Early Human Development 88 (2012) 503–507

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Early Human Development

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Neonatal side effects of maternal labetalol treatment in severe preeclampsia

Karst Y. Heida a, Gerda G. Zeeman a, Teelkien R. Van Veen a, Christian V. Hulzebos b,⁎
a
Department of Obstetrics and Gynecology, University Medical Center Groningen, The Netherlands
b
Department of Neonatology, University Medical Center Groningen, The Netherlands

a r t i c l e i n f o a b s t r a c t

Article history: Objective: Labetalol is often used in severe preeclampsia (PE). Hypotension, bradycardia and hypoglycemia
Received 14 March 2011 are feared neonatal side effects, but may also occur in (preterm) infants regardless of labetalol exposure.
Received in revised form 7 November 2011 We analyzed the possible association between intrauterine labetalol exposure and such side effects.
Accepted 17 December 2011 Study design: From 1 January 2003 through 31 March 2008, all infants from mothers suffering severe PE
admitted to one tertiary care center were included. Severe PE was defined according to the International
Keywords:
Society for the Study of Hypertension in Pregnancy (ISSHP) criteria. Infants exposed to labetalol in utero
Labetalol
Hypotension
(labetalol infants) were compared with infants, who were not exposed to labetalol (controls). Neonatal
Bradycardia records were reviewed for hypotension (RR b mean gestational age in weeks), bradycardia (heartrateb 100/
Hypoglycemia min) and hypoglycaemia (glucose b 2.7 mmol/L) in the first 48 postnatal hours.
Patent ductus arteriosus (PDA) Results: Of 109 infants, 55 had been exposed to labetalol, whereas 54 were not (controls). Gestational age at
delivery and birthweight were similar in both groups (31.8 vs. 32.8 weeks (p = 0.06) and 1510 vs. 1639
grams (p= 0.25), respectively for the labetalol vs. control group). Hypotension occurred significantly more in
conjunction with labetalol exposure (16, (29.1%) vs. 4 (7.4%); p = 0.003), irrespective of the route of administra-
tion. Patent ductus arteriosus (PDA) was present in 9 (56%) of hypotensive labetalol infants compared to 1 (24%)
infant in the hypotensive control group (NS). In a multivariate regression model, labetalol exposure, the need for
intubation and PDA appeared independently associated with hypotension (Pb 0.001). Hypoglycemia occurred in
26 (47.3%) of labetalol infants and in 23 (42.6%) of control infants (p= 0.62). Bradycardia occurred in 4 (7.3%) of
labetalol infants and in 1 (1.9%) of control infants (p = 0.18). Hypoglycemia was more common in premature
infants (n = 45 (48,9%) vs. n = 4 (23.5%), p = 0.05) in both labetalol and control infants.
Conclusion: Hypotension is more common after maternal labetalol exposure, regardless of the dosage and
route of administration. The need for intubation and the presence of a PDA also play a role. Hypoglycemia
is a very common finding in this population and is merely related to prematurity and independent of labetalol
exposure as was the incidental occurrence of bradycardia. These findings on the neonatal side effects of maternal
labetalol treatment in preeclampsia underline the importance of frequent blood glucose and blood pressure
measurements in the first days of life, especially in intubated preterm infants with a PDA.
© 2012 Elsevier Ireland Ltd. All rights reserved.

1. Introduction
Hypertensive disorders represent the most common medical compli-
cation during pregnancy, affecting 3 to 10% of gestations, depending
on the population and definitions used [1]. In women with severe
preeclampsia perinatal neonatal as well as maternal mortality and
morbidity are substantially increased. For neonates, the risk of death
and morbidity, including fetal growth restriction, depends mainly on
gestational age at onset of preeclampsia as well as on gestational age
at delivery and the severity of the disease process [2].
Prolongation of a preeclamptic pregnancy may, depending on the
gestational age and anticipated risk to the mother, be favorable for
⁎ Corresponding author at: Department of Pediatrics, Division of Neonatology, Beatrix
Children's Hospital, University Medical Center Groningen, Hanzeplein 1, CA 51, 9700 RB
Groningen, The Netherlands.
E-mail address: c.v.hulzebos@umcg.nl (C.V. Hulzebos).
the fetus. Antihypertensive drugs are commonly used for the acute
management of hypertensive episodes in preeclampsia and, in general,
are considered safe and effective. However, significant maternal and
neonatal side effects have been described for such drugs [3,4].
Labetalol, a non-selective β and α1 antagonist, is often favored in
the Netherlands and is also worldwide one of the most commonly
administered drugs for both long-term treatment as well as the
acute management of severe maternal hypertension in preeclampsia
[5,6]. Because labetalol has not been associated with clinically signifi-
cant β-blockade, it is, considered a safe drug in term pregnancies [7,8].
However, β-blockers have been associated with severe symptoms
of β-adrenergic blockade in neonates, especially in preterm infants,
such as hypotension, bradycardia and hypoglycemia, as described
in several case reports [9–14]. However, such symptoms may also
occur in preterm and small for gestational age infants’ regardless of
labetalol exposure [15,16]. It has been suggested that labetalol may
interfere with catecholamine-mediated circulatory responses and

0378-3782/$ – see front matter © 2012 Elsevier Ireland Ltd. All rights reserved.
doi:10.1016/j.earlhumdev.2011.12.012
504 K.Y. Heida et al. / Early Human Development 88 (2012) 503–507

this may be particularly deleterious in acidotic asphyxiated infants were reviewed for the incidence of hypotension (defined as mean arte-
[17]. However, short-term labetalol infusion should not impair cardiac rial pressure lower than the gestational age in weeks), bradycardia in
function and peripheral vascular resistance [18]. To the best of our the first minutes after birth and during the first 48 h (defined as heart
knowledge, the incidence, severity and consequences of the β-blockade rate b 100 bpm) and hypoglycemia (defined as glucose b 2.7 mmol/L)
effect on the newborn have not been evaluated in a well-described cohort in the first 48 postnatal hours as well as the need for interventions. Ini-
of infants, aside from the aforementioned case reports [9–14]. Because tial glucose delivery rate is 5 mg/kg/min and immediately started after
of the fear of neonatal β-adrenergic side effects for the newborn, it admission. Glucose measurements are performed at 3,6,9,12,18,24 h
is our observation that hypertensive women are sometimes denied postnatally. In case of hypoglycemia glucose delivery rate is increased
sufficient antihypertensive therapy. In addition, in our hospital preterm with 50% until blood glucoses are >2.7 mmol/L. During the study peri-
neonates (gestational age b 37 weeks) exposed to labetalol are routinely od, management of newborn infants admitted to the NICU with hypo-
admitted to the Neonatal Intensive Care Unit (NICU) for monitoring of tension and hypoglycemia has not changed. Echocardiography was
heart rate, blood pressure and glucose during the first 24–48 h of life. considered indicated in neonates with persistent respiratory, circulatory
Such an empiric policy [19], lacks firm evidence and sufficient data and/or metabolic disturbances. Diagnosis of a significant patent ductus
from the literature. arteriosus (PDA) was made by echocardiography and based on patency,
The purpose of this study, is to clarify the relation between labetalol degree of constriction and magnitude of shunting. Small for gestational
exposure and the most important neonatal side effects such as hypoten- age (SGA) was defined as a birth weight below the 10th percentile for
sion, bradycardia and hypoglycemia as well to asses the influence of the gestational age, derived from The Netherlands Perinatal Registry Birth
route and dosage of maternal labetalol treatment. weight percentiles, corrected for parity, sex and ethnicity [20].
Neonates of hypertensive mothers, who were exposed to labetalol
2. Material and methods (cases or “labetalol” infants) were compared with neonates of hyper-
tensive mothers, who were not exposed to labetalol (controls). Con-
The University Medical Center Groningen (UMCG) is one of ten tinuous variables were compared with use of Mann–Whitney, whereas
tertiary perinatal referral centers for high risk pregnancies in The categorical variables were compared with Chi-square. A logistic
Netherlands. The Obstetrics Department has an Obstetric High Care regression model was constructed with all variables (P-valueb 0.05)
Unit (OHC) for those women who are severely ill, for instance women for a possible association with hypotension. Variables entered into
with severe preeclampsia and/or HELLP syndrome. The population in the model included: exposure to magnesium sulfate, labetolol exposure,
the Northern part of the Netherlands is predominantly Caucasian. In gestational age, birth weight, apgar score b 7 after 1 and/or 5 min, pH
our center, labetalol is the first drug of choice for those women umbilical artery b 7.10 and b7.20, the need for intubation and PDA. All
with significant hypertension. Intravenous treatment is started tests were 2-tailed with an alpha set at. 0.05. All statistical analyses
when mean blood pressure (BP) is ≥ 120 mm Hg. According to our were performed with SPSS 17.0 for Windows software (SPSS, Chicago,
protocol an intravenous bolus of 20 mg is administered, followed Illinois).
by a continuous infusion of 20 mg/h. When not effective within
20 min, a 40 mg bolus is administered and the continuous infusion
rate increased to 40 mg/h. When still not effective within 20 min, a 3. Results
80 mg bolus is administered and the continuous infusion increased to
80 mg/h. The maximal cumulative dose in 1 h is limited to 220 mg. Of a total of 109 included infants 55 infants were exposed to labetalol
The primary endpoint is the successful reduction in BP (mean arterial in utero. Of 18 of these newborns, the mother received exclusively
pressure b120 mm Hg) for at least one hour. When effective and deliv- oral treatment. The other 37 were also exposed to intravenously ad-
ery does not seem imminent within the next 24 h, conversion to oral ministered labetalol. Thirty-one infants were exposed to intravenous
labetalol treatment is favored. In our center, all neonates who are magnesium sulfate prior to and around the time of delivery. None of
preterm (gestational age b 37 weeks) and/or exposed to significant the mothers in the control group (n = 54) received antihypertensive
doses (> 600 mg oral maternal labetalol daily as well as all intrave- agents, 17 received intravenous magnesium sulphate.
nous maternal labetalol use within the last 24 h prior to delivery), There were no significant difference in gestational age (GA),
are admitted to the NICU for monitoring of heart rate, blood pressure birth weight and preterm birth between the labetalol group and
and glucose during the first 24–48 h of life. the control group (Table 1) (Fig. 1). Hypotension occurred significantly
Over a 2-year period (January 1, 2005 and December 31, 2006) all more frequent in the labetalol group. Crystalloids and dopamine/
women (n = 95) admitted to the OHC with severe preeclampsia and/ hydrocortisone therapy was used in 8 of the 16 hypotensive “labetalol”
or HELLP-syndrome were included in this retrospective study. Severe infants, 6 received crystalloids only, whereas 2 were not treated. In
preeclampsia and/or HELLP-syndrome were defined according to the
internationally agreed standards [5]. Thirteen women were excluded,
7 due to intrauterine demise of an immature fetus, 4 due to termination
Table 1
of pregnancy at a gestational ageb 24 weeks because of severe maternal Patient characteristics and neonatal symptoms with and without labetalol exposure.
illness, and 2 because of missing records. Of 82 remaining women, 53
Labetalol No exposure to P-value
were treated with labetalol, including two twin gestations. Blood
exposure antihypertensive agents
pressure of the remaining 29 women remained controlled without (n = 55) (n = 54)
use of antihypertensive drugs. The pregnancies of these 29 women
Male/female (n) 28/27 25/29
were considered “controls”. In order to extend the control group, Gestational age (week) 31.8 ± 3.8 32.8 ± 3.4 0.06
the NICU database was searched between 1 January 2003–31 March Premature birtha 49 (89.1%) 43 (79.6%) 0.17
2008 to identify all neonates whose mothers were diagnosed with PE/ Birth weight (gram) 1510.6 ± 855.4 1639.1 ± 807.6 0.25
HELLP-syndrome, but who did not need admission to the OHC due to SGAb (n) 12 (21.8%) 12 (22.2%) 0.96
Hypotension (n) 16 (29.1%) 4 (7.4%) 0.003
less severe disease. Medical records were verified for absence of labetalol
PDA (n) 13 (23.6%) 9 (16.7%) 0.37
exposure and other hypertensive agents. Twenty-five of such neonates Hypoglycemia (n) 26 (47.3%) 23 (42.6%) 0.62
were identified, resulting in a total of 54 control infants. Bradycardia (n) 4 (7.3%) 1 (1.9%) 0.18
All maternal medical records were reviewed for accurateness of Mortality (n) 5 (4.6%) 0 (0%) 0.02
diagnoses, labetalol dosage, timing and route of administration as well a
Premature birth = delivery before 37 weeks gestation.
b
as for gestational age at delivery and birth weight. Neonatal records SGA = birth weight below the 10th percentile for gestational age.
 K.Y. Heida et al. / Early Human Development 88 (2012) 503–507
comparison, the 4 hypotensive infants of the control group recovered
after treatment with crystalloids only. The incidence of patent ductus
arteriosus (PDA) was similar in both groups and also in the infants
with hypotension. Nine of 16 hypotensive labetalol infants (56%)
had a PDA of whom 6 where treated with crystalloids and dopamine/
hydrocortisone i.v. One hypotensive infant (25%) in the control group
was diagnosed with a PDA and required treatment with crystalloids
only.
Incidences of hypoglycemia and bradycardia in the first 48 h after
birth were similar in both groups (Table 1). In the first 10 min after
birth, bradycardia occurred in 22 (40%) of “labetalol” infants and in
16 (29.6%) of infants in the control group. Treatment with atropine
was necessary in 5 labetalol infants and in 1 control infant. These results
were not statistically significantly different between both groups.
To explore whether the route of labetalol administration affects the
increased incidence of hypotension after labetalol exposure, a separate
analysis of the labetalol treated infants was performed (Table 2). The
mothers of 37 infants received i.v. labetalol in the last 24 h prior to
giving birth. The oral group (n = 18) represents exclusively maternal
oral labetalol treatment in the last 24 h prior to birth. Table 2 shows
similar incidences of hypotension, hypoglycemia, and bradycardia in
neonates after oral and intravenous maternal treatment.
To explore whether the dose of labetalol affects the increased inci-
dence of hypotension, separate analysis of the intravenously labetalol
treated infants was performed in 2 groups: b600 mg and >600 mg
total intravenous dose within the last 24 h (Table 3).
Although not statistically significantly different, hypotension oc-
curred in 33% of infants exposed to >600 mg labetalol in the previous
24 h versus in 14% of infants who were exposed to b600 mg in the
previous 24 h.
To assess the effect of birth weight and gestational age on the
occurrence of side-effects for the entire cohort, we performed sep-
arate analyses for those infants who were SGA (n = 24) or preterm
(b37 weeks gestation, n = 92). Neonatal side effects did not occur
more often in SGA infants, although a trend for hypoglycemia was
observed (n= 14 (58.3%) in SGA versus n = 35 (41.2%) in appropriate
for gestational age (AGA) infants, p = 0.14)). All 20 cases of hypoten-
sion occurred in preterm infants (21.7%, p = 0.03). Not unexpectantly,
hypoglycemia was also more common in preterm infants compared to
their term counterparts/infants born > 37 weeks' gestation (48.9%
versus 23.5%, p = 0.05).
To assess the effect of SGA on side effects, we compared the SGA
infants in the labetalol group with those in the control group. In
these relatively small groups of 12 infants each, hypotension occurred
only in SGA infants (n = 5 (41.7%), p = 0.012) while the gestational
age was similar (33.5 versus 33.1 weeks) in the labetalol versus con-
trol SGA group.
All 5 infants who died had a gestational age below 30 weeks and
were all in the labetalol group. Median (range) postnatal day of death
Percentiles
Labetalol exposure
1,82%
21,82%
23,64%
14,55%
38,18%
Fig. 1. Birth weight (BW) percentiles of infants exposed to labetalol and infants not exposed to antihypertensive agents.
505
Table 2
Side-effects in infants exposed to intravenous versus oral labetalol within 24 h prior to
delivery.
Labetalol i.v. Oral labetalol* P-value
(n = 37) (n = 18)
Hypotension (n) 8 (21.6%) 6 (33.3%) 0.35
Hypoglycemia (n) 16 (43.2%) 10 (55.6%) 0.45
Bradycardia (n) 2 (5.4%) 2 (11.1%) 0.39
*
Oral labetalol group consists of infants whose mothers used only oral treatment
within the last 24 h prior to delivery.
was 57 (10–113) days. Two died because of ongoing sepsis, 2 due to
progressive respiratory insufficiency and 1 infant suffered a gastrointes-
tinal perforation.
Univariate analysis of all 109 infants revealed 6 variables that were
significantly associated with hypotension: The need for intubation
(p= 0.000), PDA (p= 0.001), apgar scoreb 7 after 1 min (p= 0.002),
gestational age (p= 0.003), labetalol exposure (p= 0.006) and birth
weight (p= 0.018). These 6 variables were incorporated into a multiple
regression model. In this model, the need for intubation, labetalol
exposure and PDA appeared independently associated with hypo-
tension as shown in Table 4. Apgar scoreb 7 after 1 min, birth weight
and gestational age were excluded in this model, since these variables
brought no significant improvement. Variables such as magnesium
sulfate exposure, apgar score b 7 after 5 min, umbilical artery pHb 7,10
or b 7,20 were not significantly associated with hypotension.
4. Discussion
This study evaluated the incidence and severity of side effects in a
well-described cohort of infants who were exposed to labetalol in
utero. The main finding is that, irrespective of the dosage and route
of administration, such infants more often demonstrate periods of
hypotension in the first 48 h of life. Another important finding is
that hypoglycemia appeared very common in this population and
was related to prematurity and independent of labetalol exposure
as was the incidental occurrence of bradycardia.
The presence of a PDA appeared independently associated with
the manifestation of hypotension. This high prevalence of PDA in
the hypotensive cohort is possibly related to prematurity, while we
can not exclude ascertainment bias due to selective screening, and
also, depends on the definition used for diagnosis [21].
Labetalol causes peripheral vasodilatation and, therefore, a decrease
in total peripheral vascular resistance through α1-adrenoreceptor
blockade while β-blockade prevents reflex tachycardia and maintains
cardiac output [27]. Even though hypotension from a β-blocking effect
would be unlikely without a substantial reduction in heart rate, it re-
mains to be determined whether α1-adrenoreceptor blockade and/
No exposure to antihypertensive agents
7,41% BW perc
5,56% p<10
p10-20
p20-50
22,22%
p50-p80
p>80
16,67% Pies show percents
48,15%
506 K.Y. Heida et al. / Early Human Development 88 (2012) 503–507
Table 3
Side-effects in infants exposed to b 600 mg total dose intravenous labetalol and infants
exposed to ≥600 mg total dose intravenous labetalol within the last 24 h prior to
delivery.
b 600 mg labetalol ≥600 mg labetalol
i.v. (n = 22) i.v. (n = 15)
Hypotension (n) 3 (13.6%) 5 (33.3%)
Hypoglycemia (n) 10 (45.5%) 6 (40.0%)
Bradycardia (n) 2 (9.1%) 0 (0.0%)
or β-blockade contribute to hypotension in newborn infants exposed
to labetolol. Labetalol crosses the placenta rapidly producing fetal
concentrations which are estimated to be approximately 50% of
maternal concentrations [28]. Even though its safety in compromised
fetuses has been questioned, labetalol seems to have a relatively wide
hemodynamic safety margin [17]. A short term infusion of labetalol
(1 mg/kg ×15 min), enough to reduce maternal blood pressure in cases
of preeclampsia, demonstrated no effects on the peripheral vascular
resistance in the uterine and fetal arteries or on fetal cardiac function
[18].
Even though a considerable number of infants in our cohort suffered
hypotensive episodes, our findings on the neonatal side effects of labe-
talol are not nearly as dramatic as suggested by several case reports
[9–14]. Besides hypotension, hypoglycemia and bradycardia, a case of
cardiac arrest [12], congestive heart failure [13], a case of fetal death fol-
lowing administration of a 50 mg bolus dose [14] as well as two cases of
myocardial hypertrophy and pericardial effusion attributed to maternal
labetalol therapy have been [29]. Common in these case reports is the
description of the adrenergic blockade side effects of labetalol exposure
on a preterm and mostly asphyxiated infant.
In contrast to a previously published paper [30], in our cohort hy-
poglycemia appeared not more common in infants exposed to labetalol.
A possible contributing factor to the high but similar incidence of
hypoglycemic episodes in our study might be the fact that most of
the infants admitted to the NICU receive a standard intravenous glu-
cose infusion which may have adequately prevented the presence of
hypoglycemia.
In the study now described, labetalol exposure did not appear to
be associated with neonatal bradycardia in the first 48 h after birth.
The high incidence of bradycardia in the first 10 min was explained
by asphyxia and/or prematurity. Pickles et al. [31] found no difference
between low dose orally administered labetalol and placebo in women
with non-severe nonproteinuric pregnancy induced hypertension. On
the contrary, Vigil-De Gracia et al. [3] compared in a randomized
clinical trial, intravenous hydralazine and intravenous labetalol
treatment in two hundred women with severe hypertension, and
showed that bradycardia (1.9% vs 10.6%; P = .008) and hypotension
(3.9% vs 10.6%; P = .05) appeared significantly more frequent in the
labetalol group.
Postnatal mortality occurred only in the labetalol exposure group
and were all remote from delivery. We hypothesize that mortality
cases are likely a result of the severe disease of the mother and, not
merely due to labetalol exposure.
Several limitations of our study deserve merit attention. First, the
retrospective nature of this study with its inherent difficulties, such as
Table 4
Neonatal parameters increasing the odds of hypotension (after multiple logistic regression
analysis).
Odds ratio (range)
Need for intubation 5.778 (1.647–20.277)
Labetalol exposure 6.115 (1.616–23.141)
PDA 3.651 (1.035–12.878)
ascertainment bias needs to be recognized. However, the electronic
database of our department, existent since 1988, has proven to be
highly accurate when selecting cases based on diagnoses. Second,
the relatively high prevalence of PDA in the hypotensive cohort is
P-value likely related to prematurity and SGA, and as previously reported,
depends on the definition used for diagnosis [26] Since PDA appeared
0.153 independently associated with hypotension, it is difficult to differentiate
0.742
between labetalol versus PDA effects. Furthermore, the study group
0.230
appears to be somewhat more preterm compared to the controls.
Even though this difference did not reach statistical significance
there is potential that this could have affected the incidence of hy-
potension. It is known that gestational age and SGA are related to
hypotension [15,21–25]. Inherent difference between cases and
controls form another limitation; the mothers of the cases are by
definition significantly more hypertensive. The enrichment of the
control group from the lower risk unit increases this difference. It is
not unlikely that this difference in disease severity has impact on the
condition of the neonate, such as pertaining to metabolic derangements.
Furthermore, the absence of a dose dependent effect may also suggest
that the observed association with labetalol may be due to factors
associated with maternal severity of disease rather than pharmacolog-
ical effects of labetalol. In addition, the investigated groups are rather
small and therefore, the conclusions should be interpreted with caution
until larger cohorts will be assessed and described.
In our opinion our findings currently do not mandate a change in
perinatal management of hypertensive mothers nor of their newborn
infants exposed to labetalol at our department, but should preferably
be tested in a prospective fashion. Mothers can be safely treated with
the current dosage regimen and should not be withheld adequate
therapy for fear of neonatal side effects. Our findings on the neonatal
side effects of labetalol underline the importance of neonatal monitoring,
including measurements of blood pressure and blood glucoses in the
first 48 h of life, especially in intubated preterm infants with a PDA. If
neonatal side effects do occur, these should be adequately recognized
and treated, particularly in stressed and preterm infants.
Conflict of interest
None.
Acknowledgments
The authors wish to thanks J.G.M. Burgerhof for his expertise with
statistical analysis.
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