European Journal of Obstetrics & Gynecology

and Reproductive Biology 59 Suppl. (1995) S17-S29

Influence of epidural analgesia on fetal and neonatal well-being

R. Scherer*a, W. Holzgreve b
'CheJarzt der K/inik jUr Anasthesio[ogie und operative /ntensivmedizin. Clemenshospi/a/ GmbH, Duesbergweg 124. 48153 Munster, Germany
bGeschaJtsjUhrender Oberarzt des Zen/rums jUr Frauenheilkunde. Westfiilische Wilhe/ms-Universitiit, A/bert-Schwei/zer-Str. 33, 48/29 Munster.
Germany

Abstract

Epidural analgesia is a frequently used method to reduce the pain of child-bearing. Concerns regarding the safety and potential
hazards still persist in the medical community. This review intends to examine how epidural analgesia determines the various factors
of fetal and neonatal well-being. Placental drug transfer of opiates like morphine, pethidine and fentanyl is rapid and can lead to
neonatal depression. Sufentanil seems to be the safest opiate to administer epidurally. Local anaesthetics are transferred to the fetus
in substantial amounts, but the reported effects are subtle and are probably inconsequential. Utero- and fetoplacental blood flow
seems to be improved by epidural analgesia with local anaesthetics. Even when using stronger solutions for more extensive blockade
in patients for caesarean section, no adverse effects could be demonstrated using pulsed Doppler technique as long as prolonged
hypotension (> 2 min) is avoided. Hypotension is best prevented with 20-25 ml/kg crystalloid preload and prompt treatment with
ephedrine or etilephrine. Addition of adrenaline to local anaesthetics is considered to be safe for the healthy mother and fetus but
it should best be avoided in mothers with pregnancy induced hypertension. Fetal and neonatal acid-base balance and gas-exchange
are not adversely affected by epidural analgesia. Many studies show that epidural analgesia can indeed protect the fetus if hypoten-
sion is prevented. Neonatal well-being evaluated by APGAR, BRAZELTON, SCANLON and NACS scores is not significantly
influenced by local anaesthetics. Neonatal depression can occur however with epidural use of morphine, fentanyl and alfentanil.
Sufentanil, again in doses up to 30 p.g in association with bupivacaine seems to be devoid of depressive effects on the neonate.
In summary, the anaesthetist has good arguments to reassure his obstetrical colleagues that providing epidural analgesia for
pregnant women in labour is a justifiable intervention to support the natural process of child-bearing.

Keywords: Epidural analgesia; Local anaesthetics; Epidural opioids; Epidural adrenaline; Fetal well-being; Neonatal well-being

1. Introduction transfer, uteroplacental blood-flow, acid-base balance

Epidural analgesia during labour enjoys increasing
popularity among obstetricians and pregnant women.
However, pain relief during child birth is still considered
by many to be optional. In particular epidural analgesia,
the most invasive form of pain relief, may be assumed
to be potentially harmful for the baby. Harmful effects
of epidural analgesia could originate directly from the
drugs used to induce analgesia (local anaesthetics and
opioids), or from epidurals conducted in a less than pro-
fessional manner, allowing hypotension to occur.
In this article the authors intend to review the influ-
ence of epidural analgesia on the various factors deter-
mining fetal and neonatal well-being: placental drug
• Corresponding author.
and gas-exchange and their impact on the clinical assess-
ment of neonatal outcome.
2. Factors determining placental transfer
The haemomonochorial structure of the human
placenta allows rapid diffusion of liposoluble substances
up to a molecular weight of 600-1000 [I]. Hydrophilic
substances and ions depend on diffusion through
transcellular aqueous pathways and therefore cross the
placenta much more slowly, the surface area available
for their diffusion being 10- 5 fold smaller [2].
Local anaesthestics are weak bases that can cross the
placenta in the non-ionised form only. Placental drug
transfer depends on membrane thickness, surface avail-
able and concentration gradient. As fetal blood pH is

0028-2243/95/$09.50 © 1995 Elsevier Science Ireland Ltd. All rights reserved

SSDI 0028-2243(95)002059-2
SI8 R. Scherer, W Holzgreve / European Journal of Obstetrics & Gynecology and Reproductive Biology 59 (1995) 517-529

lower than that of maternal plasma, weak bases are Table I

more ionised in fetal plasma. In fetal acidosis ionisation Maternal artery and fetal artery levels after epidural injection of 50 J.l.g
sufentanil and 50 J.l.g fentanyl. Modified from Kumar [18]
of weak bases maintains a concentration gradient for the
non-ionised drug form, therefore increasing fetal trans- Time (min) Sufentanil (50 J.l.g)a Fentanyl (50 J.l.g)b
fer rates for basic drugs. Thus, the compromised fetus is
at increased risk from local anaesthetics. However, this Maternal Fetal Maternal Fetal
(pglml) (pglml) (pglml) (pglml)
ion-trapping effect is masked by the effect of protein
binding. I 32 ± 29 ND 20 ± 30 ND
Protein binding is an important factor determining 10 48 ± 25 ND 20 ± 20 10 ± 30
45 54 ± 34 ND 30 ± 30 20 ± 30
the free fraction of a drug and the resulting equilibrium
60 48 ± 52 ND 50 ± 50 10 ± 20
fetal/maternal (F/M) ratio. A rise in fetal plasma protein 90 52 ± 44 ND 40 ± 60 10 ± 10
binding would increase maternal-to-fetal drug transfer 120 38 ± 29 ND 30 ± 60 3 ± 3
rate.
aData from Vertommen et al. [17].
Fetal albumin concentration at term slightly exceeds bData from Craft et al. [14].
maternal [3], thus the F/M ratio of albumin-bound ND. not detectable.
drugs such as fentanyl may exceed unity at equilibrium.
The other important drug binding protein is aI-acid
glycoprotein, which rises in fetal plasma much more
slowly [3]. Therefore, F/M ratio of drugs bound to this phine [10], and 30-65% bound mainly to at-acid glyco-
protein, like local anaesthetics, could be less than unity protein. Pethidine rapidly crosses the placenta in
at equilibrium, despite the ion-trapping effect. High humans [11] so that F/M ratios rise quickly, exceeding
fetal protein binding increases fetal transfer of drugs unity as maternal levels fall.
given in multiple doses [4]; the protein-bound drug com- Fentanyl is highly liposoluble and bound principally
ponent may act as a store that prolongs the effect of the to albumin. Free fentanyl crosses the rabbit placenta
drug well into to the neonatal period. more rapidly than free pethidine [12]. Following epi-
Placental blood flow has a more marked effect on dural administration F/M ratios rose to 0.7 after the
transfer of highly diffusable drugs, than on transfer of third dose [13]; it has therefore a potential for producing
poorly diffusable drugs. Gaylard et al. [5] showed that neonatal depression. Placental transfer of 50-100 p,g
bupivacaine highly bound to maternal protein may still epidural fentanyl was shown to occur within 15-45 min
be transfered to the fetus in spite of a substantial fall in in chronically instrumented pregnant sheep [14], with no
maternal flow in the rabbit. adverse effect, however, on mother or fetus. There is
F/M ratios should be interpreted with caution. On also a redistribution of fentanyl from neonatal tissues
brief exposures they may give a measure of transplacen- back into the maternal blood [15].
tal transfer rate, on prolonged exposure however F/M Sufentanil has an equally high lipophilicity. Follow-
ratios reflect the equilibrium distribution of a freely ing epidural administration of 0.125% bupivacaine with
diffusable drug [6]. F/M ratio may be particularly adrenaline 1:800 000 and sufentanil up to 30 p,g, plasma
misleading when considering bolus administration of a levels in mother and neonate were measured. No sufen-
highly liposoluble drug compared to a more hydrophilic tanil was detected in the plasma of 88% of the neonates
one. Maternal plasma concentration of the former drug and in the remaining 12% the sufentanil plasma levels
falls rapidly, while placental transfer is also rapid and was at the limit of detectability (0.02 ng/ml) [16].
the F/M ratio will rapidly exceed unity. Maternal plas- In the chronically instrumented pregnant sheep
ma concentration of the latter drug falls less rapidly, model, fentanyl was detected in the fetal arterial blood
placental transfer is slower and the F/M ratio rises slow- within 10 min of epidural administration of 50 p,g of fen-
ly. Fetal exposure, however, to the more hydrophilic tanyl to the mother [14]. In the same model Vertommen
drug may actually be greater, because of the more sus- et al. [17] showed that no sufentanil could be detected
tained maternal plasma load [7]. following an epidural injection of 50 p,g sufentanil
(Table I).
2.1. Placental transfer of opioids These studies appear to suggest that epidural sufen-
tanil is the safest opiate to administer epidurally [18].
Morphine is very poorly liposoluble and weakly
bound to aI-acid glycoprotein. Epidural injection of 2.2. Placental transfer of local anaesthetics
4-6 mg morphine to the mother was rapidly transferred
in a significant amount to the fetus [8]. The phar- Bupivacaine is the most widely used local anaesthetic
macokinetics of epidurally administered morphine are in obstetrical analgesia because of its low incidence of
similar to those by intramuscular route [9]. maternal and fetal side effects. Bupivacaine crosses the
Pethidine is 20-30 times more liposoluble than mor- placenta, its F/M ratios varies between 0.2-0.4 [19-21].
 R. Scherer. W. Holzgreve / European Journal of Obstetrics & Gynecology and Reproductive Biology 59 (1995) 517-529
Bupivacaine is highly (90%) bound to maternal ai-acid
glycoprotein, while only moderately (50%) bound to
fetal plasma [22]. The differential protein binding be-
tween mother and fetus largely explains bupivacaine's
low F/M ratio. However, more recent and sensitive anal-
ytical techniques have shown that substantial amounts
of bupivacaine are transferred across the placenta and
taken up in fetal tissues following epidural administra-
tion [23], and fetal dose clearly rises with duration of
maternal administration [24].
Fletcher et at. [25] suggested an association between
altered protein binding and increased F/M ratios when
adrenaline is added to bupivacaine. Adrenaline may
enhance overall fetal equilibration but does not reduce
fetal exposure.
However, in spite of clear evidence for considerable
placental transfer of bupivacaine, any reported effects
have been subtle and are probably not clinically signi-
ficant.
Lignocaine is often chosen by anaesthetists for epi-
dural anaesthesia for caesarean section because of its
more rapid onset of action compared to bupivacaine.
Lignocaine's F/M ratios are reported as 0.5-0.7 [26,27J.
It is metabolized by hepatic enzymes to two active me-
tabolites, monoethylglycinexylidide and glycinexylidide.
The neonate is able to metabolize lignocaine [28]; a rela-
tionship between the active metabolites and neonatal
outcome has not been demonstrated.
Chloroprocaine has gained some popularity in the
United States, but has never been approved for use in
Europe. Rapid hydrolysis by plasma cholinesterase in
the mother and neonate with normal plasma
cholinesterase limits its potential for toxicity. Active
drug levels can be measured following epidural anal-
gesia; these levels are very low and probably inconse-
quential to mother an fetus [29].
3. Effect of epidural analgesia on utero-and fetoplacental
blood flow
Uterine blood flow at term is estimated to reach
500-700 ml/min, while only 350-550 ml/min perfuse the
intervillous space and are available for metabolic-
exchange with the fetus. Uterine perfusion is pressure
dependent, therefore maternal hypotension always re-
sults in a decrease of intervillous blood flow. Uterine
and spiral arteries are capable of vasoconstriction due to
stimulation of sympathathetic a-adrenoreceptors, either
as a reflex to maternal hypotension or by direct stimula-
tion of receptors via vasoactive drugs. Pregnancy-
induced hypertension (PIH) is associated with increased
sensitivity of uterine vessels to catecholamines [30].
Umbilical blood flow is estimated to reach 250
mVmin, accounting for about 50% of fetal cardiac out-
put. Umbilical vessels possess both a- and {3-
SI9
adrenoreceptors but are devoid of autoregulation. Apart
from direct receptor stimulation, isolated human umbili·
cal vessels have been shown to contract in response to
bupivacaine but not to chloroprocaine [3IJ. Therefore,
intervillous blood flow may be reduced in response to
maternal hypotension or uterine vasoconstriction and
hence become an important factor in the development of
fetal asphyxia.
Measurement of uterine and intervillous blood flow
initially was attempted using radionuclide methods.
After intravenous injection of 99Tc or inhalation of
133Xe, disappearance of accumulation of radioactivity
was used as a semiquantitative estimation of intervillous
blood flow per unit volume. A Finish group, headed by
Hollmen and Jouppila, systematically studied the effect
of regional anaesthesia on intervillous blood flow using
the intravenous 133Xe technique, giving a semiquan-
titative estimate of intervillous blood flow in the central
part of the placenta.
Even though the radiation dose to mother and fetus
is small, serious reservations persist among obstetricians
and their patients regarding routine use of radionuclide
methods. With the development of pulsed Doppler
techniques, obstetricians have focused on this non-
invasive method to study changes in blood flow during
epidural analgesia on both sides of the placenta, the
uterine artery or arcuate artery on the maternal side,
and the umbilical artery and aorta on the fetal side.
Measurement of blood flow is difficult due to variations
in vessel diameter and insonation angle, but the exami-
nation of blood velocity waveforms such as resistance
index (RI), pulsatility index (PI), or systolic/diastolic
ratio (SID) give valuable information that is indepen-
dent of insonation angle.
Radionuclide studies by Hollmen and his group
[32,33J had shown that epidural analgesia during nor-
mal labour improved intervillous blood flow significant-
ly; the more extensive the sympathetic blockade, the
more marked was the observed increase in intervillous
blood flow.
Using pulsed Doppler, Marx et at. [34] found a
decrease in resistance in the umbilical artery following
epidural analgesia in 13 of 16 fetuses during labour. Pat-
ton et at. [35] in 1991 examined the hemodynamic
changes associated with fluid preload and epidural
anaesthesia, using umbilical artery Doppler velocimetry
in 12 normally labouring gravidas at term. Although on
the maternal side, fluid preload was associated with sig-
nificant increases in heart rate, stroke volume and car-
diac output, as well as with a decrease in vascular
resistance, there were no changes in uterine or umbilical
artery SID ratios during any stage of the study. Other
authors reported no change in pulsatility index, fetal
aortic and umbilical flow [36] following epidural anal-
gesia. However, when comparing effects of epidural
analgesia on blood flow velocity waveforms, preload,
S20 R. Scherer, W. Holzgreve / European Journal of Obstetrics & Gynecology and Reproductive Biology 59 (1995) 517-S29

position of the patient and extension of the sympathetic Table 2a

block may affect the results [37J. Doppler flow profile (pulsatility indices) of the arcuate artery in 11 pa-
When considering epidural analgesia for labour, tients before and following combined spinal epidural anaesthesia for
caesarean section
radionuclide studies and Doppler studies seem to in-
dicate that there are no major changes in, or detrimental Patient Pre-prim. Post-prim. 3-5 15-20
effects on, uteroplacental and intervillous blood flow. (gestational age min min
Epidural analgesia for labour using local anaesthetics in weeks)
in low concentrations differs in many aspects, however, E.K. (38) 0.75 0.75 0.79 0.79
from epidural anaesthesia for caesarean section. Stron- R.S. (38) 0.73 0.38 0.57 0.66
ger anaesthetic solutions in larger doses are necessary A.S. (41) 0.8 0.74 0.69
and therefore potentially dangerous side effects of major RM. (36) 1.26
J.J. (36) 0.92 0.91 1.53
regional anaesthesia are reported more frequently. Non-
M.K. (33) 1.14 1.28 1.29 1.22
laboring mothers had significantly higher incidence of S.O. (35)' 0.82 0.84 1.39 1.62
hypotension than laboring mothers, 36% vs. 24% in a G.O. (31) 1.02
study by Brizgys et al. [38] during epidural anaesthesia C.H. (36) 0.66 I 0.72 1.07
for caesarean section. Already in 1988 Veille et al. [39] S.B. (38) 1.07 0.73 0.92 1.05
tried to evaluate the umbilical artery flow velocity R.E. (39) 0.57 0.57 0.55 0.72

waveform before and during epidural anaesthesia for aRR (syst): 120 - 90 mmHg; 2 mg vasoconstr. - 130 mmHg.
elective caesarean section in 18 patients, using range
garted pulsed Doppler. They found that the waveform Table 2b
analysis of the umbilical artery close to its placental Doppler flow profile (pulsatility indices) of the umbilical artery in II
insertion did not change significantly. patients before and following combined spinal epidural anaesthesia
The perinatal research group at the Department of for caesarean section
Obstetrics and Gynecology in Zurich [40] also perform- Patient Post-prim. 3-5 15-20
Pre-prim.
ed pulsed Doppler evaluations in 13 women undergoing (gestational age min min
elective caesarean section. They found no changes in the in weeks)
resistance and pulsatility indices of the umbilical artery 1.08
E.K. (38) 1.14 1.1 1.12
velocity waveforms, even though there were changes in RS. (38) 1.47 1.02 1.61 1.42
the maternal femoral arterial and venous flow pattern A.S. (41) I 0.73 0.82
indicating an increase in leg blood flow after epidural P.M. (36) 0.78 0.67 0.6
anaesthesia. J.1. (36) 0.74 0.7 0.65
M.K. (33) 0.9 0.84 0.86 0.85
A study using combined spinal-epidural anaesthesia
S.O. (35)a 1.16 0.86 1.03 0.96
for caesarean section enrolled II women from the G.O. (31) 0.75 1.18 0.97
obstetrics service of the center for Women's Diseases at C.H. (36) 1.11 1.23 1.02 0.98
the University of Munster. They all had single in- S.B. (38) 1.25 1.11 0.94 1
trauterine pregnancies, no maternal medical problems R.E. (39) 0.78 0.88 1.07 0.93
or maternal drug intake and no signs of threatening fetal aRR (syst): 120 - 90 mmHg; 2 mg vasoconstr. - 130 mmHg.
asphyxia or fetal malformations. The combined spinal-
epidural anaesthesia was applied with an ultrathin spi- Table 2c
nal needle (29,27 G) and the local anaesthetics were first Doppler flow profile (pulsatility indices) of the fetal aorta in II
applied spinally and later epidurally for an extension of patients before and following combined spinal epidural anaesthesia
for caesarean section
the effect. The dosage for the combined spinal and epi-
dural anaesthesia was 1.5-2 ml and 5-10 ml 0.5% Patient Pre-prim. Post-prim. 3-5 15-20
bupivacaine, respectively. (gestational age min min
The Doppler evaluation consisted of a baseline mea- in weeks)
surement taken before fluid preload, with further 1.7 1.89 1.6
E.K. (38) 2.09
measurements after intravenous fluid preload and 3-5 R.S. (38) 1.81 1.94 1.53 2.43
min and finally 15-20 min after achieving adequate A.S. (41) 2 2.1 2.24
anaesthesia. We measured the SID ratio, the resistance P.M. (36) 2.02 1.56 1.71
and pulsatility indices of the umbilical artery, the fetal J.J. (36) 2.21 1.68 1.3
M.K. (33) 1.68 1.81 1.35
aorta and arcuate (uterine) artery and surveyed the ma- 1.62
S.O. (35)' 1.41 1.16
ternal blood pressure and heart-rate continuously as G.O. (31) 2.05 1.98 1.79
well as the fetal well-being by continuous CTG- C.H. (36) 2.12 2.32 2.06 1.95
monitoring. A more detailed description of the patients S.B. (38) 2.14 2.1 1.86 1.84
and methods will be given elsewhere. RE. (39) 1.66 1.55 1.87 1.71
Table 2a-c summarizes the pulsatility indices for the aRR (syst): 120 - 90 mmHg; 2 mg vasoconstr. - 130 mmHg.
 R. Scherer. W. Holzgreve / European Journal of Obstetrics & Gynecology and Reproductive Biology 59 (/995) SJ7-S29 S21

three vessels, and Fig. la-c shows, as a graphical depic-
tion, the changes of the resistance index of the three ves-
sels at the four measurement points. It can clearly be
seen that there were no significant changes, not even in
the one case where the systolic blood pressure fell from
120 to 90 mmHg, but recovered quickly after 2 mg of
etilefrin had been given. Table 3 summarizes data of an
additional case where the measurements were performed
in a patient with combined aortic stenosis/insufficiency,
who had a pressure gradient of 40 mmHg at 39 weeks
of pregnancy. She received an epidural anaesthesia with
75 mg bupivacaine injected in 40 min. Also in this case
there were no significant changes either in blood pres-
sure, maternal heart rates or in the umbilical and ar-
cuate artery resistance and pulsatility indices. Our study
therefore showed no significant changes in the Doppler

-- E.K. (38.)
°1,-----------------------, + A.S. (38.)

'* A.S. (41.)

0,8 -D- P.M. (36.)

L----+-----____:=:~ * J.J. (36.)

.. M.K. (33.)
... 5.0. (35.) *
%G.O. (31.)

0,4 .C.H. (36.)

5\l- 5.8. (38.)

0,2
'* A.E. (39.)

* AA (syst): 120 •• > 90

--> (2 mg vasoconstr.)
--> 130
ol.----------------------!
Pre-prim. Post-prim. 3·5 min 15·20 min
-- E.K. (38.)
®1 r--------------------,
- A.S. (38.)

* A.S. (41.)
-0- P.M. (36.)
*J.J. (36.)
.. M.K. (33.)
... S.O. (35.) *
% G.O. (31.)

0,4 .C.H. (36.)

s;;- 5.8. (38.)

0,2
'* A.E. (39.)

* AA (syst): 120 --> 90

--> (2 mg vasoconstr.)
oL- ~
-- > 130
Pre-prim. Post-prim. 3-5 min 15·20 min
Fig. 1. A and B. (continued next page).
522 R. Scherer. W. Holzgreve / European Journal of Obstetrics & Gynecology and Reproductive Biology 59 (1995) S17-S29

--- E.K. (38.)

+ R.S. (38.)

* A.S. (41.)
-G- P.M. (36.)

* J.J. (36.)
-+- M.K. (33.)

* S.O. (35.) *
% G.O. (31.)

0,7 • C.H. (36.)

~ S.B. (38.)

0,6
*" R.E. (39.)

* RR (syst): 120 --> 90

--> (2 mg vasoconstr.)
0,5 L...- _ --> 130
Pre-prim. Post-prim. 3-5 min 15-20 min
Fig. I. Doppler flow profile (resistance indices) of (a) the arcuate artery, (b) the umbilical artery and (c) the fetal aorta.

flow profile after epidural and spinal anaesthesia on the
maternal (arcuate artery) or the fetal side (umbilical
artery/fetal aorta).
These studies support the conclusion that epidural
analgesia for labouring mothers, or a major epidural or
spinal-epidural block for caesarean section, has not
shown a negative effect on the fetus, as long as pro-
longed hypotension is avoided.
3.1. Maternal hypotension and aortocaval compression
Maternal hypotension is the most frequent complica-
tion of epidural blockade; it is mostly mild with epidural
analgesia for labour but can be severe when a major
epidural blockade is attempted for caesarean section.
Hypotension is usually defined as a fall of blood pres-
sure greater than 20-30% froIJl the preanaesthetic level.
Hypotension is caused by vasodilatation induced by
3.2. Prevention and treatment of maternal hypotension
epidural blockade and exacerbated by aortocaval com-
pression if the parturient adopts the supine position.
Vena cavae compression is an important cause of
decrease in intervillous blood flow resulting in fetal
hypoxaemia [41,42].
In the supine position intervillous blood flow may fall
by 20-30% [43]. It has been shown with 133Xe washout,
that a change from the lateral to the supine position can
induce a significant decrease in intervillous blood flow
[43]. Doppler studies have shown that resistance in
uterine and umbilical artery increased significantly in
mothers passing from full lateral to supine position
without any change in maternal blood pressure [44,45].
Hence, supine position should be avoided during la-
bour whenever possible. In situations where supine posi-
tion cannot be avoided, it is essential to remember that
left lateral tilt will only relieve aortic compression, but
to avoid compression of vena cava left uterine displace-
ment is just as important.
Only very short periods of maternal hypotension (not

Table 3
Doppler flow profile of 24-year-old gravida (39 weeks) with combined aortic stenosis insufficiency

Blood pressure Maternal Umbilical Umbilical Arcuate Arcuate

(mmHg) heartrate artery RI artery PI artery RI artery PI
(beats/min)

After volume priming 126/66 72 0.7 1.15 0.48 0.66

After prophyl. vasoconstr. i. v. 131/61 73 0.57 0.82 0.55 0.89
5 min after 50 mg bupivacaine 120/65 89 0.60 0.97 0.48 0.69
5 min after 75 mg bupivacaine 118/63 91 0.62 1.03 0.59 0.89
 R. Scherer. W. Hol;greve / European Journal of Obstetrics & Gynecology and Reproductive Biology 59 (1995) S17-S29
exceeding 2 min and corrected rapidly) do not result in
impaired neonatal status [46]. Therefore, effective pre-
vention, early detection and prompt treatment of mater-
nal hypotensive episodes are mandatory. As discussed in
the previous chapter, if hypotension is prevented,
neither epidural nor spinal anaesthesia decrease inter-
villous blood flow or umbilical artery flow velocity
[35,36,39,40,47-49]. Preloading maternal circulation
with either crystalloid or colloid solutions is considered
an important measure to prevent hypotension. Most
authorities advocate the infusion of at least 500 ml of
lactated Ringer's solution prior to administering epi-
dural analgesia; much larger fluid volumes may be re-
quired with epidural anaesthesia for caesarean section.
Using 25 ml/kg crystalloid preload, Alahutha et al. [50]
found no increase in uteroplacental resistance. Based on
these results Hollmen [37] recommends preloading with
20-25 ml/kg crystalloid solution to prevent maternal hy-
potension. For early detection of maternal hypotension
most anaesthetists and obstetricians rely on frequent
noninvasive measurement of blood pressure in the arm.
However, maternal hypotension was detected at least I
min earlier when blood pressure was taken in the leg
instead of the arm [51].
Despite preventive measures such as full lateral posi-
tion and preloading with crystalloid solutions, hypoten-
sion does occur and a vasopressor may be needed.
Ephedrine, an indirect acting smypathomimetic drug
stimulating a- and f)-receptors in doses up to 15 mg
given slowly, has been shown to produce no significant
change in intervillous blood flow [52]. ]n a more recent
study using Doppler technique, Rasanen et al. [53] com-
pared the effects of ephedrine to etilephrine, a mixed a-
and f)-stimulant with more a-adrenergic dominance
than ephedrine. Both drugs significantly increased
pulsatility index in the uterine artery after bolus admin-
istration. In a more dilute form, however, ephedrine did
not increase uterine and arcuate artery pulsatility index,
which could be well demonstrated with phenylephrine,
a pure a-stimulant [54]. Neither ephedrine, etilephrine
nor phenylephrine were able to increase resistance in the
umbilical artery; therefore these vasopressors may be
considered safe for the healthy fetus at least [53,54].
3.3. Effect of adrenaline with local anaesthetics
Adrenaline is frequently added to local anaesthetic
solutions as a test dose to detect unintentional, intravas-
cular placement of the epidural catheter or to improve
the quality and duration of an epidural blockade. Can
adrenaline absorbed from the epidural space effect
uteroplacental perfusion? Neither 20 IJ-g of adrenaline
with bupivacaine nor 100 IJ-g of adrenaline with ligno-
caine induced any change in intervillous blood flow in
two studies by Jouppila et al. [32,55]. Adding 100 IJ-g of
adrenaline to bupivacaine or lignocaine in studies using
S23
Doppler technique produced no change in uterine artery
resistance or umbilical flow velocities [56,57]. Therefore,
the unintentional i. v. injection of 15 IJ-g adrenaline with
a test dose of local anaesthetic, or the basic addition of
a concentration of adrenaline not exceeding 1:200 000,
is considered to have no lasting and harmful effect on
healthy mother or healthy fetus [37].
]n contrast to normal pregnancy, parturients with
chronic or pregnancy-induced hypertension may toler-
ate sympathetic drugs obviously less well. Pregnancy-
induced hypertension is associated with a significantly
decreased intervillous blood flow [58] and increased sen-
sitivity of uteroplacental vessels to cathecholamines
[30]. ]n this situation epidural analgesia using 10 ml
bupivacaine 0.25%, without a vasoconstricting agent,
has been shown to improve intervillous blood flow
significantly [59]. Ramos-Santos et al. [61] performed
Doppler velocimetry of the uterine and umbilical
arteries before and after intravenous fluid loading and at
30 and 60 min after epidural blockade, while monitoring
the maternal vital signs and fetal heart rate continuously
in small groups of patients with preeclampsia (n 7), =
=
chronic hypertension (n 8) and no complications
(n = 10). Although mean maternal blood pressure fell
significantly in all groups, no maternal hypotension or
change in mean maternal and fetal heart rates were
observed. Similar to our findings, they did not notice
any changes in the umbilical artery SID ratios in any of
the three groups after epidural block.
However, because the mean uterine artery SID ratio
fell significantly in the preeclamptic group to values
similar to those of the normal group, the authors con-
cluded that in these patients, epidural anaesthesia may
even help to reduce uterine artery vasospasm and
therefore may prevent intrapartum fetal asphyxia. By
contrast, on the basis of preliminary evidence, addition
of adrenaline to a local anaesthetic should be avoided in
the compromised fetus [60] as increases in uterine and
umbilical resistance have been observed [37,44].
4. Effects of epidural analgesia on fetal and neonatal acid-
base balance and gas-exchange
Umbilical cord blood-gas and acid-base
measurements, together with fetal heart rate (FHR)
monitoring and APGAR scores, are the most frequently
used parameters to predict and evaluate fetal outcome.
Umbilical venous (UV) pH, evaluating placenta func-
tion, and umbilical artery (UA) pH, reflecting fetal
status, make umbilical cord blood pH a sensitive indica-
tor of birth asphyxia [62]. Fetal hypoxaemia and
acidaemia are closely related to reductions in inter-
villous blood flow.
Before discussing effects of epidural analgesia on fetal
acid-base balance, the normal blood gas/acid-base
values should be known.
S24 R. Scherer. W. Holzgreve / European Journal of Obstetrics & Gynecology and Reproductive Biology 59 (/995) S/7-S29
Umbilical cord blood pH values at birth derived from
large series varies are: UV pH, 7.32-7.35; UA pH,
7.24-7.27 [62-64). Analysing blood samples obtained
by cordocentesis before labour, Nicolaides et al. (65)
found slightly higher pH values in well-grown fetuses
than at birth.
Fetal acidaemia being the hallmark of fetal asphyxia
is best diagnosed using UA pH (66). A UA pH of 7.25
is considered to be the lower limit of normal and values
< 7.20 are considered diagnostic of fetal acidaemia
[66,67). However, recently an even lower cut-off point of
UA pH of 7.00 has been proposed (68).
However, even low values of UA pH (:5 7.05) have lit-
tle prognostic value in cases of neurologic dysfuntion or
hypoxic ischaemic encephalopathy [64,66). Only in
8-21% of patients with cerebral palsy can birth asphyxia
be determined as the cause of hypoxic or ischaemic
encephalopathy [69,70).
In order to provide valid evidence of the effect of epi-
dural analgesia on fetal blood gas/acid-base balance,
one has to sort out all confounding factors that con-
tribute to peripartum intrauterine asphyxia, such as pre-
maturity, growth retardation, pregnancy-induced
hypertension, maternal disease and umbilical cord com-
pression. Umbilical blood data obtained at birth should
be related to blood data from samples taken by
ultrasonographic cordocentesis before starting an epi-
dural analgesia (71).
In the first stage of labour, in the absence of epidural
analgesia, a progressive but modest degree of acidaemia
can be observed in the blood of the mother and in fetal
scalp blood. However, pH and base excess gradients be-
tween mother and fetus increased slightly during active
labour. With epidural analgesia and mothers adopting
full lateral position, maternal and fetal acidaemia
almost disappeared [72,73). In the second stage of natu-
rallabour acidaemia worsened more rapidly than during
the first stage (74), while mothers receiving epidural
analgesia did not develop second stage acidaemia
whether they pushed or not. Epidural analgesia had also
a positive effect on cumulative fetal acidaemia. Bearing
down during the expulsive phase of labour tended to
hasten the onset of fetal acidaemia. However, as most
mothers were in a supine position, aorto-caval compres-
sion may have been a confounding factor (75). Many
other studies confirmed the hypothesis that epidural
analgesia can protect the fetus [76,77).
Epidural analgesia reduces pain-induced maternal hy-
perventilation during labour, preventing left shift of the
haemoglobin dissociations curve in the mother, which
can have detrimental effects on fetal haemoglobin satur-
ation (78).
There is one study by Shyken et al. [79], however, that
seems to contradict all previous studies. These authors
compared two groups of vaginally delivered patients
with and without epidural analgesia. In the epidural
group mean UA pH was 7.26 ± 0.04 compared to
7.29 ± 0.04 in the nonepidural group; the authors con-
cluded that epidural analgesia does not offer any c1ear-
cut advantage to the normal term fetus. This study has
been heavily criticized by Downing et al. (80) on the
bases of the study being retrospective, non-randomized
and non-matched for age and parity design. Considering
the small sample size « 30 patients in each group),
neither the statistical power of the study nor the re-
quired sample size were defined to avoid type B error.
Maternal hypotension following regional anaesthesia
(epidural or spinal) may also be a factor promoting fetal
acidaemia. In patients with epidural anaesthesia, severe
hypotension was associated with significant fetal
acidaemia UA pH 7.16 ± 0.07 compared to non-
hypotensive patients with UA pH 7.27 ± 0.04 [81).
However, umbilical artery acidaemia resulting from hy-
potension was less severe with epidural than with spinal
anaesthesia [82-84).
If hypotension following regional blockade was
minimized by prehydration and/or prompt treatment
with vasopressors, fetal acidaemia was negligible
[85,86).
5. Effect of EDA on neonatal well-being
In addition to fetal and neonatal blood chemistry,
neonatal well-being is routinely assessed by APGAR
score and neurobehavioural testing.
The APGAR score evaluating colour, heart rate,
reflex irritability, muscle tone and respiratory effort, is
taken at I, 5 and 10 min after birth. A low I-min
APGAR score poorly correlates with late outcome; cor-
relation is slightly better for the 5-min score. Slow im-
provement of APGAR scores, however, can indicate an
increased risk of brain damage. Therefore, neurological
evaluation is a much more accurate method to assess
CNS function of the newborn.
The Brazelton neonatal behavioural assessment scale
(BNBAS) consist of 49 items exploring tone, activity,
reflexes and responses to stress and social interactive be-
haviour (87). The test must be performed by a specially
trained observer and takes 45 min, which explains the
scarce use of this test by anaesthetists and pediatricians
in the delivery room.
The Scanlon early neonatal neurobehavioural scale
(ENNS) [88) is easier and faster to perform, evaluation
of the 15 items does not need a specialized observer, but
unlike the BNBAS, does not explore the behavioural
aspects.
The neurologic and adaptive capacity score (NACS)
(89) consists of a neurological examination comprising
15 items in four sections (passive tone, active tone, prim-
itive reflexes and general behaviour) and a behavioural
evaluation with five items derived from the BNBAS.
The normal score range from 35 to a maximum of 40
 R. Scherer. W. Holzgreve / European Journal of Obstetrics & Gynecology and Reproductive Biology 59 (/995) S/7-S29
points. The neonates are tested 50 min and 2 h after
birth and again after 24 h if the score was < 35. The
NACS takes only 4-5 min to perform. Its 15
neurological items help to distinguish between drug
effects and brain oedema caused by birth asphyxia or
trauma [90].
5.1. Influence of local anaesthetics
Bupivacaine, the most widely used local anaesthetic
for epidural analgesia during labour, does reach the
fetus in substantial amounts (Chapter I). Its relatively
long half life of 14 h in the newborn [91], its known car-
diotoxicity and its increased placental transfer during
fetal acidaemia, could render bupivacaine a potentially
troublesome drug in obstetrics.
However, apart from transient abnormal fetal heart
rate patterns, which occurred more frequently with
bupivacaine, no significant differences in APGAR
scores or acid-base status has been detected when
bupivacaine was compared with lignocaine or chloro-
procaine [92,93].
A reduced neonatal muscle tone has been associated
with a mean total dose of bupivacaine of 130 mg [94];
other authors found a depressed sucking response 24 h
after bupivacaine was used for caesarean section [95].
The vast majority of published studies, however,
showed apparently complete absence of neonatal effects
of bupivacaine [96,97] with excellent scores with ENNS
[88,92] and NACS [93].
Lignocaine is rarely used for pain relief during labour,
therefore few studies exist. Scanlon et al. [88] reported
neonates whose mothers received lignocaine for epidural
analgesia as being 'floppy but alert', compared with neo-
nates born without maternal analgesia. A more recent
study by Abboud et al. [98] attested to the relative safety
of lignocaine even in high doses.
Chloroprocaine, not approved in Europe, has not
been related to any deleterious effects with regard to
fetal heart rate, APGAR scores or acid-base status
[92,93].
5.2. Influence of opioids
The epidural administration of opioids has the great-
est potential of neonatal adverse effects. Morphine 2-4
mg given epidurally resulted in slight changes in alert-
ness and general behaviour in six of eight neonates
evaluated with ENNS [99]. In one of 20 neonates, a sin-
gle epidural dose of 5 mg morphine to the mother was
associated with repeated episodes of apnoea in the im-
mediate post natal period [8].
Doses of up to 7.5 mg of morphine had no effect on
APGAR score and NACS in 30 neonates [100].
Fentanyl in repeated doses of 150 p.g up to a total dose
of 600 p.g induced respiratory depression in one out of
S25
38 neonates reported by Carrie et al. [101]. Small doses
of fentanyl 100-150 p.g may produce respiratory depres-
sion in the mother [102] eventhough some authors claim
that small doses of fentanyl seem devoid of depressant
effects in mother and baby [103,104].
Alfentanil in a dose of about 200 p.g/kg given by con-
tinuous epidural infusion resulted in hypotonic infants
with low NACS scores, though APGAR scores and um-
bilical pH were normal [105].
Pethidine, 100 mg given epidurally to mothers may be
associated with normal APGAR scores or ENNS [106],
but neonatal depression in three of 10 babies was also
reported [107].
Sufentanil in a dose of < 50 p.g had no effect on
APGAR scores [108].
However, epidural opioids are seldom given as the
sole analgesic agent. More and more frequently, opioids
are combined with local anaesthetics in low concentra-
tions. The claimed advantages of this combination are
reduction of total dose of both drugs, avoidance of
major sympathetic and motor blockade, decreased inci-
dence of instrumental delivery and an improvement of
the analgesic quality [109].
Fentanyl has been the most widely studied drug in
combination with lignocaine and bupivacaine. In gener-
al fentanyl seems to have little effect; normal fetal heart
rate pattern and APGAR scores were associated with
100 p.g of fentanyl [110,111]. Even a mean total dose of
350 /log did not cause neonatal depression [112].
Alfentanil 0.05-1.0 mg did not cause fetal heart rate
abnormalities or depressed APGAR, ENNS or NACS
[113,114].
Sulfentanil seems to be the most promising opioid in
obstetrical practice. As already mentioned above, to
date sulfentanil could not be detected in fetal blood
following an epidural dose of up to 30 /log [16,115].
In doses up to 30 /log sulfentanil in association with
bupivacaine did not depress NACS or ENNS tests
[109,116,117]. Higher doses, however, exceeding 50 /log
resulted in neonatal depression with low NACS scores
[116].
There is an increasing body of evidence that the addi-
tion of opioids to local anaesthetics decreases the inci-
dence of instrumental delivery. Chestnut [118], adding 2
/log/ml of fentanyl to a continuous infusion of 0.0625%
bupivacaine in the second stage of labour did not
increase the instrumental delivery rate. Likewise Ver-
tommen [109] showed that adding sulfentanil to a
0.125% bupivacaine solution led to a lower forceps rate
than a larger dose of 0.125% bupivacaine.
In summary, epidural analgesia definitively seems to
have more beneficial than detrimental effects on fetal
and neonatal well-being in normal and high-risk preg-
nancies. Possible deleterious effects mainly result from
maternal hypotension and administration of large doses
of local anaesthetics to the mother. Incremental doses of
S26 R. Scherer. W. Hol~greve I European Journal of Obstetrics & Gynecology and Reproductive Biology 59 (1995) 517-529
dilute local anaesthetic solutions and possibly the addi-
tion of opioids will improve the quality of analgesia dur-
ing labour and increase fetal and neonatal safety.
Even sophisticated monitoring techniques, such as the
pulsed Doppler technique, were so far unable to detect
previously unknown risks of epidural analgesia regar-
ding blood flow to the fetus. Elaborate neuro-
behavioural tests could only describe subtle and trans-
ient alterations.
Therefore, the anaesthetist has good arguments to
reassure his obstetrical colleagues that providing epi-
dural analgesia for pregnant women in labour is a
justifiable intervention to support the natural process of
child-bearing.
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