohort might have impacted our findings.
Five-minute Apgar scores <7 are associated with
increased neonatal neurologic morbidity and mortality and
adverse long-term effects, but previous studies’ findings
regarding the association between maternal anemia and
Apgar scores have been inconsistent [7, 28]. In our study,
newborns of anemic mothers had significantly lower 1- and
5-min Apgar scores, but no statistically significant differences
were detected in the incidence of 5-min Apgar scores <7,
umbilical artery pH values at delivery, and NICU admission
rates. We interpret these findings as reassuring regarding
long-term outcomes but suggest that follow-up studies are
warranted to determine this explicitly.
In the present study, there were almost 300% more
postpartum infections (e.g., wound infection, endome-
tritis, urinary tract infection, and sepsis) in mothers with
gestational anemia than in the reference group. Previously
Chaim et al. have reported an association between post-
partum endometritis and postpartum anemia, but largely
the relationship between gestational IDA and postpartum
infections is unclear [17, 30]. Cesarean delivery is an in-
dependent risk factor for infection, but in our study, ce-
sarean section rates did not differ between the groups,
suggesting that mothers with gestational IDA have an
increased risk of postpartum infections despite the mode of
delivery. Chronic tissue hypoxia caused by anemia leads to
decreased resistance to infection and, thus, may partly
explain this finding. In addition, mothers with gestational
IDA were more likely to receive red blood cell transfusions
postnatally. Red blood cell transfusions are associated
with post-transfusion infections [13], and could have
played a role in the increased postpartum infection rate
among anemic mothers. Increased postpartum morbidity
and blood cell transfusions explain the longer postpartum
recovery period of the anemic group and underscore the
importance of timely detection and treatment of gesta-
tional IDA.
Previous research has concluded that intravenous iron
supplementation elevates Hb levels more efficiently and
rapidly than oral iron supplementation [19, 31], but the
effect on clinical outcomes remains unclear [19, 32]. In our
retrospective study, mothers treated with intravenous iron
had significantly lower pretreatment Hb levels but a
significantly greater Hb level increase than those treated
with oral iron supplementation. However, no differences in
the highest Hb levels prior to delivery were detected be-
tween groups, which indicates that patients with severe
anemia were more likely to be treated with intravenous
iron. Furthermore, this finding could partly explain why no
statistically significant differences in adverse maternal and
neonatal outcomes were detected between the intravenous
and oral iron supplementation groups (i.e., intravenous
iron supplementation had a positive effect on maternal and
neonatal outcomes). Our findings are consistent with the
results of a very recent Indian randomized trial comparing
oral and intravenous supplementation in moderate to se-
vere gestational anemia [19], which was stopped due to
futility prior to full recruitment. The authors concluded
that there was insufficient evidence to show that intrave-
nous iron supplementation effectively reduced adverse
clinical outcomes compared with oral iron medication [19].
Despite oral or intravenous iron supplementation,
maternal and neonatal morbidity in our study was
increased in the group with gestational IDA, suggesting
that studies addressing this problem should be conducted
to develop evidence-based guidelines for effective iron
supplementation that minimizes adverse outcomes.
We acknowledge several limitations of this study. Due
to its retrospective nature, maternal Hb measurements
were performed at variable time points during pregnancy.
This predisposed the mothers to varying periods of anemia,
reflecting the current follow-up policy. Logically, longer
periods of anemia worsen maternal and neonatal out-
comes; thus, plans for preventive pregnancy interventions
and serial gestational Hb measurement during follow-ups
with primary care providers, as well as proper treatment for
anemia, are needed to address this problem early in preg-
nancy. Adjustments for maternal clinical conditions in the
retrospective plotted reference cohort was not possible, but
was performed in subgroup analyses with smaller group
sizes and non-plotted data. Although patients treated with
intravenous iron had significantly lower pretreatment Hb
levels, we noted that the patient selection criteria for
intravenous iron supplementation varied with no precise
Hb cut off values or associated clinical findings. The lowest
Hb levels were 88.5 and 95.0 g/L in the intravenous and
oral supplementation groups, respectively. This un-
derscores the need for established guidelines on the use of
iron supplementation during pregnancy and prospective,
large trials to analyze the impact of iron supplementation
methods.
Conclusions
Gestational IDA was associated with young age, multi-
parity, pregestational diabetes, hypertension and maternal
alcohol consumption. There was an increased risk of pre-
mature delivery, FGR, and maternal postpartum infections

and lengthened postpartum recovery in the gestational
IDA group suggesting that the proper treatment for
gestational IDA might be beneficial. Intravenous iron
supplementation increased Hb levels more effectively
than oral treatment with no difference in maternal and
neonatal outcomes. Large prospective randomized trials
are needed to determine the clinical impact of timely
corrected iron status on maternal and neonatal short-
and long-term outcomes.
Acknowledgments: The Finnish Medical Foundation.
Research funding: This article was supported by The
Finnish Medical Foundation (3611).
Author contributions: All authors have accepted
responsibility for the entire content of this manuscript
and approved its submission.
Competing interests: Authors state no conflict of interest.
Informed consent: No informed consent was required due
to retrospective registry based nature of the study.
Ethical approval: The study obtained approval from the
Turku Clinical Research Centre (CRC Approval 11/2018,
T07/017/18).
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