Expert Review ajog.

org

Umbilical cord pH, blood gases, and lactate

at birth: normal values, interpretation, and
clinical utility
Per Olofsson, MD, PhD, BSc

Normal birth is a eustress reaction, a beneficial hedonic stress with extremely high catecholamines that protects us from intrauterine
hypoxia and assists in the rapid shift to extrauterine life. Occasionally the cellular O2 requirement becomes critical and an O2 deficit in blood
(hypoxemia) may evolve to a tissue deficit (hypoxia) and finally a risk of organ damage (asphyxia). An increase in Hþ concentration is
reflected in a decrease in pH, which together with increased base deficit is a proxy for the level of fetal O2 deficit. Base deficit (or its negative
value, base excess) was introduced to reflect the metabolic component of a low pH and to distinguish from the respiratory cause of a low
pH, which is a high CO2 concentration. Base deficit is a theoretical estimate and not a measured parameter, calculated by the blood gas
analyzer from values of pH, the partial pressure of CO2, and hemoglobin. Different brands of analyzers use different calculation equations,
and base deficit values can thus differ by multiples. This could influence the diagnosis of metabolic acidosis, which is commonly defined as
a pH <7.00 combined with a base deficit 12.0 mmol/L in umbilical cord arterial blood. Base deficit can be calculated as base deficit in
blood (or actual base deficit) or base deficit in extracellular fluid (or standard base deficit). The extracellular fluid compartment represents
the blood volume diluted with the interstitial fluid. Base deficit in extracellular fluid is advocated for fetal blood because a high partial
pressure of CO2 (hypercapnia) is common in newborns without concomitant hypoxia, and hypercapnia has a strong influence on the pH
value, then termed respiratory acidosis. An increase in partial pressure of CO2 causes less increase in base deficit in extracellular fluid than
in base deficit in blood, thus base deficit in extracellular fluid better represents the metabolic component of acidosis. The different types of
base deficit for defining metabolic acidosis in cord blood have unfortunately not been noticed by many obstetrical experts and organi-
zations. In addition to an increase in Hþ concentration, the lactate production is accelerated during hypoxia and anaerobic metabolism.
There is no global consensus on definitions of normal cord blood gases and lactate, and different cutoff values for abnormality are used. At
a pH <7.20, 7% to 9% of newborns are deemed academic; at <7.10, 1% to 3%; and at <7.00, 0.26% to 1.3%. From numerous studies
of different eras and sizes, it can firmly be concluded that in the cord artery, the statistically defined lower pH limit (mean -2 standard
deviations) is 7.10. Given that the pH for optimal enzyme activity differs between different cell types and organs, it seems difficult to
establish a general biologically critical pH limit. The blood gases and lactate in cord blood change with the progression of pregnancy toward
a mixed metabolic and respiratory acidemia because of increased metabolism and CO2 production in the growing fetus. Gestational age-
adjusted normal reference values have accordingly been published for pH and lactate, and they associate with Apgar score slightly better
than stationary cutoffs, but they are not widely used in clinical practice. On the basis of good-quality data, it is reasonable to set a cord
artery lactate cutoff (mean þ2 standard deviations) at 10 mmol/L at 39 to 40 weeks’ gestation. For base deficit, it is not possible to
establish statistically defined reference values because base deficit is calculated with different equations, and there is no consensus on
which to use. Arterial cord blood represents the fetus better than venous blood, and samples from both vessels are needed to validate the
arterial origin. A venoarterial pH gradient of <0.02 is commonly used to differentiate arterial from venous samples. Reference values for pH
in cord venous blood have been determined, but venous blood comes from the placenta after clearance of a surplus of arterial CO2, and
base deficit in venous blood then overestimates the metabolic component of fetal acidosis. The ambition to increase neonatal hemoglobin
and iron depots by delaying cord clamping after birth results in falsely acidic blood gas and lactate values if the blood sampling is also
delayed. Within seconds after birth, sour metabolites accumulated in peripheral tissues and organs will flood into the central circulation
and further to the cord arteries when the newborn starts to breathe, move, and cry. This influence of “hidden acidosis” can be avoided by
needle puncture of unclamped cord vessels and blood collection immediately after birth. Because of a continuing anaerobic glycolysis in
the collected blood, it should be analyzed within 5 minutes to not result in a falsely high lactate value. If the syringe is placed in ice slurry,
the time limit is 20 minutes. For pH, it is reasonable to wait no longer than 15 minutes if not in ice. Routine analyses of cord blood gases
enable perinatal audits to gain the wisdom of hindsight, to maintain quality assurance at a maternity unit over years by following the rate of
neonatal acidosis, to compare results between hospitals on regional or national bases, and to obtain an objective outcome measure in
clinical research. Given that the intrapartum cardiotocogram is an uncertain proxy for fetal hypoxia, and there is no strong correlation
between pathologic cardiotocograms and fetal acidosis, a cord artery pH may help rather than hurt a staff person subjected to a
malpractice suit based on undesirable cardiotocogram patterns. Contrary to common beliefs and assumptions, up to 90% of cases of
cerebral palsy do not originate from intrapartum events. Future research will elucidate whether cell injury markers with point-of-care
analysis will become valuable in improving the dating of perinatal injuries and differentiating hypoxic from nonhypoxic injuries.
Key words: acidemia, acidosis, Apgar, asphyxia, base deficit, base excess, birth, cerebral palsy, cord blood analysis, cord blood gases,
encephalopathy, hypoxia, lactate, metabolic acidosis, neonatal outcome, perinatal outcome, pH, pregnancy

S1222 American Journal of Obstetrics & Gynecology MAY 2023

ajog.org
Introduction
The oxygenation of Earth 2.4 billion
years ago was a result of O2 synthesized
by plants and organisms as a waste
product of photosynthesis, converting
light energy to chemical energy. Many
obligate anaerobes then went extinct,
whereas organisms that could resist
oxidative stress and utilize the energy
charge survived and evolved.1 The
cellular requirement for O2 became
critical, and hypoxia thus became the
greatest challenge to O2-dependent
organisms.
The atmospheric O2 content has var-
ied dramatically during the history of
Earth, from approximately 18% 380
million years ago during the Devonian
period, to 35% during the Carbonif-
erous period, referred to as the “oxygen
pulse.”2 During the following millions of
years the concentration fell to 11%, but
rose again, and has during the last 200
million years set at 21%. It was not until
large land plants and forests first evolved
that the present oxygenated Earth system
settled.3
These variations challenged the evo-
lution on Earth. The increase of atmo-
spheric O2 concentration allowed
animals to evolve beneficial physiolog-
ical traits and grow larger, but they also
had to develop defense mechanisms
against hypoxia. Thriving was facilitated
by the evolution of the placenta 60 to 80
million years ago.2
In the 1930s, Sir Joseph Barcroft
coined the phrase “Everest in utero,”
linking the low fetal O2 pressure to
oxygenation at high mountain
From the Department of Clinical Sciences
Malmö, Lund University, Malmö, Sweden.
Received April 7, 2022; revised July 6, 2022;
accepted July 6, 2022.
The author reports no conflict of interest.
Corresponding author: Per Olofsson, MD, PhD,
BSc. permu@telia.com
0002-9378
ª 2022 The Author(s). Published by Elsevier Inc. This is
an open access article under the CC BY license (http://
creativecommons.org/licenses/by/4.0/).
https://doi.org/10.1016/j.ajog.2022.07.001
altitudes.2,4e6 The mountaineer and the
fetus share the experience of low blood
O2 content, which at overstrain may
result in severe tissue hypoxia, acidosis,
and death. The lowest ever recorded
arterial partial O2 pressure (pO2) in a
human adult is 19.1 mm Hg (2.55 kPa),
recorded at an altitude of 8400 m while
climbing Mount Everest (summit, 8848
m). Climbers sampled arterial blood
from each other when breathing
ambient air, and the mean pO2 was 24.6
mm Hg (range 19.1e29.5 mm Hg; 3.28
kPa, range 2.55e3.93 kPa),7 which is in
the range of a human fetus at term.5
Whereas the mountaineer relies on
supplemental cylinder O2 during ascent,
the fetus relies on the placenta and the
mother’s respiration and circulation
during descent.
The good stress of being born
Lagercrantz6 has called the neonatal stress
of normal birth as “the happiness of being
born.” Normal birth is a eustress reaction,
a beneficial hedonic stress with extremely
high catecholamines that protects us
from intrauterine hypoxia and assists in
the rapid shift to extrauterine life by
facilitating changes in lung function, cir-
culation, and metabolism. Never in life is
the catecholamine surge higher than
when we are born (Figure 1).6,8
Fetal circulation and oxygenation
The growing fetus (particularly its brain)
has during normal conditions a higher
O2 consumption than the adult.
Although pO2 is reduced by 70% relative
to the adult, the O2 saturation (SaO2) is
reduced by only 35%.9 Because of a
hyperdynamic blood circulation with a
high baseline fetal heart rate (FHR), a
high O2 transport capacity facilitated by
a high hemoglobin (Hb) concentration,
and the unique fetal type of Hb (HbF)
with enhanced O2 binding and delivery
capacities, oxygenation of tissues can be
maintained adequately. Oxygenated
blood from the placenta reaches the fetus
via the umbilical cord vein and is shun-
ted via the ductus venosus and foramen
ovale to reach prioritized organs such as
the myocardium, brain, and adrenal
glands. Shunting via the ductus arterio-
sus detours the lungs.
MAY 2023 American Journal of Obstetrics & Gynecology
Expert Review
Deoxygenated blood returns to the
placenta via the 2 umbilical cord arteries,
and neonatal acid-base status at birth is
therefore best determined in arterial
cord blood. Arterial cord blood gases are
thus objective chemical imprints of life
in utero, reflecting metabolic processes
and exposure and endurance to resist
hypoxia.
During labor the fetus is intermit-
tently deprived of O2, with a fall of 5% to
10% in SaO2 below baseline10 when the
intrauterine pressure exceeds approxi-
mately 30 mm Hg during myometrial
contractions.11 At 35 mm Hg of intra-
uterine pressure, which is the level at
which we can usually feel the contrac-
tions on the abdominal wall, the utero-
placental blood flow disappears at the
end of diastole, and at 60 mm Hg dia-
stolic flow ceases completely.12,13 The
occurrence of FHR decelerations
accompanied by transient shunting of
blood from peripheral to central organs
during such O2 deprivation is a normal
physiological fetal response, known as
the “diving reflex” in aquatic mammals
and birds.4 The diving reflex thus strives
to preserve an aerobic metabolism in
central organs, provided by the
concomitant metabolic down-regulation
in peripheral organs.
In a fetus already suffering a baseline
O2 deficit when at rest, such as with
placental insufficiency in fetal growth
restriction (FGR), the superimposed
hypoxic stress by uterine contractions
may progressively cause severe hypoxia,
acidosis, and severe FHR decelerations.
A loss of umbilical artery end-diastolic
flow may then appear during both vari-
able14 and late FHR decelerations.15,16
The umbilical artery flow resistance in-
creases concomitantly,17 which further
compromises the O2 diffusion across the
placental membranes.
The nadir of SaO2 is reached at the end
of a contraction, and it takes up to 2
minutes after the peak of contraction to
recover to baseline.10 Thus, when >5
labor contractions per 10 minutes occur,
a full recovery might not be reached
between contractions, and a super-
imposed fetal hypoxemia develops
(Figure 2). An intact fetus resists the
strain of normal labor, but with
S1223
Expert Review ajog.org

tachysystole (>5 contractions every 10

FIGURE 1
minutes) a critical limit might be
Normal birth is a beneficial hedonic stress with sky-high catecholamines reached, which then also affects a pre-
viously healthy fetus.
If the O2 supply is not restored, the
hypoxic process develops in 3 steps:
hypoxemia, with a lower O2 content in
arterial blood but with intact cell and
organ functions; hypoxia, with anaer-
obic metabolism starting in peripheral
tissues; and asphyxia, where the O2
depletion also affects central organs with
development of metabolic acidosis and
risk of damage of vital organs.

Fetal defense mechanisms against

hypoxia
The fetus has a battery of well-developed
defense mechanisms for withstanding
hypoxia4,18:

1. High Hb concentration to increase

O2 transportation.
Never in life is the catecholamine surge higher than when we are born. Normal birth is a beneficial 2. HbF has a greater affinity to O2 than
hedonic stress that protects us from intrauterine hypoxia and assists in the shift to extrauterine life. adult Hb (HbA) at the same pO2
(Histogram modified from Lagercrantz.6,8 Drawing by Lasse Persson reproduced with permission from Läkartidningen). (Figure 3).
Olofsson. Umbilical cord blood pH, blood gases, and lactate. Am J Obstet Gynecol 2023. 3. Sympatheticoadrenal activation
with increases in FHR and cardiac
output.
4. Reduction of O2 consumption by
reducing nonessential movements.
5. Switch to anaerobic metabolism
via beta-adrenergic stimulation of
FIGURE 2 glycolysis.
Uterine contractions transiently deplete oxygen delivery to the fetus 6. Shunting of oxygenated blood from
the placenta through the liver and
heart directly to the myocardium and
brain.
7. Redistribution of blood flow to vital
organs such as the brain, heart, and
adrenals at the price of perfusion of
peripheral organs and tissues.
8. Redistribution of cerebral blood flow
from the cortex to central nuclei and
brainstem.

Deoxygenated Hb (deoxyHb) has a

higher affinity for CO2 than oxyhemo-
Placental O2 delivery from mother to fetus decreases when the intrauterine pressure exceeds 35 mm globin (oxyHb), thus changes in the
Hg, and the fetal SaO2 decreases concomitantly. During a uterine contraction, SaO2 decreases, and partial pressure of CO2 (pCO2) affect the
the return to the baseline SaO2 takes approximately 180 seconds from start. During tachysystole (>5 oxyHb dissociation curve (Figure 3). The
contractions per 10 minutes), a critically low SaO2 level might be reached, which varies with the metabolism causes acidity and increased
prelabor fetal condition. pCO2 in tissues, which shift the dissoci-
SaO2, O2 saturation. ation curve to the right, which is known
Olofsson. Umbilical cord blood pH, blood gases, and lactate. Am J Obstet Gynecol 2023. as the Bohr effect. With the right-shift,
the O2 affinity for Hb decreases, and

S1224 American Journal of Obstetrics & Gynecology MAY 2023

ajog.org Expert Review

O2 is more easily released in the needed

FIGURE 3
tissues, whereafter surpluses of free
hydrogen ions (Hþ) and CO2 bind to
Factors shifting the oxyhemoglobin dissociation curve sideways
deoxyHb and are transported with arte-
rial cord blood to the placenta. The re-
action HþþHbO24HþHbþO2 is
known as the Haldane effect, where
deoxyHb has a higher affinity for CO2
because it is a better proton acceptor
than oxyHb.
With advancing gestational age, HbF is
gradually replaced by HbA, and at term
approximately 20% of Hbs are HbA.
Because HbF and HbA have different O2-
carrying and O2-delivering properties,
the change toward term shifts the O2
dissociation curve to the right (Figure 3).

Aerobic and anaerobic metabolism

During prolonged O2 deprivation, the
aerobic metabolism switches to anaerobic
metabolism with production of Hþ. The
increase in Hþ concentration [Hþ] is re-
flected in a decrease in pH (“power of
hydrogen”), which is the negative loga-
rithm of [Hþ]. Thus, pH (and base deficit,
see below) is a proxy for the level of
oxygenation. Nota bene, the pH scale is
logarithmic, and a step change at acidotic
pH values represents a much larger change
in [Hþ] than an equal step at normal pH
values. For example, a pH difference of
7.27 and 7.25 corresponds to a [Hþ] of
2531 nEq/L, whereas a difference of 7.02
and 7.00 corresponds to 4501 nEq/L
(calculated from tables by Fiorica).19
A surplus of Hþ will result in meta-
bolic acidosis, and a surplus of CO2 in
respiratory acidosis. The metabolic and
respiratory influences on pH are illus-
trated by the HendersoneHasselbalch
equation for defining pH:
pH¼6:1þlog½HCO
3 =ð0:03pCO2 Þ;
where HCO3 is bicarbonate and 0.03 is
the carbonic dissociation constant at
37 C (98.6 F).
At an increase in [Hþ], HCO3 will be
consumed for the buffering of Hþ, and
carbonic acid (H2CO3) will be produced
(see below), reflecting the metabolic in-
fluence on pH. At hypercapnia, repre-
senting the respiratory influence on pH,
the pCO2 will increase. In both instances
pH will decrease.
The O2 saturation is a function of pO2, where the HbF and HbA O2 dissociation curves are displaced.
Changes in pH, pCO2, temperature, and 2,3-diphosphoglycerate shift the curve sidewise.
HbA, adult hemoglobin; HbF, fetal hemoglobin; pCO2, partial pressure of CO2; pO2, partial pressure of O2.
Olofsson. Umbilical cord blood pH, blood gases, and lactate. Am J Obstet Gynecol 2023.
Beyond the critical limit of O2 deficit, buffering capacity. In the placenta, CO2
which is individual and varies with fetal is eliminated from fetal erythrocytes into
prelabor condition, the switch to anaer- the intervillous space and further evac-
obic metabolism results in a much lower uated by the maternal circulation and
energy output from every metabolized respiration.
molecule of glucose. The difference is in Because labor influences the gas ex-
the range of 30 to 36 adenosine triphos- change across the placenta (Figure 2),
phate (ATP) at aerobic metabolism vs 2 some degree of acidemia will always
ATP at anaerobic metabolism (Figure 4). develop. Arterial and venous pH and
CO2 and H2O are waste products in bicarbonate will decrease, and base
the citric acid cycle (Figure 4). CO2 dif- deficit (BD, the positive value of base
fuses across the cell membranes to the excess) will increase with duration of
blood, where it is picked up by the labor21; pCO2 will increase in the cord
erythrocytes and converted to H2CO3 artery but not in the vein because an
and HCO3. In this way, an excess of Hþ excess of CO2 (hypercapnia, hyper-
is buffered by HCO3: carbia) in arterial blood is effectively
cleared in the placenta. The increased
CO2 þH2 O 4 H2 CO3 4Hþ þHCO
3:
maternal progesterone level in preg-
nancy induces a relative hyperventilation
The 2 major fetal buffering systems and subsequent decrease in pCO2,22
are HCO3- in plasma and Hb in eryth- which facilitates the escape of fetal CO2
rocytes, with each of them accounting across the placental membranes. In
for approximately 35% of the total normal labor a mixed metabolic

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Expert Review
FIGURE 4
ATP production during aerobic and anaerobic glucose metabolism
The fate of glucose during aerobic (blue arrows) and anaerobic (red arrow) metabolisms. During
restored aerobic conditions, the anaerobic trait pyruvateelactate can reverse and lactate be oxidized
back to pyruvate, and further to glucose and glycogen through gluconeogenesis.
ATP, adenosine triphosphate; CoA, coenzyme A.
(Figure simplified from Despopoulos and Silbernagl).20
Olofsson. Umbilical cord blood pH, blood gases, and lactate. Am J Obstet Gynecol 2023.
(increased BD) and respiratory
(increased pCO2) acidemia develops in
cord arterial blood according to the
length of labor.21
Evaluation of the metabolic
component in acid-base status by
base deficit
The BD was introduced to reflect the
metabolic component of a low pH. It is a
theoretical estimate of the “oxygen debt”
S1226 American Journal of Obstetrics & Gynecology MAY 2023
and is not a measured parameter, but is
calculated by the blood gas analyzer from
values of pH, pCO2, and Hb concentra-
tion. Different brands of analyzers use
different calculation equations. Some
brands use predetermined fixed Hb
values and some use truly measured Hb
values. This will result in significantly
different BD values and potentially also
influence the diagnosis of metabolic
acidosis.23 When calculating with
ajog.org
different equations and in different BD
compartments (provided below), we
found an interanalyzer difference in
diagnosing BD >12.0 mmol/L of up to
426%.24
BD is defined as the amount of base
that must be added (or extracted if BD is
negative, ie, excess of base) to a liter of
blood to shift pH in plasma to 7.40 at a
temperature of 37 C (98.6 F) and pCO2
of 40 mm Hg (5.33 kPa). This is called
the actual BD in blood (BDblood), in
contrast to standard BD, which is BD in
the extracellular fluid (BDecf ). The
extracellular fluid (ecf) compartment
represents the blood volume diluted
with the interstitial fluid, with a Hb
concentration standardized to 5 g/L (3
mmol/L). BDecf is also termed “BD
in vivo.”25 BDecf thus represents the
nonrespiratory, non-H2CO3 (metabolic)
component of the acid-base status.
The type of BD analysis is an option in
the blood gas analyzer, and clinicians and
researchers need to be aware of which
type of BD compartment is calculated.
The calculation of BDecf in different
blood gas analyzers is more standardized
than the calculation of BDblood.25
Rosén and Murphy26 and others have
advocated the use of BDecf in newborns
because hypercapnia is common and it
has a strong influence on cord arterial
pH (provided HendersoneHasselbalch
equation above). Cord arterial pCO2
correlates positively with BDblood but not
with BDecf. An increase in CO2 is
handled by the erythrocytes with a
resultant increase of HCO3 in plasma.
Some bicarbonate ions are lost to equil-
ibrate with the interstitial fluid, which
results in a BD in plasma and an increase
in BDblood. An acute increase in pCO2
will thus cause a smaller increase in BDecf
than in BDblood. This is particularly
relevant in the fetus because it has a
proportionally large ecf compartment.
As illustrated in Figure 5, BDecf is
typically 1 to 2 mmol/L lower than
BDblood in arterial cord blood, and BDecf
and BDblood vary with gestational age.23
The different calculation equations in
different brands of blood gas analyzers
further complicate the interpretation
and comparison of BD values. Figure 5
shows an example of difference in
ajog.org
BDecf algorithms, but also with different
BDblood algorithms the difference might
be approximately 2 mmol/L (Figure 6).
A well-established equation21,23 for
calculating BDecf in cord blood speci-
mens is:
BDecf ¼  0:9149 ð0:23  pCO2
 10½pH6:1  24:1 þ 16:21
 ½pH  7:4Þ;
which is based on the fundamental acid-
base chart by Siggaard-Andersen.27
When reporting BD in obstetrics, it is
important to define which type of BD
compartment and which equation is
used. Some do, like the Danish Society of
Obstetrics and Gynaecology,30 but un-
fortunately some do not, like the Inter-
national Cerebral Palsy Task Force31 and
the American College of Obstetricians
and Gynecologists (ACOG).32
To illustrate the importance of BD
type, a case of medical litigation is pre-
sented. A woman at term had fetal sur-
veillance with cardiotocography (CTG)
combined with fetal electrocardiogram
ST analysis (STAN).9 The system alarmed
for an ST event, but because the CTG
pattern was classified as intermediary/
suspicious and not pathologic, the ST
event was judged not significant and labor
was allowed to continue. There was no
further deterioration of the CTG pattern.
At delivery the cord blood gas values were:
Artery pH ¼ 6:9; pCO2 ¼ 14:3 kPa;
BDblood ¼ 22:6 mmol=L;
Vein pH ¼ 7:13; pCO2 ¼ 6:4 kPa;
BDblood ¼ 15:3 mmol=L:
For practitioners unskilled in perinatal
acid-base interpretation and unfamiliar
with the difference between BDblood and
BDecf, this may seem to indicate a clear
case of metabolic acidosis when defined
as cord artery pH <7.0 and BD 12.0
mmol/L,32,33 and thus the obstetrician
was subjected to a malpractice suit.
However, there are 2 important obser-
vations: a high arterial pCO2 and a large
difference between arterial and venous
Expert Review
FIGURE 5
Base deficit estimation in umbilical cord blood is influenced by
gestational age, choice of fetal fluid compartment, and algorithm for
calculation
Gestational age-dependency of umbilical artery BDblood and BDecf in blood gas analyzers with
different calculation algorithms (N¼28,213, 5-minute Apgar score >8). Mean values with 95%
confidence intervals are indicated. The lower (line in red) represents the BDecf equation presented in
this article (provided in the text), derived from the Siggaard-Andersen Acid Base Chart.27
BDblood, base deficit in blood; BDecf, base deficit in extracellular fluid.
(Figure simplified from Wiberg et al).23
Olofsson. Umbilical cord blood pH, blood gases, and lactate. Am J Obstet Gynecol 2023.
pH, implying a considerable influence of acidosis, and the obstetrician was
respiratory acidosis. acquitted of malpractice.
Because BDblood is not the STAN Given that arterial cord blood is
standard for defining metabolic acidosis effectively cleared from an excess of fetal
in the newborn,9,26 the BDecf values were CO2 when passing through the
calculated post hoc by using the pH and placenta,21 venous BDecf values are not
pCO2 values in the STAN-stipulated reliable for assessing metabolic acidosis.
BDecf equation presented above, with Because of a lower venous than arterial
the following results: pCO2, the metabolic component is
overestimated in venous blood, as
demonstrated in the presented case.
Artery BDblood ¼ 22:6/
BDecf ¼ 10:5 mmol=L;
Umbilical cord blood gas and lactate
reference values
Vein BDblood ¼ 15:3/
Many authors have addressed the issue of
BDecf ¼ 11:6 mmol=L: normal cord blood gases, but there is no
global consensus on the definition.
The transformation from BDblood to Cutoffs for pH abnormality have in
BDecf illustrates the influence of respi- research and clinical practice varied
ratory acidosis on different types of BD from 7.20 to 7.00. At a pH <7.20, 7% to
values. An arterial pH of 6.9 combined 9% of newborns will be deemed acide-
with a BDecf of 10.5 mmol/L did not mic despite most being vigorous.34e38
fulfill the criteria of neonatal metabolic With a limit of <7.10, the incidence
MAY 2023 American Journal of Obstetrics & Gynecology S1227
Expert Review ajog.org

different sizes and quality, there is thus

FIGURE 6
robust evidence that the statistically
Reciprocal differences for different BD calculation algorithms at a value defined limit for cord artery acidemia
of 12.0 mmol/L after labor with uterine contractions is a
pH of 7.10 in the cord artery when the
definition of mean 2 SD is used. In
most studies 1 SD was equal to 0.07.
Given that a mixed metabolic and
respiratory acidemia develops in cord
arterial blood according to the length of
labor,21 these normal range reference
values might not be valid for elective ce-
sarean deliveries (CD). During the pro-
cess of preparing for and performing a
CD, factors such as type of anesthesia,
extent of sympathetic blockade, aorto-
caval compression, intravenous fluid
loading, oxygenation, vasopressor sub-
stances, and predelivery knife-time could
influence the neonatal acid-base status.
Because spinal anesthesia is consid-
ered more practical and safer for the
mother than general anesthesia at CD,
it is believed to be safer also for the
newborn. However, in a meta-analysis
comprising 27 studies reporting
neonatal acid-base data with different
types of anesthesia, Reynolds and
Seed46 found that spinal anesthesia was
associated with a higher degree of fetal
metabolic acidemia than was either
general or epidural anesthesia (EDA).
Distribution of BDblood values (N¼15,354) when calculated with BDblood algorithms described in the From data presented in the article and
Radiometer ABL700 manual28 and by the CLSI.29 Reciprocal differences between the BDblood cutoff including the 24 studies with arterial
at 12.0 mmol/L are illustrated. data, the meanSD cord artery pH can
BDblood, base deficit in blood; CLSI, Clinical and Laboratory Standards Institute. be calculated to 7.2530.062 (N¼527)
(Modified from Mokarami et al).24 for CD with spinal anesthesia, to
Olofsson. Umbilical cord blood pH, blood gases, and lactate. Am J Obstet Gynecol 2023. 7.2740.049 (N¼1203) with general
anesthesia, and to 7.2690.053
(N¼630) with EDA (P.O.: processing
ranges from 1% to 3%, and with a cutoff corresponded to approximately 7.10 in article data by StatView computer
of <7.00 it ranges from 0.26% to the artery and 7.20 in the vein. In a study software [SAS Institute, Cary, NC] with
1.3%.38e42 of 23,016 births from our hospital, the the sizes of the individual studies
A cutoff of <7.05 has been used by Skåne University Hospital (Malmö and weighted). Larger doses of ephedrine
Westgate et al,43 which in their compa- Lund, Sweden), where cord pH mea- could explain the difference between
rably small series of 1448 deliveries cor- surements have been routine since 1981, spinal and EDA.46 Reynolds and Seed46
responded to the 2.5th percentile, but in the mean arterial pH was 7.28 and the concluded that spinal anesthesia could
a series of 23,016 cases published by mean 2 SD limit was 7.10.44 Finally, in not be considered safer for the fetus
Herbst et al,44 it corresponded to the 1st a compilation of 26 studies of various than the other methods, stating that
percentile. quality, published from 1964 to 2004 and neonatal welfare cannot be included
In a compilation of 5 studies by with 61 to 24,390 deliveries, the Danish among the several good reasons to use
Armstrong and Stenson,45 the mean Society of Obstetrics and Gynaecology spinal anesthesia for CD.
arterial pH ranged from 7.24 to 7.27 and calculated a mean pH value of 7.26 and a No study on normal reference values of
the mean venous pH from 7.32 to 7.34. mean 2 SD value of 7.10.30 cord artery pH at elective CD in an un-
The statistically defined lower limit of From these and the other studies selected population could be found in the
mean -2 standard deviations (SD) mentioned, from different eras and of literature. In a population-based series

S1228 American Journal of Obstetrics & Gynecology MAY 2023

ajog.org
collected from 2001 to 2010, of the 2639
elective CDs from our hospital, the
meanSD cord artery pH was
7.2890.056 (P.O.; unpublished data).
Incomplete data on anesthesia methods
hindered further analysis, but the domi-
nant anesthesia method for elective CD
during the period was EDA. Considering
data from small and large series with
different types of anesthesia, the
meanSD of cord artery pH at elective
CD can thus be estimated to
7.25e7.290.05e0.06. Given that spinal
anesthesia is dominant today, a practically
useful lower normal limit (mean 2 SD)
would be a pH of 7.13, which may seem
surprisingly close to the lower limit of
7.10 in all other births except elective CD,
but the difference represents in fact a 7%
difference in [Hþ] (calculated from tables
by Fiorica19).
A statistically defined lower pH limit is
not necessarily in agreement with a
biologically critical limit. A general bio-
logically critical pH limit seems difficult
to establish because the pH for optimal
enzymatic activity varies between
different cell types.
A possible arousal effect of a slightly
lowered pH (and a respiratory drive of
high pCO2) was recognized already in
1958 by James et al.47 Actually, at a
moderate degree of cord artery acidemia
but with pH maintained >7.00, Svirko
et al48 found an inverse relation between
pH and childhood literacy and intelli-
gence. Such a possible neuroprotective
adaptation to moderate acidemia has
also been reported by others.49,50
The ACOG and the American Acad-
emy of Pediatrics advocate a clinically
relevant cutoff limit for severe arterial
acidemia at pH <7.00 and BD 12.0
mmol/L.32,51 Recalculating 7.00 to SDs
would correspond to slightly more than
3 SD below the mean value, or approxi-
mately the 0.14th percentile. Thus, only
14 newborns per 10,000 would suffer
severe acidemia.
Gestational age-dependent changes
in cord blood gases and lactate
Several other factors than anaerobic
metabolism influence cord blood gas
and lactate values, such as the maternal
condition, temperature, gestational age,
fetal body mass, mode of delivery, length
of labor, obstetrical intervention, infec-
tion, etc.21,45,52 In practice, adjustments
are realistic only for mode of delivery
and gestational age.
In cord blood obtained at cordocent-
esis or fetoscopy, it has been shown that
cord blood gases change with the pro-
gression of pregnancy.53,54 Nicolaides
et al55 demonstrated that in both the
artery and vein, pH and pO2 decrease
and pCO2 increases with advancing
gestational age, whereas the lactate con-
centration does not change. In cord
blood sampled at birth, pH and bicar-
bonate decrease and pCO2, BDecf, and
lactate increase with the progression of
pregnancy.21,56e58 The changes occur in
both the artery and vein, with the
exception of venous pCO2 because the
surplus of CO2 from the fetus in the cord
artery is cleared by the placenta.21 Thus,
the clearance of CO2 is not affected in
normal pregnancy by any “ageing
placenta,” not even in the postterm
period.21
We have in large population-based se-
ries of cord blood gas and lactate de-
terminations defined the normal ranges
for arterial cord pH,56,58 venous cord
pH,58 arterial and venous BDecf,23 and
arterial and venous lactate57 relative to
gestational age. Both arterial and venous
pH decrease linearly with the progression
of pregnancy, and arterial and venous
BDecf and lactate increase linearly.
In a population-based study
(N¼24,390), we found that the mean -2
SD pH values at 37, 40, and 42 weeks’
gestation were 7.10, 7.08, and 7.06,
respectively.56 The SD over strata was
0.07. If a stationary pH cutoff at 7.10 was
applied to these gestational age-adjusted
reference cutoffs, the acidemia diagnosis
would be false-positive in 25% of term
neonates and 35% of postterm neonates.
In another study (N¼18,584), we found
that the 2.5th percentile values (which is
close to but not identical to mean 2
SD) at 37, 40, and 42 weeks’ gestation
were 7.11, 7.10, and 7.09, respectively.58
For cord arterial BD, it is not possible
to establish reference values based on
statistics because BD is calculated by
different equations in different blood gas
analyzers and fetal compartments.23
MAY 2023 American Journal of Obstetrics & Gynecology
Expert Review
However, different curves run parallel
to each other relative to gestational age
(Figure 5), and the same equation can
therefore be used to describe all courses:
BD ðmmol=LÞ ¼ 4:288 þ 0:0319
 ðGA  280:0905Þ;
where GA denotes gestational age in
days. This equation can be used to
compare BD values of different gesta-
tional ages.
Likewise, the linear courses of cord
artery pH56 and lactate57 can be
described:
pH ¼ 7:238 þ ð  0:00096
 ½GA  280:1Þ;
Lactate ðmmol=LÞ ¼  0:1533 þ GA
 0:002799:
Lactate increases linearly with
advancing gestational age from 34 to 35
weeks’ gestation onward in both the cord
artery and vein (N¼10,169).57 It is thus
not possible to define any stationary
cutoff value for abnormal values over
gestational age strata. At 39þ3 weeks, the
mean þ2 SD value was 9.8 mmol/L, and
at 40þ3 weeks it was 10.2 mmol/L.57
Thus, it is reasonable to set the statisti-
cally determined cutoff at 10 mmol/L for
a gestation at 39 to 40 weeks. Corre-
spondingly, it would be 9 mmol/L at 37
weeks and 11 mmol/L at 42 weeks.
In a study of 13,735 deliveries, we
assessed the accuracy of arterial lactate,
pH, and BD in reflecting low 5-minute
Apgar scores and hypoxic-ischemic en-
cephalopathy (HIE) stages 2 to 3.59 The
gestational age-adjusted reference stan-
dards were compared with stationary
reference values, where the optimal
cutoffs were determined by receiver
operating characteristic curves (ROCC).
Gestational age-adjusted values were
significantly better than the stationary
ROCC-optimal values for all blood gas
and lactate parameters in indicating an
Apgar score <7, but for Apgar score <4
there were no significant differences. It
was pointless to perform statistical ana-
lyses for HIE because there were only 6
S1229
Expert Review
neonates with HIE stages 2 to 3
(0.046%); only 3 of them had a pH
<7.10 and none a pH <7.00.
The ACOG Committee on Obstetric
Practice32 has advocated umbilical cord
blood gas analyses in selected cases
where metabolic acidosis is defined as a
cord artery pH <7 and BD 12 mmol/L.
At a BD of 12 to 16 mmol/L, 10% of
newborns will develop moderate or se-
vere encephalopathy or respiratory
complications, and at >16 mmol/L this
figure is 40%. Low et al33 have concluded
that the threshold for metabolic acidosis
associated with moderate or severe
neonatal complications is 12.0 mmol/L.
However, Low as well as ACOG and
several other organizations failed to
mention from which fetal compartment
(blood or ecf) their BD calculations
stem. As discussed elsewhere in this re-
view and illustrated in Figures 5 and 6,
the difference could be up to 2 mmol/L
between BDblood and BDecf, but also
between different BDblood equations
(Figure 6), which could be decisive for a
positive or negative diagnosis of neonatal
metabolic acidosis.
How to validate the origin of cord
blood samples
Given that the blood gas content is
different in arterial and venous cord
blood, it is necessary to validate the
origin of the samples. Arterial cord
blood matches the condition of the fetus
and newborn best. There is a risk of mix-
up of the samples at sampling, labeling,
or at analyses, or the same cord vessel
might be sampled twice.
Because a lower pH in the cord vein
would be unphysiological, the venoar-
terial pH gradient, denoted DpH, is used
to validate the samples and confirm their
correct origins. After the original intro-
duction by Westgate et al,60 a DpH<0.02
is commonly used to deem the samples
unreliable,61 where 0.02 corresponds to
the 5th percentile in large population-
based materials.60,62,63 Five percent of
potentially correct arterial values are
thus rejected to avoid interference with
venous values.
However, in a large population-based
series (N¼37,763), White et al61 found
that the 5th percentile value of DpH was
S1230 American Journal of Obstetrics & Gynecology MAY 2023
0.01, and the small difference between
the 0.02 and 0.01 cutoffs resulted in a
sample rejection difference of 2.2% of
paired samples. The pH electrodes in
blood gas analyzers have a “standard
default electrode drift tolerance,” which
is 0.020 for the analyzers that we used
(Radiometer, Copenhagen, Denmark),63
that is, it is equal to the DpH cutoff limit.
Considering the findings in their study,
the magnitude of electrode drift, and the
instability in the electrode calibration
solution, White et al61 concluded that a
DpH of <0.01 should be used for vali-
dation. In practice that means that only
when DpH is 0 or negative the samples
should be discarded.
In their pioneering study, Westgate
et al60 advocated that both DpH and
arteriovenous DpCO2 should be
included as validation criteria. They
advocated a validation cutoff of DpCO2
at 0.5 kPa (3.75 mm Hg), which corre-
sponded to their 10th percentile. The
10th percentile was chosen because of a
higher instability in the pCO2 electrode
than in the pH electrode. In the series of
White et al,61 the 5th percentile corre-
sponded to a DpCO2 of 0.027 kPa (0.2
mm Hg).
White et al61 explored the impact on
rejection rate with different published
validation criteria of DpH and DpCO2
and calculated that in their series of
29,874 consecutive paired samples, be-
tween 10% and 27% of cases would be
rejected. It can be discussed whether
such high rejection rates are tenable, and
whether it is the blood sampling tech-
nique or the validation criteria that are
most inappropriate.
We explored in a study of 27,233 de-
liveries with paired cord blood samples
the possibility of using not only DpH
and DpCO2 as validation tools, but also
DpO2 and Dlactate.63 We found that the
only undisputed validation tool is DpO2
because the fetus cannot produce O2.
Arteriovenous Dlactate cannot be used
at all because 35% of values are either
negative or null. We also concluded that
double validation with both DpH and
DpCO2 is not needed because the dif-
ference between DpH alone and DpH
combined with DpCO2 is small; DpH
validation alone is enough.
ajog.org
Effects of delayed cord blood
sampling and sample analysis on
acid-base and lactate values
The practice of delaying cord clamping to
improve Hb concentrations and iron
stores in infants64 will distort pH and
other blood gas parameters toward acid-
emia, hypercapnia, and lacticemia
(Figure 7).65,66 Because the fetal circula-
tion is centralized during labor to ensure
sufficient O2 delivery to the brain, heart,
and adrenals, the perfusion of low-
priority organs such as the lungs,
carcass, and peripheral tissues is
concomitantly reduced. This is a normal
physiological phenomenon and is recog-
nized as acrocyanosis in the newborn,
with bluish hands, feet, and earlobes
persisting for hours after birth. Acidic
metabolites accumulated in peripheral
tissues during labor surge into the central
circulation when the peripheral circula-
tion is restored as the newborn starts to
breathe, cry, and move. Because of such
“hidden acidosis” occurring within a few
seconds after birth, the values of pH and
bicarbonate decrease and pCO2, pO2, BD,
and lactate increase in still pulsating cord
arteries.65,66
The hidden acidosis phenomenon
complicates the interpretation of cord
blood gases if cord sampling is delayed,
and initially normal blood gas values may
falsely be judged abnormal when capil-
laries in low-priority organs and tissues
open and trapped acidic metabolites flood
into the circulation. As expected, the
change is more pronounced in vigorous
than in depressed newborns because the
cardiac action and cord flow is stronger.66
As a routine, the ACOG recommends
delayed cord clamping by 30 to 60 seconds
after birth, and the National Institute for
Health and Care Excellence recommends
1 minute.67,68 As evident from Figure 7,
already a 30-second delay will change the
blood gas values considerably.
To solve the dilemma of early cord
clamping (with accurate blood gas de-
terminations) vs late cord clamping (with
better infant Hb and iron stores but risk of
falsely acidemic cord blood gas values), we
advocate a sampling technique with nee-
dle puncture of intact cord vessels imme-
diately after birth, and delayed clamping.
The immediate puncture technique might
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need an extra hand but improves the

FIGURE 7
sample quality with fewer erroneous
samples and a decrease in the proportion
Hidden acidosis: acidic metabolites trapped in peripheral tissues flood
of single-vessel samples.66 We compared
into cord blood after birth
the different sampling techniques between
our maternity units in Malmö and Lund,
with early cord clamping having been
practiced in Malmö and immediate cord
vessel puncture in Lund, and we found
that the proportion of unphysiological
negative venoarterial DpO2 was 32.2% in
Malmö and 7.5% in Lund. Given that
DpO2 cannot be negative, this suggests a
flawed sampling technique in Malmö with
a high proportion of delayed samples.
The time elapsing from sampling to
analysis could influence the measured
values of blood gases and lactate. Changes of umbilical cord blood gases and lactate when blood sampling is delayed with maintained
Whether blood is kept in a syringe or in a flows in arteries and vein. Note that artery and vein scales are not similar.
double-clamped piece of the umbilical HCO3, bicarbonate; pCO2, partial pressure of CO2; pO2, partial pressure of O2.

cord, the blood cell metabolism con- (Modified from Wiberg et al).65

tinues in the sample, and pCO2 and Olofsson. Umbilical cord blood pH, blood gases, and lactate. Am J Obstet Gynecol 2023.

lactate can then increase and pH and pO2

decrease.69e72 In cord segments, the
metabolism in vascular endothelial cells
also contributes considerably.68
Conversely, there are several studies
showing that in double-clamped cords
kept in room air, no statistically signifi-
cant changes in pH, pO2, pCO2, and BD
occur up to 40 to 60 minutes after
sampling.69,73e75 However, some of
these studies should be interpreted with
caution because they are small, with a
risk of type II errors, and the statistics
used were not always adequate. The
manufacturer of the Radiometer blood
gas analyzers that we used recommends
analysis within 30 minutes,72 but some
researchers have shown significant
changes occurring earlier, with a drop in
pH of 0.05 after 30 minutes.70,76 It is thus
reasonable to postpone analysis for no
longer than 15 minutes after sampling.
Because of continuing anaerobic
glycolysis in blood cells and vascular
endothelial cells, lactate is particularly
sensitive to delayed analysis,71 and more
so if the cord is not clamped and isolated
from the placenta.69 A remaining vascular
connection with the placenta results in a
considerable lactate contribution even
ex vivo. In double-clamped cords, the
arterial lactate concentration increases
linearly with time, and a 10-minute delay
of analysis will result in an approximately
0.6 mmol/L higher value, irrespective of
mode of delivery and initial value.69,71 A
reliable lactate analysis must therefore be
performed immediately after delivery
even if the cord is double-clamped.
Furthermore, when the blood is
collected and stored in syringes, the
lactate level increases significantly within
5 minutes unless the syringe is placed in
an ice slurry,77 where the lactate level re-
mains constant for up to 20 minutes.
Routine analysis of umbilical cord
blood gases and lactate
The research and clinical interest in hu-
man cord blood gases goes back to at least
the 1920s.47,78 In 1958, James et al47
recognized the value of umbilical cord
blood gases in evaluating the newborn.
Starting in 1962, Saling used cord blood
gases as outcome measures in high-risk
cases, and from 1970 as a routine.79 In
connection with Saling’s introduction of
fetal scalp blood sampling (FBS) for pH
determination during labor,80 a pH-meter
became standard at many maternity units
using FBS, and it then became easy to also
sample and analyze cord blood.
Routine umbilical cord blood sam-
pling with determination of arterial and
venous pH was implemented at the
Skåne University Hospital in Malmö in
1981, and since several years ago it has
been routine in most hospitals in Swe-
den. Comparative hospital statistics on
low arterial pH are included in the
annual national pregnancy report: for
example, in 2014 cord artery pH was
determined on average in 82% of de-
liveries (range, 17%e98%; median,
91%), with a mean incidence of pH
<7.00 of 0.56% (range, 0.16%
e1.26%).81 However, a low testing rate
and high incidence of acidemia at many
hospitals indicate that cord blood gases
are still tested selectively.
The ACOG Committee on Obstetric
Practice32 has advocated that a segment of
the umbilical cord be double-clamped
immediately after delivery in all de-
liveries, and that the cord segment be
discarded if the 5-minute Apgar score is
satisfactory and the newborn is vigorous.
Arterial and venous blood gas de-
terminations should thus be limited to
selected cases, such as CD for fetal
compromise, low 5-minute Apgar score,
severe FGR, abnormal CTG, maternal
thyroid disease, intrapartum fever, and
multifetal gestation.32 However, by selec-
tive determinations several important
benefits of routine analyses will be wasted.
The purpose of routine cord blood
analysis is multiple: to enable perinatal

MAY 2023 American Journal of Obstetrics & Gynecology S1231

Expert Review
audit and gain the wisdom of hindsight,
to maintain quality assurance at a ma-
ternity unit by following the rate of
neonatal acidosis over years, to compare
results with those of other clinics on
regional or national bases, and to obtain
an objective outcome variable in clinical
research. Malin et al82 found in an
extensive review and meta-analysis that
the odds of neonatal complications
with fetal acidemia were high in an un-
selected population (for mortality higher
than in a high-risk population), which
implies that cord blood gas determina-
tion should not be limited to high-risk
cases.
The case presented above demon-
strates that cord blood gases are essential
in perinatal audits. However, White
et al83 did not find among Australian
doctors and midwives an overwhelming
enthusiasm for routine cord blood gas
analyses: 60% to 70% considered it
beneficial to perinatal care, and regarded
it as an objective marker of neonatal
status, valuable in medicolegal issues,
audit, and teaching, whereas 8% believed
it had no relevant place in perinatal care.
The main barriers were insufficient time
for blood sampling following delivery,
increased workload, and encroachment
of technology into the birth process.
White et al84,85 also evaluated the
impact of introducing routine umbilical
cord blood gas analyses on perinatal
outcomes and costs. Independently of
obstetrical interventions, the imple-
mentation of routine cord blood ana-
lyses resulted in a progressive
improvement in blood gas and lactate
values and perinatal outcomes at their
maternity unit, which they attributed to
the learning from fetal acid-base data
and the subsequent influence on intra-
partum care.84 Universal analyses were
more cost-effective than selective ana-
lyses, and the incurred costs were
exceeded by the savings with fewer ad-
missions for special neonatal care.85
Some obstetrical staff mistrust routine
cord blood gas analysis because it could
be a powerful tool for lawyers in lawsuits.
However, as illustrated by the case pre-
sented above, cord blood gas determi-
nation at birth might be helpful rather
than detrimental in such cases.
S1232 American Journal of Obstetrics & Gynecology MAY 2023
The Table illustrates our belief: without
blood gases liability for malpractice is
probable in cases of neonatal birth injury
when there are undesirable CTG patterns.
Pathologic cord blood gases will then
probably make little difference for the
jurisdiction. However, CTG is an uncer-
tain proxy for fetal hypoxia, and there is
not a strong correlation between patho-
logic CTG traces and fetal acidosis.86 CTG
has a high false-positive rate, and the
blood gases might be unaffected or only
moderately affected despite a pathologic
CTG trace, which would then refute a
severe intrauterine hypoxia. Not more
than 10% of cerebral palsy (CP) cases are
owing to intrapartum events.31 Without
cord blood gases it is difficult to objec-
tively prove deleterious intrapartum
hypoxia.
This discussion is not new. Thorp
et al87 implemented routine cord artery
pH determinations in 1986 and stated
when publishing their experience in
1989 that “cord artery pH is extremely
useful in ruling out birth asphyxia in the
depressed newborn.” They pleaded for
routine analysis also in vigorous
newborns.
Figure 8 illustrates a battery of
outcome variables of “standard
primiparae” at the Skåne University
Hospital in Malmö compared with
those of 8 other hospitals in our region.
Many outcomes were significantly bet-
ter and a few worse than in other
hospitals. Although the correlation be-
tween pH and Apgar score is weak,52,88
the contradiction between a signifi-
cantly higher rate of arterial pH <7.10
but a significantly lower rate of 5-
minute Apgar score <7 at our hospital
made us suspicious about the relevance
of the pH determinations. After inves-
tigation, we found a decisive error in
the reporting: the chief neonatologist
had decided that cord arterial pH values
<7.15 should be followed-up by a
neonatal heel capillary sample, which
upset many midwives and led to
omission of cord blood sampling in fit
and vigorous newborns. Our pH data
were thus biased toward proportionally
more acidotic values because of delayed
sampling65,66 and selective testing with
proportionally more affected newborns.
ajog.org
Single cord vessel blood gas
determination
It frequently happens that blood from
only 1 cord vessel is obtained. This can
happen in situations of stress or of fetal
compromise with small amounts of
blood left in the cord. It can also happen
when the cord is clamped late. Because
the vein is larger than the arteries and
easier to puncture, it is a common belief
that single-vessel blood samples more
often contain venous blood.
We found in a population-based study
of 76,710 cord samples that 16% were
single-vessel samples, with 7% labeled
artery and 9% labeled vein (P.O.; unpub-
lished data). This is in accordance with the
rate of 14% of single-vessel samples re-
ported by White et al.61 In our material,
the single-vessel samples showed signifi-
cantly less acidemia, hypercapnia, and
lactemia than vessels in paired samples,
suggesting no overrepresentation of hyp-
oxic newborns among cases with single-
vessel samples. However, the compari-
sons were confounded by shorter pushing
time, more spontaneous vaginal de-
liveries, and lower birthweight in the
single-vessel group, all pointing toward
less affected blood gases and lactate.
Association between neonatal
acidosis and short- and long-term
outcomes
The International Cerebral Palsy Task
Force has stated that >75% of neonates
showing encephalopathy have no clinical
signs of intrapartum hypoxia.31 Con-
trary to common beliefs and assump-
tions, most cases of CP originate from
the antenatal or postnatal period of
life.31,86 Epidemiologic studies suggest
that in approximately 90% of CP cases
an intrapartum hypoxia could not be the
cause. The International Cerebral Palsy
Task Force states that a realistic cutoff to
define pathologic acidemia is arterial pH
<7.00 and BD >16 mmol/L. In cases of
BD <12 mmol/L or arterial pH >7.00,
an acute intrapartum hypoxia is unlikely
to be the cause of CP.31
The continuum of casualty of no, mild,
moderate, or severe intrapartum hypoxia
or asphyxia has been addressed by
Handley-Derry et al,89 who in a case-
control study followed up children with
ajog.org
mild intrapartum hypoxia (BD >12
mmol/L, but no or only mild cerebral ir-
ritability) until the age of 4 to 8 years. No
differences between the groups were
found in motor or cognitive development
or in memory ability. Likewise, Hafström
et al90 in a case-control study found that
neonates who had metabolic acidosis (pH
<7.05, BDecf >12 mmol/L) at birth but
appeared well had no increased risk of
neurodevelopmental impairments at the
age of 6.5 years. Furthermore, among
children in the control group who showed
neurodevelopmental impairments, none
had had signs of intrapartum asphyxia
(normal Apgar score, arterial pH, and
BDecf ), neonatal encephalopathy, or need
of neonatal care.
Ruth and Raivio91 elucidated why
metabolic acidosis at birth is such a
poor predictor of perinatal brain
damage: the abnormal outcomes in
their study were not related to peri-
natal asphyxia although known ante-
natal risk factors were excluded. It is
therefore a self-fulfilling prophecy
that fetal intrapartum surveillance
methods, aimed to detect impending
severe hypoxia and metabolic acidosis,
will have a low sensitivity for CP.
Neonatal metabolic acidemia is
comparably common, occurring in
approximately 2% of all deliveries, and
fortunately a vast majority of neonates
do not develop CP.31,89 Among acide-
mic newborns, approximately 6% will
develop neonatal encephalopathy.92,93
Malin et al82 performed a thorough
analysis of the predictive value of fetal
acidemia with regard to poor perinatal
and long-term outcomes. In a meta-
analysis of 51 articles with 481,753 in-
fants, they found a strong, consistent, and
temporal association between low um-
bilical cord pH and poor outcomes. Fetal
acidemia was associated with increased
risks of neonatal mortality, HIE, cerebral
intraventricular hemorrhage, periven-
tricular leukomalacia, and CP. The au-
thors also explored the threshold effect on
mortality: threshold effects were found at
pH <7.10 and <7.20, but not at <7.00.
However, the only study exploring all 3
thresholds found the strongest association
at 7.00.94 Because of the small number of
studies reporting CP, it was not possible in
TABLE
Routine umbilical cord blood gas determination might help the defendant
in cases of medical litigation
Intrapartum
cardiotocography
Pathologic
Pathologic
Pathologic
Olofsson. Umbilical cord blood pH, blood gases, and lactate. Am J Obstet Gynecol 2023.
the Malin study to explore the threshold
effect on CP.82
The association between low pH and
mortality was stronger in the unselected
population than in the high-risk popu-
lation, which Malin et al attribute to
the diluting effect of factors such as
prematurity and low birthweight in the
high-risk group.82 Among 322 children
born extremely preterm (at 22e26
weeks’ gestation), we found no associa-
tion between acidosis at birth and risk of
death or neurodevelopmental impair-
ment at the age of 6.5 years.95
In an unselected series of 29,787
newborns by Johnson et al,88 7 neonates
(0.07%) underwent hypothermia treat-
ment for presumed intrapartum
hypoxia-ischemia, but 3 of them had a
cord artery pH >7.15. Such a poor
agreement between cord blood pH and
clinical signs of encephalopathy was also
demonstrated in our own unselected
series of 13,735 newborns, where alto-
gether 6 neonates (0.046%) developed
HIE stages 2 and 3 despite all of them
having a cord artery pH >7.00.59
In conclusion, and as stated by the
International Cerebral Palsy Task
Force,31 a vast majority of neonates with
metabolic acidosis at birth do not
develop CP.
Association between Apgar score
and cord blood pH
After the introduction of the Apgar
scoring system in 1953 by Virginia
Apgar,96 obstetricians and pediatricians
began using the system not only as a
neonatal evaluation and outcome
parameter, but also as an index in lon-
gitudinal studies for assessment of
asphyxial damage in infancy. However, it
MAY 2023 American Journal of Obstetrics & Gynecology
Expert Review
Arterial cord blood pH
and base deficit Probable outcome
Missing Conviction
Pathologic Conviction
Normal Possibly acquittal
was soon recognized that low Apgar
scores and later neurologic impairments
are not always coherent,31,97,98 and that a
low Apgar score alone should not be
interpreted as evidence of intrauterine
asphyxia.99
A Norwegian study of >500,000 de-
liveries showed a strong association be-
tween low 5-minute Apgar score and
CP.100 Among children with Apgar score
<4, over birthweight strata 10% to 17%
developed CP. Given that the link be-
tween Apgar score and perinatal
asphyxia is weak, the authors concluded
that “the causes of CP are closely linked
to factors that reduce infant vitality,”
implying contribution of factors other
than asphyxia. The degree of Apgar score
depression correlates inversely with the
risk of developing CP and epilepsy, but
the false-positive rate is high.51,101
The incoherence between Apgar score
and cord artery pH is well
established.52,59,88,91,97 In the prediction
of neonatal complications, van de Riet
et al102 in a meta-analysis found that a
cord artery pH <7.00 had the strongest
association with neonatal death, whereas
both a low Apgar score and a poor Sarnat
score had stronger associations with
development of CP.
The Apgar score is influenced not only
by intrauterine hypoxia but also by
neonatal maturity, FGR, maternal medi-
cations, congenital anomalies, etc., and it
is then no surprise that the congruence
between fetal acidosis and Apgar score is
rather poor. Ruth and Raivio91 found that
in a consecutive cohort of 899 term in-
fants, 9 showed neurodevelopmental dis-
ease or delay at the age of 1 year, but only
one had had a 5-minute Apgar score <4
and none of them a cord artery pH <7.15.
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Expert Review
FIGURE 8
Outcome parameters for comparative quality assurance in a maternity unit
Perinatal outcome of “standard primiparae” (age 20e35 years, normal pregnancy, spontaneous onset of labor) in Malmö (N¼4077) compared with 8
other hospitals in the southern region of Sweden (N¼14,594).
Olofsson. Umbilical cord blood pH, blood gases, and lactate. Am J Obstet Gynecol 2023.
Other biomarkers of fetal hypoxia
The O2 concentration in the body is
much lower than in the atmosphere, and
the normal mammalian development
occurs in a physiologically hypoxic
environment. The O2 concentration in
utero ranges from 1% to 5% (pO2,
0.5e30 mm Hg).103 In adult human
blood the O2 concentration is approxi-
mately 12%, and in tissues it varies: 0.5%
to 7% in the brain, 1% to 5% in the eyes,
4% to 12% in the liver, heart, and kid-
neys, and 3% to 5% in the uterus.104
Unphysiological hypoxia (<2% O2)
disturbs cell function and results not only
in shifted acid-base balance but also in cell
and organ dysfunctions with a spectrum
of physiological, biochemical, molecular,
and epigenomic alterations. Many acutely
evolving changes during labor are how-
ever too slow to be accordingly reflected in
increases of tissue injury markers occur-
ring already at birth.
Erythropoietin and nucleated red
blood cells
During erythropoiesis, erythroblasts
develop into normoblasts in the bone
marrow, whereafter the nucleus is
extruded and reticulocytes are formed
S1234 American Journal of Obstetrics & Gynecology MAY 2023
and released into the circulating blood.
The erythropoiesis ends with re-
ticulocytes losing the organelles, and
mature erythrocytes are then created.
Several physiological and pathophysio-
logical conditions stimulate the pro-
duction of erythropoietin (EPO) and
enhance a premature release of imma-
ture erythrocytes from the bone marrow,
called nucleated red blood cells (NRBC),
into the circulation.105
NRBC are normally found in fetal
blood, with a lowering number toward
term. The number of NRBC is reported
either as an absolute number per unit
volume, where the mean value in healthy
newborns is 500 NRBC/cmm (0.1% of
all RBC), and a value >1000 NRBC/
cmm is regarded elevated, or as NRBC
relative to 100 white blood cells.105 In the
latter expression, processes that increase
or decrease the leukocyte number will
then mislead the NRBC count.
Physiological processes that increase
the NRBC number are labor and
vaginal birth, and pre- and post-
maturity; pathologic processes are
chronic hypoxia (FGR, maternal
smoking, preeclampsia, diabetes melli-
tus, anemia), virus infections, etc.105
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However, the NRBC number increases
also after acute and subacute hypoxia
and chorioamnionitis.
Hypoxia accelerates transcription of
the EPO gene, with an activation of EPO
synthesis within 90 minutes and elevated
EPO levels occurring within 1 to 4 hours,
and subsequent emergence of NRBC
into the circulation within 24 to 36
hours.105e107 An increase of EPO and
NRBC in cord blood is thus a proxy for
fetal hypoxia, and the magnitude of in-
crease is related to the severity and
duration of hypoxia. However, there is a
large overlap between chronic, subacute,
and acute hypoxia, and there is a
considerable proportion of false posi-
tives and negatives.105
In a large series of fetal blood sam-
pling for prenatal diagnosis of mainly
toxoplasmosis infection, Forestier
et al108 found that EPO levels in umbil-
ical venous blood of healthy fetuses
remained stable during pregnancy. The
increase in EPO from midgestation to-
ward term observed in other studies
could be explained by the inclusion of
laboring women and complicated preg-
nancies. Teramo and Widness109 in a
review article stated that in
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uncomplicated pregnancies, the mean or
median fetal cord plasma EPO levels
range from 20 to 35 mU/mL before the
onset of labor, with an upper normal
limit ranging from 50 to 60 mU/mL.
Their Finnish research group defined the
upper normal limit as <40 mU/
mL.107,110
In another Finnish study, Rancken
et al111 found in a follow-up of 878
nonanomalous live newborns no signif-
icant difference in cord EPO concentra-
tions between children with and without
a neurodevelopmental diagnosis at an
age of 2 to 6.5 years. Only when they
divided their series into low (<20 mU/
mL), average (20e39 mU/mL, control
group), elevated (40e100 mU/mL), and
high (>100 mU/mL) EPO levels could
they demonstrate a significantly
increased risk of severe morbidity in the
high-level group compared with con-
trols. For minor neurodevelopmental
morbidity there were no significant dif-
ferences. The authors concluded that
cord blood EPO seems to be of low
clinical value.
Interestingly, exogenous EPO has a
potential therapeutic role in asphyxiated
neonates.112 EPO receptors are largely
expressed in the central nervous system,
where EPO inhibits apoptotic pathways,
reduces proinflammatory cytokines, and
dampens glutamate excitotoxicity.
It can be summarized that the role of
EPO as a marker of fetal hypoxia is
complex, and EPO and NRBC in cord
blood seem to be of limited value in
indicating intrapartum acute fetal hyp-
oxia because of the time it takes to acti-
vate EPO synthesis and release more
NRBC. Furthermore, the significance of
indicating acute hypoxia is often blurred
by chronic factors influencing fetal
oxygenation. A NRBC count in new-
borns should thus not be relied on as the
sole determinant of severity and dura-
tion of intrauterine hypoxia.105
Biological cell injury markers
Serious brain ischemia may lead to tissue
damage and cell death with leakage of
intracellular proteins to body fluids.
Increased amounts of biochemical brain
injury markers are used to diagnose and
predict injury in cases of trauma to the
head, stroke, subarachnoid bleeding,
meningitis, encephalitis, etc. in adults.
The significance of some markers has
been evaluated also in perinatal medicine.
S-100 is a dimeric protein with an a and
a b subunit, where the b subunit is brain-
specific, found in astrocytes (astroglia)
and Schwann cells. Protein S-100b
(S100B) is released mainly from glial cells
in response to neuronal injury and is
detectable in fluids such as urine, cere-
brospinal fluid, blood, and amniotic fluid.
The concentration of S100B is associated
with the severity of neuronal injury, which
has led to a special interest in S100B in
asphyxiated newborns. Several studies
have shown a direct relation between
neonatal S100B concentrations and the
severity of encephalopathy, but the pro-
tein has a half-life of only 30 minutes.113
Wirds et al114 collected arterial cord
blood from vigorous newborns imme-
diately after birth and found a higher
S100B after vaginal delivery than after
elective and emergency CD. We collected
cord blood immediately after birth and
compared it in a small series of severely
asphyxiated newborns (N¼13 with HIE
stages 2 and 3, follow-up to age of 6e7
years) with that of healthy controls
(N¼21) and found that the S100B con-
centration was related to the severity of
encephalopathy and the risk of devel-
oping permanent neurologic sequelae or
death.115 Furthermore, the S100B con-
centrations were elevated relative to cord
blood acidemia and the grade of pa-
thology of electroencephalograms.
Bouvier et al116 reported cord blood
S100B concentrations from 200 term and
183 preterm deliveries to establish normal
reference values. The material was not
population-based, however. In term neo-
nates the 95th percentile value corre-
sponded to 0.96 mg/L (median, 0.34 mg/L)
and for preterm neonates it was 1.36 mg/L
(median, 0.42 mg/L). The S100B concen-
tration was higher in vaginal deliveries
than in (unspecified) CDs, but after
adjusting for instrumental deliveries no
statistical difference remained.
Bouvier et al116 also investigated the
sensitivity and specificity of S100B in a
case group of 272 neonates admitted for
intensive care, where 11 neonates pre-
sented with neurologic complications. A
MAY 2023 American Journal of Obstetrics & Gynecology
Expert Review
ROCC showed an optimal cutoff value of
1.27 mg/L, resulting in a sensitivity of
46% and specificity of 89%. In combi-
nation with a cord artery pH <7.25 the
sensitivity increased to 91%, whereas the
specificity decreased to 51%. The ROCC
calculations resulted in areas under
curves (AUC) of 0.67 and 0.76, respec-
tively, which is not very impressive.
There is no globally defined threshold
for what should be considered a good or
excellent AUC, but Hosmer et al117 have
labeled an AUC of 0.5 to 0.7 as poorly
discriminatory and 0.7 to 0.8 as
acceptable.
Ubiquitin carboxyl-terminal hydrolase
L1 (UCH-L1) is a cytoplasmic enzyme
specific to neurons and concentrated in
dendrite cells, and glial fibrillary acidic
protein (GFAP) is an important cyto-
skeleton intermediate filament protein
specific to astrocyte cells. Both biomarkers
are released into the blood stream after
ischemic cell injury and disruption of the
bloodebrain barrier. Both biomarkers are
elevated in neonates with moderate to
severe HIE,118e123 but biomarkers in cord
blood sampled at birth have been studied
only rarely. We found in a series of neo-
nates with HIE stages 2 and 3 no differ-
ences in cord blood UCH-L1 and GFAP
concentrations relative to healthy con-
trols, and no associations of biomarker
concentrations with severity of disease or
with development of the condition into a
permanent or fatal injury.124
Lactate dehydrogenase (LDH) is a
cytoplasmatic enzyme that catalyzes the
reduction of pyruvate to lactate in essen-
tially all body tissues during anaerobic
glycolysis (Figure 4). LDH consists of 5
isoenzymes, but in clinical practice the
total LDH activity is measured. Extracel-
lular appearance of LDH indicates cell
damage or death. Owing to its widespread
distribution in the body, LDH is highly
sensitive but nonspecific, that is, it does
not mark neuronal damage specifically. It
has been suggested that LDH analysis
could be used to predict the need of hy-
pothermia treatment after intrapartum
asphyxia and predict the long-term
outcome,125e128 but temporal blood
sampling studies124,127 indicate that LDH
determined early in the course has low or
no predictive value. Lackmann and
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Expert Review
Töllner125 collected neonatal blood from
0 (cord blood) to 144 hours postpartum,
but only in the interval of 12 to 72 hours
could a significant difference in LDH ac-
tivity be demonstrated between neonates
with mild, moderate, or severe HIE and
the controls.
There is no significant difference be-
tween arterial and venous LDH con-
centrations in the cord, which eases
blood sampling and enables use of either
arterial, venous, or mixed blood.129 We
analyzed LDH in mixed cord blood of
neonates with moderate or severe HIE
and of controls and found that LDH was
associated with development and
severity of HIE, and with an intact sur-
vival or not (P.O., Karlsson M., Wiberg
N., Lundberg F.; unpublished data). The
relatively small overlap between controls
and HIE cases with sequelae or death
generated a hypothesis that LDH in cord
blood might be a useful biomarker for
high-risk cases.
Verspyck et al130 performed cordo-
centesis in 108 healthy fetuses (mainly
because of maternal toxoplasmosis sero-
conversion) and found a mean (SD) value
of 305 (47) U/L in venous blood, with no
correlation with gestational age. However,
the study was too small to be a normal
reference guide because the International
Federation of Clinical Chemistry and
Laboratory Medicine has recommended a
minimum sample size of 120 to determine
normal reference ranges.131
Some studies have reported median
LDH values but not distribution
data,132,133 making them insufficient as
normative references. Wiberg-Itzel et al129
sampled arterial and venous cord blood
consecutively from healthy women with
uncomplicated pregnancies at term. In the
total series (N¼549), the mean (SD) and
median (range) LDH values were 403
(100) and 396 (84e834) U/L in the cord
artery and 402 (97) and 390 (81e828) U/
L in the vein. The 97.5th percentiles cor-
responded to 612 and 636 U/L, respec-
tively. The difference between arterial and
venous blood was not statistically
significant.
The mode of delivery influences the
cord LDH concentration. Exposure to la-
bor contractions results in higher LDH
compared with elective CD,133 and
S1236 American Journal of Obstetrics & Gynecology MAY 2023
instrumental delivery and acute CD in-
crease it further.129
The normal reference values reported
by Wiberg-Itzel129 included cases with
hemolysis (>0.3 g/L free Hb in plasma),
which occurred in 30% of arterial and
21% of venous samples. Hemolysis is a
scourge in LDH analysis, however. Lippi
et al134 showed in a dilution experiment
that the LDH activity increases signifi-
cantly with the content of free Hb in the
samples and may exert a strong influence
on result reliability.
The 97.5th percentile cutoff at 612 U/L
was used by Wiberg-Itzel’s group to eval-
uate the impact of maternal disease on
cord artery LDH.132 Significantly higher
median LDH values were found among
women with chronic disorders (diabetes
mellitus, endocrine disease, epilepsy, kid-
ney disease, essential hypertension,
asthma) than among healthy women, but
the proportion of values >612 U/L was
not significantly increased. No difference
in cord artery LDH was found between
healthy women and women with
pregnancy-related disorders.
Equipment for point-of-care LDH
analysis is now available,135 but the role
of cord LDH in predicting HIE suc-
ceeding acute intrapartum hypoxia is yet
to be established.
Oxidative biomarkers
Neonatal brain injury associated with
HIE develops in mainly 3 phases, with a
primary O2 deprivation (0e6 hours:
mitochondrial dysfunction, primary
ATP depletion, cell necrosis, apoptosis,
oxidative stress, nitrosative stress), fol-
lowed by energy depletion (6e72 hours:
secondary ATP depletion, cell apoptosis,
lipid/protein/nucleic acid peroxidation,
microvascular damage, inflammation),
and finally reoxygenation (>72 hours:
free radicals, epigenetic changes,
inflammation, glial activation, decreased
neurogenesis).112 These reactions
contribute in generating harmful reac-
tive oxygen species (ROS) and reactive
nitrogen species, which interact with
proteins, nucleic acids, and membrane
lipids to produce free radicals. Specific
antioxidant enzymes are released to
counteract ROS, where an imbalance
results in oxidative stress.
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Martini et al112 have recently listed
current biomarkers of oxidative and
nitrosative stress. Such biomarkers are
antioxidant enzymes (superoxide dis-
mutase, glutathione peroxidase, catalase),
uric acid, nitric oxide, nonprotein-bound
iron, lipid peroxidation markers (malon-
dialdehyde, 4-hydroxynonenal, iso-
prostanes, neuroprostanes, neurofurans),
protein oxidation markers (protein car-
bonyls, advanced oxidation protein
products), and a DNA peroxidation
marker (8-hydroxydeoxyguanosine).
Among these, a few have been investigated
in cord blood: superoxide dismutase and
glutathione peroxidase are positively
related to HIE stages, and isoprostane 8-
iso-15(R)-PGF2a to severity of perinatal
asphyxia. Normal reference values for
cord blood are available for nonprotein-
bound iron (<6.91 mmol/L), isoprostane
8-iso-15(R)-PGF2a (<124.47 pg/mL),
and advanced oxidation protein products
(<80.39 mmol/dL).112 However, small
and heterogeneous studies and lack of
reference standards have so far hindered
the clinical validation of these markers.
Conclusions
Blood gases and lactate in the umbilical
artery are objective markers of fetal
hypoxia. Abnormal values are, however,
only proxies of intrauterine hypoxia and
have thus a limited value in predicting
long-term adverse outcomes. It has been
estimated that up to 90% of cases of CP
are not related to intrapartum hypoxia.
Cord blood is easy to sample but there
are several pitfalls in collecting the blood
and interpreting the test results. Unfor-
tunately, many authorities are unaware
of some of the most important pitfalls:
the risk of falsely abnormal values if the
blood sampling or analysis are delayed;
the physiological changes toward acide-
mic values with progression of preg-
nancy; BD being a theoretical measure
calculated by the blood gas analyzer and
not something it analyzes; BD calcula-
tion equations differing across analyzers,
and thus the possibility of BD values
differing by multiples across analyzers;
and the essential difference between BD
in blood and in extracellular fluid in
evaluating the respiratory component
(CO2) of acidosis.
ajog.org Expert Review

Routine blood gas determination at

GLOSSARY birth was introduced 50 years ago but is
still under debate. Routine instead of
ACOG American College of Obstetricians and Gynecologists selected measurements enable perinatal
ATP Adenosine triphosphate audit also in low-risk cases with unex-
AUC Area under curve pected complications, and they are
BD Base deficit invaluable in quality assurance. Blood
BDblood Base deficit in blood gas data can be compared over time and
BDecf Base deficit in extracellular fluid between maternity units on regional and
CLSI Clinical Laboratory Standards Institute national levels. Finally, in the era of high
cmm Cubic millimeter (mm3) medical standards and obligations of
CO2 Carbon dioxide evidence-based management, very large
CD Cesarean delivery research materials are needed to show
CP Cerebral palsy significant differences in rare adverse
CTG Cardiotocography, cardiotocogram outcomes, and routine umbilical cord
D Prefix illustrating a veno-arterial or arterio-venous gradient blood gases might then be helpful as
DeoxyHb Deoxygenated hemoglobin objective outcome measures. -
Ecf Extracellular fluid
ECG Electrocardiogram
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