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4 (59)
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2023 : 001-009
009-013 • ORIGINAL
ORIGINALRESEARCH
ARTICLE

Can fetal heart

Treatment rate in twin
of gestational pregnancy with oral labetalol
hypertension
in
andthe first trimester
methyldopa be pregnant
in Iraqi useful as women
a marker
of pregnancy prognosis?
Ahmed Ibrahim Al-Yousif1*, Tagreed Hamood Hatem2, Nawfal Azzo2, Alaa Ghaith Ahmed3
AshurMalinowski
1
Witold University, Faculty
1 of Pharmacy,
(ABCD), Baghdad,
Magdalena Iraq
Klosowska-Kwapisz 2
(DEF)
1
2
Department of Obstetrics and Gynecology, Baghdad Teaching Hospital, Baghdad, Iraq
Masovian Public University in Płock. Department of Obstetrics-Gynecology Nursing
3
atDepartment of of
the Faculty Pharmacy,
Health Baghdad
Sciences,Teaching
Poland Hospital, Baghdad, Iraq
2
Clinical Department of Obstetrics and Gynecology, University Hospital in Zielona Gora, Poland

INTRODUCTION
SUMMARY

AUTHORS’ CONTRIBUTION: (A) Study Design · (B) Data Collection . (C)

AUTHORS’ CONTRIBUTION: (A) Study Design · (B) Data INTRODUCTION
Statistical Analysis · (D) Data Interpretation · (E) Manuscript Preparation
Hypertension, whether chronic or due to pregnancy,
· (F) Literature Search · (G) No Fund Collection
Collection · (C) Statistical Analysis · (D) Data Interpre-
tation · (E) Manuscript Preparation · (F) Literature Se- In the
is apast and nowadays
common pregnancythe fetal heart
concern. Aboutrate
5–10% of
arch · (G) Funds
Background: guidelines recommend labetalol as first-lineis being
NICE Collection used asare
pregnancies a confirmation
complicated byofhypertensive
the embryo/disorders of
antihypertensive therapy for gestational hypertension and pre-eclampsia,fetalpregnancy, life. Large group
which studies
result have reported
in maternal, fetal, and neonatal
Introduction.
while methyldopa Assessment of the are
and nifedipine fetalalsoheart rate become
available. Pre-existing
SUMMARY

amedications
routine manner and was
and adverse found
effect to should
profiles be helpful in makingwhenchanges
be considered in theand
morbidity heart rate
death [1].in It
early
can stage
cause of pre-and death
stroke
important
choosing anclinical decisions.therapy
antihypertensive In theduring
available literature
pregnancy. there
It investigated gnancy
if it [1-10].
is severe,Furthermore, miscarriages
but early detection and treatmentwerecan lower
howno
are well
anyoral labetalol and
information aboutoral methyldopa
fetal heart ratetreated
in twinhypertension
pregnan- in
expectant
observed
the riskinofpregnancies
these problems with
[2].abnormal
Hypertension fetalis defined
cy and it women.
usefulnessThisinstudy aims to pregnancy
predicting determine whether
outcome. labetalol can
be administered as a monotherapy for hypertension
Objective. The aim of our study was to evaluate a range of and to lower theheartas rate [1-7,11].
Systolic Blood Therefore
Pressure assessment
(SBP) ≥ 140of the
mmHg and/
dangerrates
of adverse
in theeffects, monotherapy is crucial.
heart first trimester in twin pregnancy and the fetalorheart rate Blood
Diastolic become a routine
Pressure (DBP)manner
≥ 90 mmHg and on two
influence
Methods: of the rate ofprospective
fetal heartcohort
on the outcome was of the
Observational research undertaken was different
found to be helpful
occasions duringinpregnancy.
making important
The first trimester of
pregnancy.
by the Obstetrics and Gynecology Department of Baghdad Teaching
Material
Hospital atand methods.
Medical The study
City/Baghdad, as included
well as the 89Gynecology
twin pregnan-Clinic. Asclinical
a decisions.
normal However
pregnancy sees a in the
progressiveavailable
fall li- pressure
in blood
cies between
a single agent,6using
and 11 the weeks
maximal of dosage
pregnancy A total of 60terature
(78 pregnancies
of labetalol. due tothere are no
a decrease any information
in systemic about It reaches
vascular resistance.
finished
pregnantwith
women good
wereoutcome
separatedand 11two
into with unfavorable
groups outco-
(A, and B). Group A
was given oral labetalol, whereas Group B was given oral methyldopa.
fetala heart
low pointrateatin22-24
twinweeks,
pregnancy.
and then rises from 28 weeks
me).
Results. The date shows that the heart rate of embryos / fetuses to preconception levels by 36 weeks [3].
Results: A few people require the addition of additional treatment
in the first trimester of an uncomplicated twin pregnancy
(13.3%). Methyldopa was required by almost 87% of patients, with a
progressively increases between 6 andAdditionally,
8 weeks ofwith pregnancy
AIM There are four categories, according to the American
statistically significant (p-value of 0.02). a p-value of
and then slows down in week 11. Our data shows that the rate
0.13, most patients didn't require a dose modification. Methyldopa andThe aim of our College of Obstetricians and Gynecologists (ACOG)
of fetal death in the firstsignificant
trimesterside
of twin pregnancy increases
study was to evaluate range of
labetalol had statistically effects in patients, with 83.3% criteria [4]:
progressively with decreasing
and 16.7% respectively. The mean of the heart rate.
difference In our
in SBP DBP post-heart rate in first trimester in twin pregnancy
and study
none of the
treatment wastwins
not survived
significantwhen the group.
in either observedTherate betweenand influence
of the fetal
association of rate of fetal
1. Hypertension that heart on pregnancy
is chronic or pre-existing,
heart
type of was less
side thanand
effect 110drug
beatsisper minute between
significant and half of them
using died
methyldopa
when heart rate was between 110 and 120 beats per min.
and labetalol, with a p-value of 0.03 compared to labetalol. The timeoutcome. preconception or before 20 weeks of pregnancy,
required to control
Furthermore, BP was alsodifference
the significant significant in
in the
the labetalol group.
heart rates of a with a postpartum period of more than 42 days.
set of twins was connected with a poor prognosis. In mono-
Conclusions: Treatment of pregnancy hypertensive disorders is
chorionic
correlatedpregnancies
with decreased with a significant
blood difference
pressure levels
MATERIALS AND METHODS
in hearteffects.
and adverse rate 2. Gestational Hypertension, after 20 weeks of
(20 beats/min or more) despite a normal fetal heart rate (120 pregnancy, appears and normally goes away within
Keywords: or Labetalol;
beats/min more) TTTSGestational
syndrome was confirmed later
hypertension; in
Methyldopa; The study was conducted in the Ultrasound Unit
Antihypertensive therapy; National Institute for Health and Carein Healthcare 42 days following delivery.
pregnancy. Center in Kutno from 2010 to
Excellence (NICE)
Conclusions. The heart rate in twin pregnancy more than 120
3. Preeclampsia/Eclampsia.
2016. In the study were included 89 twin pre-
beats per minute is connected with a good prognosis, whe-
reas below 110 beats per minute with a poor prognosis. gnancies between hypertension
Gestational 6 and 11 weeks of pregnan-
is accompanied by one of the
Furthermore, the significant difference in fetal heart rate (20 cy (78 pregnancies finished with good outco-
beats/min or more) can be a marker of developing TTTS syn- following:
drome later in pregnancy. me and 11 with unfavorable outcome). All
1. Proteinuria.
Key words: fetal heart rate; twin pregnancy; first trimester; pregnancies with risk factors (smoking, alcohol,
TTTS
2. Uteroplacental
drug addiction) dysfunction (diabetes
and complications (fetal growth
Address for correspondence: restriction, abnormal
mellitus, hypertension, anemia) umbilical artery Doppler
were excluded
Witold Malinowski waveform analysis, or stillbirth).
from the study
Department of Obstetrics-Gynecology Nursing at the Faculty
of Healthfor
Address Sciences, Masovian Public University in Płock, Poland
correspondence:
Measurements
3. Maternalwereorganobtained
dysfunctionusing ultraso-
includes the following:
Pl. Dąbrowskiego 2, 09-402 Płock und machine (B&K Medical 3535 and Voluson
e-mail: witold05@op.pl • Acute kidney injury.
Dr. Ahmed Ibrahim Al-Yousif, 730 PRO) with vaginal probe of 6.5 MHz fre-
Ashur University, Faculty of Pharmacy, Baghdad, Iraq,
E-mail: count:
Word ahmeds2012582@yahoo.com
1601 Tables: 2 Figures: 0 References: 28
quency. All• pregnancies were calculated
Liver involvement accor- with or
(transaminitis)
without right The
ding CRL measurement. upper quadrant age
gestational or epigastric
Received: 03.03.2021 was given in abdominal pain. formula: 7 we-
weeks according
Accepted: 08.03.2021
Published: 31.03.2021 eks = 7 weeks + 0/6 days.
• Neurological The heart rate
complications was altered
(eclampsia,
Word count: 4324 Tables: 06 Figures: 00 References: 50
performed using M-mode technique for each
mental status, blindness, stroke, clonus, severe
twin separately.
headache, persistent visual scotomata).
Received: 02.12.2023, Manuscript No. gpmp-23-121896; Editor
assigned: 04.12.2023, PreQC No. P-121896; Reviewed: 16.12.2023, • Hematological complications (decreased
QC No. Q-121896; Revised: 22.12.2023, Manuscript No. R-121896;
platelet count <150,000/uL, disseminated
Published: 29.12.2023 9
intravascular coagulation, hemolysis).
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 © GinPolMedProject 14(59)
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2023: 001-009
009-013

RESULTS
Epidemiology
Fetal heart rate in the first trimester of twin
when blood pressure is consistently increased to >160
pregnancies with unfavorable outcome is pre-
The mean fetal heart rate in the first trimester sented mmHg systolic and/or >105 mmHg diastolic, while
According to the National Health and Nutrition European in Table 2.
of twin pregnancy with good outcome is pre- guidelines recommend drug treatment in women
Examination Survey (NHANES), the prevalence of In the case of intrauterine fetal demise of
with gestational hypertension [1]. Chronic Hypertension
sented in Table 1. The above data show that the
hypertension among reproductive age (20-44 years old)bothand twins the heart rate was below 120 beats
Pregnancy (CHAP) project CHAP project randomly
heart rate of embryos / fetuses in the first tri-
is around 7.7%, and that of chronic hypertension duringper assigns minute in at least one of the twins. Further-
pregnant women to either receive antihypertensive
mester of uncomplicated twin pregnancy pro- more, we found that the difference in the he-
pregnancy varies between 0.9 and 1.5% [5,6]. therapy or no antihypertensive or low-dose therapy to keep
gressively increases between 6 and 8 weeks of art rate is as important as the heart rate itself.
pregnancy, reaches the nadir of 170 beats per In pregnancies blood pressure below
with high160/105 mmHg
difference [15]. rate
in heart
Pathophysiology
minute in week 8 and then slows down to 150 (20 or more beats/min) the outcome of the
beats
Non-pharmacological management
A per minute hypoxic,
chronically in week defective
11. The biggest
placenta dif-
releasespregnancy was unfavorable (death or TTTS
ference in
harmful heart rate
chemicals intobetween a pair blood
the maternal of twins
due tosyndrome). The In mosttwoprevalent
cases with keythefactor
fetal heart
in theratetherapy of
was found between
insufficient 6 and 7
Spiral Uterine weeks(SUA)
Artery of pregnan-
remodelingmore than 120 beats/min and high difference
hypertension is lifestyle adjustment. Between (10-
by
cy. Extra-Villous Trophoblasts
Later in pregnancy, up to(EVTs). Antiangiogenic
11+6 weeks the in the 20)heart
weeksrate, TTTS syndrome
of pregnancy, wasinobserved
especially women who are
factors,
difference microparticles
was similar and(including
remained pro-inflammatory
low. lateroverweight
in pregnancy. (BMI 25 kg/m ). Women with a BMI of less
2
mediators), cell-free nucleic acids, oxidized lipids, and than 30 kg/m2 are recommended not to acquire more than
free radicals have all been identified as placental factors
6.8 kg during pregnancy [16].
capable
Tab. 1. of
Thetriggering EDheart
mean fetal and rate
the syndrome.
Group They can
Gestational The mean Range The difference
cause
and second-order
the difference mediators
in heartsuch
rateas autoantigensagebodies
(weeks)
Pharmacological
heart rate
treatment
(beats/min) in heart rate
between
against the pair of
Angiotensin twins betwe-
receptor 1 (AA-AT1) or effectors like (beats/min.) between twins
en 6 and 11 (ET-1)
Endothelin-1 weeks of
anduncomplica-
superoxide to be produced in the (beats/min.)
ted twin pregnancy
When treating pregnant women, the efficacy of the
maternal circulation [7]. 1 (n=12) 6+0 – 6+6 141 125 - 158 11
2 (n=10) 7+0 – 7+6
antihypertensive
140
medicine
115 - 169
must be balanced
11
against the
3 (n=10) 8+0 – 8+6risks to 170 the fetus. 164For- the
176 treatment 6 of a severe form of
Risk factors 4 (n=18) 9+0 – 9+6hypertension, 165 the 136choice
- 179 of antihypertensive
6 drug and
5 (n=16) 10+0 – 10+6 160 146 - 176 5
Hypertension, obesity, diabetes mellitus, advanced
6 (n=12) 11+0age,– 11+6
method of
150
administration
136 - 164
is dependent 6
on the predicted
hypercholesterolemia, dyslipidemia, microalbuminuria, delivery time. Because of the severity of poisoning sodium
antiphospholipid syndrome, vasculitis, and thrombophilia nitroprusside, should be used only as a last option for cyanide
Tab. 2. Fetal heart rate in the first
are No.
only a few of the risk factors. A previous
trimester of twin pregnancies with
history of poisoning
Gestational Heart rate in a fetus,The
intravenous labetalol,
Type oral methyldopa,

preeclampsia (PE), multiple pregnancy, twin birth, a

age or
twinnifedipine
A / twin Bshould be administered
difference initially
of complications [1,17].
unfavorable outcome (in weeks) (beats/min) in heart
family history of PE, and nulliparity are also clinical risk rate
Beta-blockersbetween
factors [8,9].
twins
Beta-Blockers (BBs)
(beats/are the most prescribed medicine
Diagnosis & monitoring blood pressure during pregnancymin.)and breastfeeding. Asthma is a
1.
BP should be measured in either a seated or6+0
left– lateral
6+6 common
118/158 contraindication,
30 and using
death BBs might cause
of both
fetuses MCDA
recumbent posture (during labor) using an appropriately bronchospasm. One of the most prescribed medicines
sized arm cuff at heart level and Korotkoff
2. for Diastolic
7+0 – 7+6 BP for115/119
Hypertension During
4 Pregnancy
death of(HDP)
both is labetalol.
(DBP). Patient convenience, greater treatment adherence, Labetalol inhibits both alpha andfetuses
beta-adrenergic
DCDA receptors.
confirmation of white coat hypertension, 3. and7+0aid with
– 7+6 Early investigations
138/168 30 in experimental models
TTTS at 28 weeks revealed
medication adjustments, when there is a question,are that it may protect uteroplacentalMCDA blood flow to a higher
all advantages of out-of-office and4. self-monitoring.
8+0 – 8+6 extent than standard14beta-blockers,
105/129 death making
of both it the favored
fetuses MCDA
Furthermore, the majority of home blood pressure medication in this class. In cases of a severe type of HTN,
monitors are marketed without official 5. certification
9+0 – 9+6of it can also be given 14
104/118 intravenously. Because
miscarriage DCDABB can induce
exact readings [10,11]. 6. 10+0 – 10+6 fetal95/109
bradycardia or13intrauterine growth
death retardation, the
of both
fetus must be closely monitored. fetuses
When MCMA
administered early
Prevention 7. 10+0 – 10+6 in pregnancy,
0/24 drugs24 that lack alpha-blocking
death of both qualities
fetuses MCMA
The ESC has been recommended 100–150 mg of (such as atenolol) have been linked to decreased placental
8. 9+0 – 9+6
aspirin daily from week 12 to weeks 36–37 for both high- and124/146
fetal weight at birth,
22 and are
TTTStypically avoided if a more
at 28 weeks
MCDA
and moderate-risk women [12]. The ACOG recommends effective treatment with a better safety profile is available
9. 7+0 – 7+6 98/106
[1,18-20]. 8 death of both
a low-dose aspirin daily beginning in the late first trimester fetuses MCDA
for women with a history of early-onset preeclampsia and
preterm delivery at less than 34 weeks 10. or for Calcium
7+0 – 7+6
of gestation 115/124 channel 9 blockers
miscarriage at 8
weeks MCD
women with more than one prior pregnancy complicated
11. 7+0 – 7+6 Most
110/122 recommendations
12 recommend Calcium
miscarriage at 10 Channel
by preeclampsia [13]. The USPSTF recommends the use
Blockers (CCBs), such as long-acting
weeks DCDA nifedipine, as a
of low-dose aspirin (81 mg/day) as preventive medication
after 12 weeks of gestation in women TTTS
who–areTwin-to-twin first-line
transfusion
at high risk treatment. In pregnancy, nifedipine is the most
syndrome

for preeclampsia [14]. often used medication in this class. It comes in three
different formulations: immediate-release rapid-acting,
Management intermediate-acting, and extended-release. We prefer to
10 utilize a recipe with an intermediate or prolonged-release
ACOG recommends antihypertensive medication time [1,21,22].

2−
 Al-Yousif AI, et al. – Treatment of gestational hypertension with oral labetalol and methyldopa in Iraqi pregnant women...
Methyldopa
Methyldopa is commonly used in pregnant women,
and its long-term safety for the fetus has been shown.
However, it is just a moderate antihypertensive with a
long onset of effect (3 to 6 hours). Methyldopa has been
used for decades, and its safety is more proven than that of
other antihypertensive drugs, administered this drug with
the belief that women who were given methyldopa had
better results than those who were given labetalol, albeit
the findings might be skewed by residual effects [23,24].
Hydralazine
Intravenous hydralazine has been widely used for the
treatment of acute severe hypertension in pregnancy for
many years and has a good antihypertensive effect. Although
hydralazine may be given orally, it might produce reflex
tachycardia and fluid retention, limiting its usage during
pregnancy. Blood pressure lowering is less predictable with
oral labetalol than with IV labetalol [25].
Thiazide diuretics
Except for the treatment of pulmonary edema, diuretics
are rarely used during pregnancy. For decades, the function
of thiazide diuretics has been a topic of debate; however,
some recommendations imply that these medications can
be continued in women with persistent hypertension who
were on them before pregnancy [6].
Drugs to avoid in pregnancy ACE
inhibitors, ARBs, and direct renin
inhibitors
When women are exposed to Renin-Angiotensin-
Aldosterone System (RAAS) inhibitors during the second
or third trimester of pregnancy, they have been linked to
oligohydramnios, intrauterine growth restriction, and a
variety of renal and other congenital disorders [4].
Mineralocorticoid receptor antagonists
Mineralocorticoid Receptor Antagonists (MRA,
e.g., spironolactone, eplerenone) are typically not
indicated for the treatment of hypertension in pregnancy.
They're also diuretics, and they're very good for salt-
sensitive hypertension and hyperaldosteronism patients.
Spironolactone has never been demonstrated to be safe
during pregnancy since it crosses the placenta. One case
report of ambiguous genitalia in a human infant delivered
to a woman who had been treated with spironolactone,
as well as a few examples of healthy newborns following
spironolactone exposure, were recorded in a review [26].
While it is uncertain if eplerenone, an MRA without anti-
androgenic properties that were released around 20 years
ago, is safe for a human pregnancy because experience is
limited to a few case studies that did not reveal severe fetal
consequences [27-29].
Nitroprusside
Nitroprusside would be the last medication for the
treatment of refractory severe HTN. As a result, in an
emergency, it should only be used for a brief time [30].
Choice of drug & dosing acute therapy for severe
hypertension
A comprehensive evaluation of medications for the
treatment of very high blood pressure in pregnancy found
that the antihypertensive drug of choice is determined by
the physician's experience and comfort with the drug, as
well as side effects and patient preferences [31].
First-line drugs Intravenous use of labetalol or
hydralazine as a first-line treatment for severe hypertension.
During acute treatment of severe hypertension, the heart
rate of a fetus should be regularly monitored.
Labetalol
Intravenous labetalol is recommended as a first-line
treatment because it is efficacious, has a fast start of action,
and has a favorable safety profile. If blood pressure stays
above aim, start with 20 mg intravenously over 2 minutes,
followed by doses of 20 to 80 mg at 10-minute intervals,
up to a maximum total cumulative dose of 300 mg if blood
pressure remains above target [21,32].
Hydralazine
Intravenous hydralazine has an acceptable
antihypertensive effect and is used to treat acute severe
hypertension in pregnant women. The hypotensive
reaction to IV hydralazine is not as dramatic as it is with
labetalol. Even though hydralazine may be given orally, it
produces reflex tachycardia and fluid retention, limiting its
usage during pregnancy. Its dosage is to start with a 5 mg
IV bolus over 1 to 2 minutes; if the blood pressure goal is
not met within 20 minutes, deliver a 5 to 10 mg bolus,
depending on the first response. If hydralazine fails to
work, ACOG recommends shifting to labetalol [30,32,33].
Nifedipine
When a patient has severe HTN (160/110 mmHg)
and symptomatic hypertension, nifedipine is utilized as
the first-line treatment for acute blood pressure lowering,
and it is recommended to use the immediate-release rapid-
acting formulation of nifedipine. Because of concerns
regarding the consequences of immediate-release quick-
acting nifedipine's rapid and significant blood pressure
lowering. In the absence of intravenous access, the ACOG
committee opinion approved immediate-release rapid-
acting nifedipine as a first-line alternative for emergency
treatment of acute, severe hypertension in pregnancy or
postpartum [30,34].
Target blood pressure
When treatment is recommended, we focus on
reducing mean arterial pressure by no more than 25%
over 2 hours to achieve goal blood pressures of (130-
150) mmHg systolic and (80-100) mmHg diastolic.
As soon as feasible, BP should be lowered to safe levels.
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RESULTS
Prolonged antihypertensive treatment might cause cerebral Fetal reducedheart ratehypertension
severe in the first incidence
trimestercompared
of twin to non-
or myocardial ischemia or infarction if blood pressure fallspregnancies with unfavorable
active treatment, outcome
with no difference is pre- perinatal
in adverse
The mean fetal heart rate in the first trimester
below the range where tissue perfusion can be maintainedsented in Table
outcomes [39].2.
of twin pregnancy with good outcome is pre- In the case of intrauterine fetal demise of
by autoregulation [35].
sented in Table 1. The above data show that the both twins Methyldopa's
the heart antihypertensive
rate was below 120 effectsbeats
stem from
heart rate of embryos
Beta-blockers (including/ fetuses in thearefirstconsidered
labetalol) tri- per methylated
minute in at catecholamine
least one ofanalogs
the twins.in the central nervous
Further-
mester of antihypertensive
fourth-line uncomplicated therapies
twin pregnancy
by NICEpro- and aremore,
system, affecting
we found thatnoradrenaline
the difference synthesis.
in the he-Randomized
gressively
not increases
recommended as between 6 andfor
first-line drugs 8 weeks of art rate
the treatment controlled studies show
is as important as no
theharmful
heart rate effects in offspring
itself.
pregnancy,
of hypertensionreaches theofnadir
outside of 170Women
pregnancy. beats per shouldIn pregnancies
[40,41]. NICE, onhigh
with the other hand, advises
difference in heart against
rate cessation
minute
be offeredintreatment
week 8 and basedthen
on slows down prescription,
their current to 150 (20 inorthe morepostnatal period the
beats/min) due outcome
to the riskofofthe depression.
beats pereffect
adverse minute in week
profiles, and11.potential
The biggest dif- pregnancy
teratogenicity. Methyldopa wasisunfavorable
the medicine (death
of choice or for
TTTShypertensive
ference in heart
Hypertension rate between
is estimated a pair ofaround
to complicate twins 8%syndrome).
conditions Inin pregnancy
two cases with in several countries.
the fetal Despite this,
heart rate
waspregnancies
of found between 6 and 7 weeks
and encompasses of pregnan-
pre-existing (chronic)morethere
thanis little
120proof of its safety
beats/min in early
and high pregnancy. So far,
difference
cy. Later in pregnancy,
hypertension, gestational up hypertension
to 11+6 weeks (dethenovoin themost methyldopa
heart rate, TTTS safety studies have
syndrome was focused
observed on therapy
difference was
hypertension similar
>140/90 mmand Hg remained low.gestation),laterduring
after 20 weeks the second and third trimesters [36,42,43].
in pregnancy.
and pre-eclampsia (worsening pre-existing or de novo
hypertension with proteinuria) [36]. PATIENTS AND METHODS
Tab. 1. The mean fetal heart rate Group Gestational The mean Range The difference
andThere
the isdifference
enough evidence to recommend
in heart rate labetalolage
as (weeks)
the
first-line
betweentherapy forofhypertension
the pair twins betwe- in pregnancy. Labetalol Study design
heart rate
(beats/min.)
(beats/min) in heart rate
between twins
isena 6racemate
and 11 weeks of uncomplica-
that inhibits alpha and non-selective beta- (beats/min.)
Observational prospective cohort research was
ted twin pregnancy
adrenoceptors. Once blood pressure1 exceeds
(n=12) 150/100
6+0 – 6+6 141 125 - 158 11
2 (n=10) 7+0 – 7+6
undertaken140
by the Obstetrics
115 - 169
and Gynecology
11
Department
mm Hg, the NICE recommends labetalol as a first-line
3 (n=10) 8+0 – 8+6of Baghdad 170 Teaching164 Hospital
- 176 at Medical
6 City / Baghdad,
antihypertensive medication for non-severe (160/110
4 (n=18) 9+0mm– 9+6as well as165the Gynecology
136 - 179 Clinic. Study 6 duration from
Hg) pregnant hypertension and pre-eclampsia 5 (n=16)[37]. 10+0 – 10+6
February 160
1, 2021, 146 - 176
until November 1, 5
2021.
6 (n=12) 11+0 – 11+6 150 136 - 164 6
NICE recommends labetalol as a first-line
antihypertensive agent for gestational hypertension and Patients
Tab. 2. Fetalsince
preeclampsia heart
it rate in the
has been first to No.
proven be "as effective and
Gestational Heart rate The Type
trimester of twin pregnancies with age
• The usefulness
twin A / twin B
of oral labetalol
difference
combined with oral
of complications
safe as other antihypertensive agents" in the treatment of methyldopa in the treatment of hypertension in
unfavorable outcome (in weeks) (beats/min) in heart
these disorders and has a pregnancy license. Beta blockade pregnant women rate was explored in this study. As a
is three to seven times more powerful than alpha blockade between
single agent,twins
using the maximal dosage of labetalol.
with labetalol. Beta adrenoceptor blockage prevents reflex A total of 60 pregnant women. In each group (30)
(beats/
sympathetic stimulation of heart rate and cardiac output women. Group min.)A was given oral labetalol, whereas
while also reducing renal renin production, while alpha Group B was
1. 6+0 – 6+6 118/158 30 given oral methyldopa.
death of both From each
blockade causes reduced peripheral vascular resistance patient, the following data fetuses
had MCDA
been collected upon
and hence vasodilation, lowering blood pressure. When admission. 4
2. 7+0 – 7+6 115/119 death of both
taken with meals, labetalol undergoes substantial first-pass
fetuses DCDA
hepatic metabolism and has higher bioavailability. Peak • Initial assessment: complete full history taking,
3. 7+0 – 7+6 138/168
including 30
age, TTTS atphone
address, 28 weeksnumber, and
plasma concentrations normally occur 2 hours after oral MCDA
intake, with the greatest blood pressure-lowering impact occupation. History of diabetes and history of other
4. 8+0 – 8+6 105/129
comorbid 14
conditions death
such as of both disorder.
cardiac
occurring 1 to 2 hours afterward [20,38]. fetuses MCDA
Lethargy, weakness, and somnolence 5. are 9+0
all possible
– 9+6 • The clinical14 examination
104/118 focuses
miscarriage DCDA on general
side effects, and it's not recommended6.for women with examinations, essential symptoms (BP, Temp.,
10+0 – 10+6 95/109 13 death of both
asthma since it might induce bronchospasm. The only Respiratory, and Heartfetuses
rates),MCMA
weight, height, and
antihypertensive medication with a 7. Medicines and BMI.
10+0 – 10+6 0/24 24 death of both
Healthcare Regulatory Agency license for use during • Laboratory study: fetuses MCMA
pregnancy is labetalol, however, this is 8.
mostly9+0
due– to
9+6the 124/146 22 TTTS at 28 weeks
challenges and indifference surrounding drug licensing - Complete Blood PictureMCDA (CBC): hemoglobin
for use during pregnancy. Despite this, 9.
the manufacturers concentration (Hb%), Red Blood Cells (RBCs),
7+0 – 7+6 98/106 8 death of both
White Blood Cells (WBCs), and platelet
fetuses MCDA count.
of labetalol recommend that it be avoided during the
first trimester because it can cause hypertension
10. 7+0 or pre-
– 7+6 - Renal function
115/124 9 testing: blood
miscarriage at 8 urea, serum
weeks MCD
creatinine, and urine analysis.
eclampsia, and it may not be feasible for women with
chronic hypertension who would benefit11. from other
7+0 –agents
7+6 110/122 12 miscarriage at 10
- Liver test profile: Serum weeksaspartate
DCDA and alanine
anyway; however, the fetal risks of labetalol appear to be aminotransferases (AST and ALT), serum albumin,
low [36]. TTTS – Twin-to-twin transfusion syndrome
serum bilirubin, serum Gamma-Glutamyl
Labetalol may be used to treat chronic hypertension in Transferase (GGT), prothrombin time and
pregnant women, but the evidence for treating persistent International Normalized Ratio (INR).
10 hypertension in the first trimester is limited. A recent
• Each participant had undergone the following
meta-analysis found that antihypertensive treatment measures related to this research:
4−
 Al-Yousif AI, et al. – Treatment of gestational hypertension with oral labetalol and methyldopa in Iraqi pregnant women...

• Measuring baseline BP using a standard mercury 2. Hypotension is a symptom of the mother.

sphygmomanometer, Seat the case for 5 to 10 mins
before BP measurements. Ethical consideration

Participant selection Approved by the Ethical Committee at Iraqi Board for

Inclusion criteria:
Pregnant who match the following inclusion criteria
and have a systolic blood pressure of 150 mm Hg or higher
or diastolic blood pressure of 100 mm Hg or higher on
repeat blood pressure measurement after 15 minutes of rest
will be included:
• At any clinical or hospital visit, any pregnant
woman who requires antihypertensive medicines
for hypertension.
• Patients who are expecting a singleton or multiple.
• Patients of all ages are accepted.
Exclusion criteria:
• Asthmatic patients.
• Patients with heart block and cardiac failure.
• Patients who have pacemakers or are experiencing
any form of cardiac arrhythmia.
• Severe hypertension.
• Preeclampsia complications.
Study objectives:
Primary outcome measures:
Controlling blood pressure with an appropriate agent
with avoiding adverse effects is possible as compared to
another agent.
Secondary outcome measures:
1. Adverse effects of both agents.
Medical Specializations, Baghdad/Iraq.
Data analysis
All the patients' data was input into computerized
statistical software (Statistical Package for Social Sciences,
version 21) (SPSS). Frequencies are represented as
percentages, and descriptive statistics are expressed as
(mean + std dev). An independent sample t-test was used
when comparing two means. In all statistical analyses, the
degree of significance (p less than 0.005) is calculated.
RESULTS
The study examined hypertensive pregnant women of
all ages, with 3.3% under 20, 61.7% between 21 and 30,
33.3% between 31 and 40, and 1.7% above 40. Patients had
gravida, parity, and abortion histories, and 96.6% had no
comorbidities. In terms of the requirement for additional
therapy, 86.7% did not require it, whereas 13.3% did.
87.5% of those who needed it were on methyldopa,
whereas 12.5% were on labetalol. There was a statistically
significant link between the requirement for extra anti-HT
and being on methyldopa, with a p-value of 0.02.
Regarding the change in the dose, 93.3% didn't need
a change in dose, one patient on labetalol, her dose being
decreased, and 3 patients on methyldopa, whose dose is
decreased. No statistically significant association between
changing the dose and type of treatment, with a p-value
of 0.13.
The majority of the patient didn't develop side effects
(80%), in those who develop side effects, 83.3% were on
methyldopa and 16.7% were on labetalol, a statistically
significant association between the development of side
effects and being treated with methyldopa, p-value 0.01, as
presented in Tab. 1. & Tab. 2.

Tab. 1. Demographic data of Characteristic N %

included patients. Less than 20 yrs. 2 3.30%
21-30 yrs. 37 61.70%
Age group
31-40 yrs. 20 33.30%
More than 40 yrs. 1 1.70%
Methyldopa 30 50.00%
Type of treatment
Labetalol 30 50.00%
Gravida less than 3 39 65%
Gravida Gravida 3-5 12 20%
Gravida more than 5 9 15%
Parity of less than 3 47 78.30%
Parity Parity 3-5 10 16.70%
Parity of more than 5 3 5.00%
No History of abortion 38 63.30%
Abortion HX of 1 or 2 abortion 21 35%
Abortion of >2 pregnancy 1 1.70%
CHD (VSD) 1 1.70%
Comorbidities DM 1 1.70%
No comorbidities 58 96.60%
HX= History, CHD (VSD)= Congenital Heart Diseases (Ventricular Septal Defect), DM= Diabetes
Mellitus

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RESULTS
The change in BP at the beginning of the study and
Fetal heart rate in the first trimester of twin
ten use methyldopa, a statistically significant association
pregnancies with unfavorable outcome is pre-
after was assessed using paired t-tests by comparing
The mean fetal heart rate in the first trimester sented systolic between using methyldopa and the development of
in Table 2.
and diastolic blood pressure before
of twin pregnancy with good outcome is pre- and after in each group. headache, leg edema, palpitation, and weight gain, with a
In the case of intrauterine fetal demise of
sented in Table
Regarding the1. users
The above
of thedata show thatgroup
methyldopa the ofbothp-value of 0.03. All had a headache, leg edema palpitation,
twins the heart rate was below 120 beats
heart rate
patients, SBPofpre-treatment
embryos / fetuseswas 149.50in the tri-DBPper minute in atgain
firstand
± 9.03
and weight were used methyldopa, as presented in
least one of the twins. Further-
mester of uncomplicated twina pregnancy Tab. 5.
pro- more, we found that the difference in the he-
pre-treatment was 99.66 ± 7.30, statistically significant
gressively increases between 6 and
decrease in the mean of SBP post-treatment (137.83 8 weeks of ±art rateThe is astimeimportant
required orasneeded
the heart
Tab. rate
6. foritself.
BP controlling
pregnancy, reaches the nadir of 170 beats per In pregnancies with high difference in heartin rate
6.11) and DBP post-treatment (88.83 ± 6.52), p-value in the labetalol group was significantly lower comparison
minute in week 8 and then slows down to 150 (20 toorthemore methyldopa group. With methyldopa the
beats/min) the outcome of 6.33 ± 3.94
0.00 and 0.00, respectively.
beats per minute in week 11. The biggest dif- pregnancy and labetalolwas4.38unfavorable
± 2.85, with(death or TTTS
a significant p-value of 0.04.
Regarding
ference the users
in heart rate ofbetween
the labetalol group
a pair of of patients,syndrome). In two cases with the fetal heart rate
twins
awas found between
statistically significant6decrease
and 7 weeks of pregnan-
in the mean of SBP post-more DISCUSSION
than 120 beats/min and high difference
cy. Later and
treatment in pregnancy, up to 11+6
DBP post-treatment (138.66 weeks the88.33in the heart rate, TTTS syndrome was observed
± 3.69,
±difference was similar
5.77) in comparison to and remained(149.00
pre-treatment low. ± 4.43,later inNational pregnancy. Institute for Health and Care Excellence
97.33 ± 6.66), p-value 0.000 and 0.003, respectively, as [NICE] (2019) has recommended labetalol as a first-
presented in Tab. 3. line antihypertensive for gestational hypertension
Tab. 1. The mean fetal heart rate Group Gestationaland The preeclampsia.
mean This is based
Range The on limited data from
difference
andBoththedrugs decreaseinBP;
difference independent
heart rate t-test was age
used(weeks)
to heart rate (beats/min) in heart rate
randomized controlled studies, but it is equally effective
assess the mean
between difference
the pair of twinsin SBP
betwe-and DBP post-treatment (beats/min.) between twins
and safe as other drugs for treating these disorders.
inen both
6 and groups
11 weeks of ofdrugs.
uncomplica-
No statistically significant (beats/min.)
ted twin pregnancy 1 (n=12) 6+0 –in6+6 141 current125 - 158 most of 11
difference in the mean of SBP post-treatment, mean In the study, the patients obtain
2 (n=10) 7+0 – 7+6 140 115 - 169 11
methyldopa (137.83 ± 6.1) and labetalol (138.66 ±8+0
3 (n=10) 3.69),
– 8+6efficacy with170 monotherapy
164 - 176(labetalol) without
6 the addition
p-value 0.52. No statistically significant difference9+0
4 (n=18) in the
– 9+6of another 165 agent 136
in treatment
- 179 (p-value=0.02).
6 While in
mean of DBP post-treatment, mean in 56methyldopa (n=16)
(n=12)
10+0 – 10+6
(88.83
11+0 – 11+6
the 160
methyldopa
150
146 - 176
group, most
136 - 164
patients 5
needed
6
an increased
± 6.52) and labetalol (88.33 ± 5.77), p-value 0.75, as dose or addition of another agent for obtaining a response
presented in Tab. 4. to treatment (p-value=0.13). Non-significant value shows
Tab. 2. Fetal heart rate in the first No. Gestational labetalol
Heart ratecan be taken Theas a stand-alone Type medication.
The association
trimester between type
of twin pregnancies withof side effect and age
anti- twin A / twin B difference of complications
hypertensive
unfavorabledrug, the result revealed that 12 of all
outcome (inincluded
weeks) In comparisonin to
(beats/min) our findings, Roychoudhary, et al.
heart
patients have a side effect. Two of them use labetalol and showed a highly significant rate labetalol in reducing blood
between
twins
Tab. 2. The need to use addi- Outcome (beats/ Labetalol
Methyldopa Total P-value
tional anti-HT agents, chang- Needed to No added therapy 23 (44.2%)min.) 29 (55.8%) 52 (86.7%)
ing the dose either increased Additional
1. 6+0 – Needed
6+6 additional
118/158 7 (87.5%) 30 death of8 both 0.02*
Agent 1 (12.5%) (13.3%)
or decreased side effects de- anti-HTN** fetuses MCDA
velopment in both treated No change 27 (48.2%) 29 (51.8%) 56 (93.3%)
groups. Change
2. in7+0
the – 7+6 115/119 4 death of 1both
Increased x1 0 (0.0%) 1 (100.0%) (1.7%) 0.13
Dose fetuses DCDA
Increased x2 3 (100%) 0 (0.0%) 3 (5.0%)
3. 7+0 – 7+6 138/168
No side effects 30 TTTS at 28 weeks
20 (41.7%) 28 (58.3%) 48 (80%)
Side Effect developed MCDA
0.01*
Development Developed side
4. 8+0 – 8+6 105/129 10 (83.3%) 14 death of12
2 (16.7%) both
(20%)
effect
fetuses MCDA
Total 30 (50.0%) 30 (50.0%) 60 (100.0%)
5. 9+0 – 9+6 104/118 14 miscarriage DCDA
*
p-value ≤ 0.05, ** anti-HTN= antihypertensive
6. 10+0 – 10+6 95/109 13 death of both
fetuses MCMA
Tab. 3. Pair test results of SBP Type of anti-HT agent Mean ± SD P-value
7. 10+0 – 10+6 0/24 24 death of both
and DBP of the two drugs in SBP pre-treatment 149.50 ± 9.03
fetuses MCMA 0.00*
pre and post-treatment. SBP post-treatment 137.83 ± 6.11
8. Methyldopa
9+0 – 9+6 DBP124/146
pre-treatment 22 99.66 ± TTTS
7.30 at 28 weeks
MCDA 0.00*
DBP post-treatment 88.83 ± 6.52
9. 7+0 – 7+6 98/106
SBP pre-treatment 8 149.00 ± 4.43
death of both
SBP post-treatment fetuses MCDA 0.00*
138.66 ± 3.69
Labetalol
10. 7+0 – 7+6 DBP115/124
pre-treatment 9 97.33 ±6.66
miscarriage at 8
0.003*
DBP post-treatment weeks MCD
88.33 ± 5.77
*
p-value
11. ≤ 7+0
0.05 – 7+6 110/122 12 miscarriage at 10
weeks DCDA

TTTS – Twin-to-twin transfusion syndrome

Type of anti-HT agent Mean ± SD P-value
Tab. 4. Mean difference in
SBP and DBP post treatment Methyldopa 137.83 ± 6.1
SBP post-treatment 0.52
in both groups of drugs. Labetalol 138.66 ± 3.69
Methyldopa 88.83 ± 6.52
10 DBP post-treatment
Labetalol 88.33 ± 5.77
0.75

*
p-value ≤ 0.05, anti-HTN= antihypertensive

6−
 Al-Yousif AI, et al. – Treatment of gestational hypertension with oral labetalol and methyldopa in Iraqi pregnant women...

Tab. 5. The association be- Characteristics Methyldopa Labetalol Total P-Value

tween type of side effect and Headache 2 (66.7%) 1 (33.3%) 3 (25%)
anti-hypertensive drug. Headache, Leg Edema 0 (0.0%) 1 (100%) 1 (8.3%)
Headache, Leg Edema,
1 (100%) 0 (0.0%) 1 (8.3%)
Palpitation,
Type of SE
Headache, Leg Edema,
7 (100%) 0 (0.0%) 7 (58.4%)
Palpitation, Drowsiness
0.03*
Total 10 (100.0%) 2 (100.0%) 12 (100.0%)
*
p-value ≤ 0.05, SE= Side Effect

Tab. 6. The time required for Methyldopa Labetalol P-value

BP controlling. Time (day) 6.33 ± 3.94 4.38 ± 2.85 0.04*
*
p-value ≤ 0.05

pressure than methyldopa with quick and more efficacious
control of BP mothers with gestational hypertension. This
was found to be statistically significant with a P-value of
<0.001. Also, Subhedar, et al. had been found a p-value =
0.008, a significant blood pressure control and efficiency
more in labetalol than methyldopa [44].
In a current study, systolic BP (pre-and post-) and
diastolic (pre-and post-) of both labetalol (0.00*, 0.003*),
and methyldopa (0.00*, 0.00*), a statistically significant
decrease in the mean of SBP post-treatment and DBP post-
treatment *p-value ≤ 0.05.
In comparison with findings in El-Sadek, et al. they
found there was a nonsignificant change among study
groups (labetalol and methyldopa) regarding BP before
management p values (0.629, 0.656). A significant change
was found among the studied group concerning the mean
drop in SBP and DBP after treatment with a p-value (0.00,
0.00) [45].
Pentareddy, et al. concluded that methyldopa decreased
BP from mean diastolic BP, there was a significant reduction
in BP before and after treatment (p-value <0.001), and
labetalol reduced mean diastolic BP, also a significant
decrease of BP before and afterward management (p
value<0.001). In comparison between methyldopa and
labetalol groups, the change in a drop in mean DBP was
nonsignificant (p-value >0.005) [46].
In the current finding, there is no statistically significant
difference in the mean of SBP post-treatment, the mean
in methyldopa and labetalol [p-value 0.52]. Also, no
statistically significant difference in the mean of DBP post-
treatment, mean in methyldopa and labetalol (p-value 0.75).
In comparison between methyldopa and labetalol
groups, Pentareddy, et al. showed the change in a drop in
mean DBP was nonsignificant (p-value >0.005) [46].
In the current study, we found a relationship between
the type of side effect and anti-hypertensive drug, which
resulted mostly from the methyldopa group. Though,
patients with labetalol also complain of side effects but
with minimal effect. A statistically significant association
between using methyldopa and the development of
headache, leg edema, palpitation, and drowsiness, with a
p-value of 0.03.
In comparison to our findings, a study conducted by
Verma, et al. stated that adverse events observed were lower
in the labetalol-treated group compared to the methyldopa
group. Also, in a study by Qarmalawi, et al. patients have
received methyldopa complained of side effects such as
drowsiness, headache, nasal congestion, and postural
hypotension. Patients in the labetalol group complained of
dyspnea, but no other side effects were noticed. With labetalol,
only a few patients (6) complain of dyspnea [47,48].
Of all the side effects, methyldopa regularly causes
drowsiness, and its tendency to cause it is significantly
more than labetalol with P = 0.023 as mentioned in Rudra
Patel, et al. [49].
Subhedar, et al. showed adverse effects seen with both
drugs are of known types and labetalol caused fewer adverse
effects compared to methyldopa and the side effects were
minor and did not necessitate stoppage of any drugs or
change of medications [44].
Furthermore, in the current study, we found that period
needed for BP control in labetalol cases was significantly
lower compared to the methyldopa group, a significant
p-value of 0.04.
A study by Subhedar, et al. concluded that the mean
period needed for BP control was different. The variance
among the studied groups was significant with labetalol
displaying former control of BP in comparison to
methyldopa [44].
Also, Alalfy, et al. revealed a decrease in the mean BP
starting from a baseline that was the BP before receiving
the anti-hypertensive therapy and the records afterward
2-days, 1, 3, 5, 7, 9-wks afterward medication receiving
and at a born time in the methyldopa and labetalol cases, a
significant change in BP controlling with levels of systolic,
diastolic and mean arterial BP records are lesser in labetalol
cases in comparison to methyldopa with p-value < 0.001,
showing more good BP control [50].
CONCLUSION
This study found labetalol could be used as a single
agent in treatment compared with the use of methyldopa.
Therefore, minimal, or fewer adverse effects were observed
with monotherapy (labetalol).
CONFLICT OF INTEREST
The authors declare no conflicts of interest.

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RESULTS Fetal heart rate in the first trimester of twin

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