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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 the fetus. Antihypertensive drugs are commonly used for the acute
management of hypertensive episodes in preeclampsia and, in general,
Hypertensive disorders represent the most common medical compli- are considered safe and effective. However, significant maternal and
cation during pregnancy, affecting 3 to 10% of gestations, depending neonatal side effects have been described for such drugs [3,4].
on the population and definitions used [1]. In women with severe Labetalol, a non-selective β and α1 antagonist, is often favored in
preeclampsia perinatal neonatal as well as maternal mortality and the Netherlands and is also worldwide one of the most commonly
morbidity are substantially increased. For neonates, the risk of death administered drugs for both long-term treatment as well as the
and morbidity, including fetal growth restriction, depends mainly on acute management of severe maternal hypertension in preeclampsia
gestational age at onset of preeclampsia as well as on gestational age [5,6]. Because labetalol has not been associated with clinically signifi-
at delivery and the severity of the disease process [2]. cant β-blockade, it is, considered a safe drug in term pregnancies [7,8].
Prolongation of a preeclamptic pregnancy may, depending on the However, β-blockers have been associated with severe symptoms
gestational age and anticipated risk to the mother, be favorable for 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
⁎ Corresponding author at: Department of Pediatrics, Division of Neonatology, Beatrix
Children's Hospital, University Medical Center Groningen, Hanzeplein 1, CA 51, 9700 RB
occur in preterm and small for gestational age infants’ regardless of
Groningen, The Netherlands. labetalol exposure [15,16]. It has been suggested that labetalol may
E-mail address: c.v.hulzebos@umcg.nl (C.V. Hulzebos). 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) 503–507 505

comparison, the 4 hypotensive infants of the control group recovered Table 2


after treatment with crystalloids only. The incidence of patent ductus Side-effects in infants exposed to intravenous versus oral labetalol within 24 h prior to
delivery.
arteriosus (PDA) was similar in both groups and also in the infants
with hypotension. Nine of 16 hypotensive labetalol infants (56%) Labetalol i.v. Oral labetalol* P-value
had a PDA of whom 6 where treated with crystalloids and dopamine/ (n = 37) (n = 18)

hydrocortisone i.v. One hypotensive infant (25%) in the control group Hypotension (n) 8 (21.6%) 6 (33.3%) 0.35
was diagnosed with a PDA and required treatment with crystalloids Hypoglycemia (n) 16 (43.2%) 10 (55.6%) 0.45
Bradycardia (n) 2 (5.4%) 2 (11.1%) 0.39
only.
Incidences of hypoglycemia and bradycardia in the first 48 h after *
Oral labetalol group consists of infants whose mothers used only oral treatment
birth were similar in both groups (Table 1). In the first 10 min after within the last 24 h prior to delivery.

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 was 57 (10–113) days. Two died because of ongoing sepsis, 2 due to
were not statistically significantly different between both groups. progressive respiratory insufficiency and 1 infant suffered a gastrointes-
To explore whether the route of labetalol administration affects the tinal perforation.
increased incidence of hypotension after labetalol exposure, a separate Univariate analysis of all 109 infants revealed 6 variables that were
analysis of the labetalol treated infants was performed (Table 2). The significantly associated with hypotension: The need for intubation
mothers of 37 infants received i.v. labetalol in the last 24 h prior to (p= 0.000), PDA (p= 0.001), apgar scoreb 7 after 1 min (p= 0.002),
giving birth. The oral group (n = 18) represents exclusively maternal gestational age (p= 0.003), labetalol exposure (p= 0.006) and birth
oral labetalol treatment in the last 24 h prior to birth. Table 2 shows weight (p= 0.018). These 6 variables were incorporated into a multiple
similar incidences of hypotension, hypoglycemia, and bradycardia in regression model. In this model, the need for intubation, labetalol
neonates after oral and intravenous maternal treatment. exposure and PDA appeared independently associated with hypo-
To explore whether the dose of labetalol affects the increased inci- tension as shown in Table 4. Apgar scoreb 7 after 1 min, birth weight
dence of hypotension, separate analysis of the intravenously labetalol and gestational age were excluded in this model, since these variables
treated infants was performed in 2 groups: b600 mg and >600 mg brought no significant improvement. Variables such as magnesium
total intravenous dose within the last 24 h (Table 3). sulfate exposure, apgar score b 7 after 5 min, umbilical artery pHb 7,10
Although not statistically significantly different, hypotension oc- or b 7,20 were not significantly associated with hypotension.
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 4. Discussion
previous 24 h.
To assess the effect of birth weight and gestational age on the This study evaluated the incidence and severity of side effects in a
occurrence of side-effects for the entire cohort, we performed sep- well-described cohort of infants who were exposed to labetalol in
arate analyses for those infants who were SGA (n = 24) or preterm utero. The main finding is that, irrespective of the dosage and route
(b37 weeks gestation, n = 92). Neonatal side effects did not occur of administration, such infants more often demonstrate periods of
more often in SGA infants, although a trend for hypoglycemia was hypotension in the first 48 h of life. Another important finding is
observed (n= 14 (58.3%) in SGA versus n = 35 (41.2%) in appropriate that hypoglycemia appeared very common in this population and
for gestational age (AGA) infants, p = 0.14)). All 20 cases of hypoten- was related to prematurity and independent of labetalol exposure
sion occurred in preterm infants (21.7%, p = 0.03). Not unexpectantly, as was the incidental occurrence of bradycardia.
hypoglycemia was also more common in preterm infants compared to The presence of a PDA appeared independently associated with
their term counterparts/infants born > 37 weeks' gestation (48.9% the manifestation of hypotension. This high prevalence of PDA in
versus 23.5%, p = 0.05). the hypotensive cohort is possibly related to prematurity, while we
To assess the effect of SGA on side effects, we compared the SGA can not exclude ascertainment bias due to selective screening, and
infants in the labetalol group with those in the control group. In also, depends on the definition used for diagnosis [21].
these relatively small groups of 12 infants each, hypotension occurred Labetalol causes peripheral vasodilatation and, therefore, a decrease
only in SGA infants (n = 5 (41.7%), p = 0.012) while the gestational in total peripheral vascular resistance through α1-adrenoreceptor
age was similar (33.5 versus 33.1 weeks) in the labetalol versus con- blockade while β-blockade prevents reflex tachycardia and maintains
trol SGA group. cardiac output [27]. Even though hypotension from a β-blocking effect
All 5 infants who died had a gestational age below 30 weeks and would be unlikely without a substantial reduction in heart rate, it re-
were all in the labetalol group. Median (range) postnatal day of death mains to be determined whether α1-adrenoreceptor blockade and/

Percentiles

Labetalol exposure No exposure to antihypertensive agents


1,82% 7,41% BW perc
5,56% p<10
p10-20
p20-50
21,82% 22,22%
23,64% p50-p80
p>80

14,55% 16,67% Pies show percents


48,15%
38,18%

Fig. 1. Birth weight (BW) percentiles of infants exposed to labetalol and infants not exposed to antihypertensive agents.
506 K.Y. Heida et al. / Early Human Development 88 (2012) 503–507

Table 3 ascertainment bias needs to be recognized. However, the electronic


Side-effects in infants exposed to b 600 mg total dose intravenous labetalol and infants database of our department, existent since 1988, has proven to be
exposed to ≥600 mg total dose intravenous labetalol within the last 24 h prior to
delivery.
highly accurate when selecting cases based on diagnoses. Second,
the relatively high prevalence of PDA in the hypotensive cohort is
b 600 mg labetalol ≥600 mg labetalol P-value likely related to prematurity and SGA, and as previously reported,
i.v. (n = 22) i.v. (n = 15)
depends on the definition used for diagnosis [26] Since PDA appeared
Hypotension (n) 3 (13.6%) 5 (33.3%) 0.153 independently associated with hypotension, it is difficult to differentiate
Hypoglycemia (n) 10 (45.5%) 6 (40.0%) 0.742
between labetalol versus PDA effects. Furthermore, the study group
Bradycardia (n) 2 (9.1%) 0 (0.0%) 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-
or β-blockade contribute to hypotension in newborn infants exposed potension. It is known that gestational age and SGA are related to
to labetolol. Labetalol crosses the placenta rapidly producing fetal hypotension [15,21–25]. Inherent difference between cases and
concentrations which are estimated to be approximately 50% of controls form another limitation; the mothers of the cases are by
maternal concentrations [28]. Even though its safety in compromised definition significantly more hypertensive. The enrichment of the
fetuses has been questioned, labetalol seems to have a relatively wide control group from the lower risk unit increases this difference. It is
hemodynamic safety margin [17]. A short term infusion of labetalol not unlikely that this difference in disease severity has impact on the
(1 mg/kg ×15 min), enough to reduce maternal blood pressure in cases condition of the neonate, such as pertaining to metabolic derangements.
of preeclampsia, demonstrated no effects on the peripheral vascular Furthermore, the absence of a dose dependent effect may also suggest
resistance in the uterine and fetal arteries or on fetal cardiac function that the observed association with labetalol may be due to factors
[18]. associated with maternal severity of disease rather than pharmacolog-
Even though a considerable number of infants in our cohort suffered ical effects of labetalol. In addition, the investigated groups are rather
hypotensive episodes, our findings on the neonatal side effects of labe- small and therefore, the conclusions should be interpreted with caution
talol are not nearly as dramatic as suggested by several case reports until larger cohorts will be assessed and described.
[9–14]. Besides hypotension, hypoglycemia and bradycardia, a case of In our opinion our findings currently do not mandate a change in
cardiac arrest [12], congestive heart failure [13], a case of fetal death fol- perinatal management of hypertensive mothers nor of their newborn
lowing administration of a 50 mg bolus dose [14] as well as two cases of infants exposed to labetalol at our department, but should preferably
myocardial hypertrophy and pericardial effusion attributed to maternal be tested in a prospective fashion. Mothers can be safely treated with
labetalol therapy have been [29]. Common in these case reports is the the current dosage regimen and should not be withheld adequate
description of the adrenergic blockade side effects of labetalol exposure therapy for fear of neonatal side effects. Our findings on the neonatal
on a preterm and mostly asphyxiated infant. side effects of labetalol underline the importance of neonatal monitoring,
In contrast to a previously published paper [30], in our cohort hy- including measurements of blood pressure and blood glucoses in the
poglycemia appeared not more common in infants exposed to labetalol. first 48 h of life, especially in intubated preterm infants with a PDA. If
A possible contributing factor to the high but similar incidence of neonatal side effects do occur, these should be adequately recognized
hypoglycemic episodes in our study might be the fact that most of and treated, particularly in stressed and preterm infants.
the infants admitted to the NICU receive a standard intravenous glu-
cose infusion which may have adequately prevented the presence of Conflict of interest
hypoglycemia.
In the study now described, labetalol exposure did not appear to None.
be associated with neonatal bradycardia in the first 48 h after birth.
The high incidence of bradycardia in the first 10 min was explained Acknowledgments
by asphyxia and/or prematurity. Pickles et al. [31] found no difference
between low dose orally administered labetalol and placebo in women The authors wish to thanks J.G.M. Burgerhof for his expertise with
with non-severe nonproteinuric pregnancy induced hypertension. On statistical analysis.
the contrary, Vigil-De Gracia et al. [3] compared in a randomized
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