CHAPTER 6
Acid-Base Homeostasis in
the Fetus and Newborn
Timur Azhibekov, MD, Istvan Seri, MD, PhD, HonD
6
• In Addition to the Buffering Systems, Fetal Acid-Base Homeostasis
Is Regulated by Maternal Respiratory and Renal Function and the
Immature Fetal Kidneys
• Fetal Acid-Base Homeostasis Affect Fetal Growth and May Have
Long-Term Consequences
• Certain Aspects of Obstetrical Management of Labor and
Delivery (e.g., Prenatal Steroid Administration or the Practice of
Delayed Cord Clamping) and Anesthesia During Labor and Delivery
Also Affect, Albeit Transiently, Fetal and Postnatal Acid-Base
Homeostasis
Introduction
This chapter addresses the regulation of fetal and neonatal acid-base balance with a
focus on the elimination of the acid load by the placenta, lungs, and kidneys, briefly
discusses the impact of acid-base disturbance on fetal and postnatal growth, and
describes the effect of selected obstetrical management approaches on fetal and
neonatal acid-base balance.
Hydrogen ion concentration is tightly regulated by the intracellular and extracellular buffer systems and respiratory and renal compensatory mechanisms. The normal
range of hydrogen ion concentration in the extracellular fluid is between 35 and
45 nEq/L (3.5–4.5 × 10−8 M), which translates to a pH range of 7.35 to 7.45 (pH =
−log10 [H+]). Under physiologic circumstances, volatile and fixed acids generated by
normal metabolism are excreted and the pH remains stable.1 Carbonic acid is the
most common volatile acid produced and is readily excreted by the lungs in the form
of carbon dioxide. Fixed acids, such as lactic acid, ketoacids, phosphoric acid, and
sulfuric acid, are buffered principally by bicarbonate in the extracellular compartment.
The bicarbonate used in this process is then regenerated by the kidneys in a series
of transmembrane transport processes linked to the excretion of hydrogen ions in
the form of titratable acids (phosphate and sulfate salts) and ammonium. Several
aspects of the regulation of acid-base homeostasis are developmentally regulated in
the fetus and neonate and thus differ from those in children and adults. These
developmentally regulated differences of acid-base homeostasis and their impact on
fetal and postnatal growth are reviewed in this chapter.
Regulation of Acid-Base Homeostasis
Respiratory Acidosis
Unlike in fetal respiratory acidosis, in postnatal respiratory acidosis, immediate
activation of the pulmonary compensatory mechanism leads to enhanced elimination
of carbon dioxide, and the resulting fall in carbon dioxide concentration increases
the pH toward normal (pH = [HCO3−] ÷ pCO2; where [HCO3−] = bicarbonate and
pCO2 = carbon dioxide tension). The rapid activation of the respiratory compensatory
85
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Acid-Base Homeostasis in the Fetus and Newborn
85.e1
Abstract
This chapter addresses the physiology and regulation of fetal and neonatal acid-base
balance at the cellular and organ system levels, with attention to the clinical relevance
of the complex interactions between the mother and the fetus ensuring the maintenance
of fetal acid-base homeostasis and the physiology of acid-base homeostasis in the
neonate following delivery. The physiologic processes regulating the elimination of
the acid load by the placenta, the lungs, and the kidneys are reviewed in more detail
along with the impact of acid-base disturbance on fetal and postnatal growth. Finally,
the effects of selected obstetrical management approaches on fetal and neonatal
acid-base balance are addressed.
Keywords
acid-base homeostasis
mother
fetus
neonate
respiratory acidosis
metabolic acidosis
maternal anesthesia
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Perinatal Mineral, Electrolyte, and Acid-Base Homeostasis
mechanism is a result of the free movement of carbon dioxide across the blood-brain
barrier,2 leading to instantaneous changes in cerebrospinal fluid (CSF) and cerebral
interstitial fluid hydrogen ion concentrations. The degree of maturity of the central
respiratory control system3 and pulmonary function determines the overall effectiveness
of the respiratory compensatory mechanism.
B
Correction of Fetal Respiratory Acidosis
Fetal respiratory acidosis develops when prolonged maternal hypoventilation occurs
with maternal asthma, airway obstruction, narcotic overdosing, maternal anesthesia,
severe hypokalemia, and magnesium sulfate toxicity. Fetal breathing movements
increase, and the fetal kidneys exert a maturation-dependent limited response by
reclaiming more bicarbonate in an attempt to restore the physiologic 20 : 1 ratio of
bicarbonate to carbonic acid, resulting in a return of the pH toward normal.4 In the
fetus, only the renal compensation has some limited physiologic significance when
respiratory acidosis develops due to prolonged maternal hypoventilation. Rather, the
placenta, coupled with maternal compensatory mechanisms, performs most of the
effective compensatory functions.
Correction of Postnatal Respiratory Acidosis
In the clinical setting, acute neonatal respiratory acidosis develops most frequently
in preterm infants with respiratory distress syndrome. Although stimulation of the
respiratory center in the brain by the decrease in pH due to the elevated interstitial
carbon dioxide concentration immediately increases respiratory rate and depth,
carbon dioxide elimination by the lungs is usually limited because of immaturity
and parenchymal disease. Importantly, in premature infants, increase in minute
ventilation is achieved primarily by the increase in respiratory rate accompanied by
only minor changes in tidal volume. On the other hand, term infants respond with
increased tidal volume first.5 Respiratory compensation can be further affected by
the decreased carbon dioxide sensitivity of the premature infant6 and the altered
interaction between arterial oxygen tension (pO2) and carbon dioxide sensitivity,
particularly at the level of central receptors, during the neonatal period as compared
with adults.7
As in the fetus, the kidneys reclaim more bicarbonate in response to respiratory
acidosis. However, renal compensation is limited by the developmentally regulated
immaturity of renal tubular functions, especially during the first few weeks of
postnatal life.
Regulation of Acid-Base Homeostasis
Metabolic Acidosis
As in respiratory acidosis, the pulmonary gas exchange serves as the immediate
regulator of acid-base homeostasis when metabolic acidosis develops. However,
because plasma bicarbonate does not readily cross the blood-brain barrier, CSF
bicarbonate levels change only with a delay.8 Therefore full activation of the respiratory
acid-base regulatory system occurs only hours after the development of metabolic
acidosis. This is different from the previously described truly immediate activation
of the respiratory acid-base regulatory system by respiratory acidosis. In the CSF,
generation of bicarbonate via hydroxylation of the dissolved carbon dioxide during
CSF formation is the primary source of bicarbonate.9 On the other hand and as
mentioned earlier, changes in arterial carbon dioxide tension rapidly affect carbon
dioxide tension in the CSF, even in the setting of primary metabolic acidosis. Changes
in CSF carbon dioxide levels also readily affect CSF bicarbonate levels.10 In addition,
the respiratory response to changes in CSF bicarbonate levels in metabolic acidosis
appears to be not as robust as that triggered by changes in carbon dioxide tension.2
Finally, the respiratory compensatory mechanism is complemented by removal of
the acid load by the kidneys.
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Acid-Base Homeostasis in the Fetus and Newborn
87
Fetoplacental Elimination of Metabolic Acid Load
Fetal respiratory and renal compensation in response to changes in fetal pH is limited
by the level of maturity and the surrounding maternal environment. However, although
the placentomaternal unit performs most compensatory functions,4 the fetal kidneys
have some, although limited, ability to contribute to the maintenance of fetal acid-base
balance.
The most frequent cause of fetal metabolic acidosis is fetal hypoxemia owing
to abnormalities of uteroplacental function or blood flow, or both. Primary maternal
hypoxemia or maternal metabolic acidosis secondary to maternal diabetes mellitus,
sepsis, or renal tubular abnormalities is an unusual cause of fetal metabolic acidosis.
The pregnant woman, at least in late gestation, maintains a somewhat more
alkaline plasma environment compared with that of nonpregnant controls. This
pattern of acid-base regulation in pregnant women is present during both resting
and after maximal exertion and may serve as a protective mechanism from sudden
decreases in fetal pH. Maintenance of the less acidic environment during pregnancy
appears to be achieved through reduced plasma carbon dioxide and weak acid
concentrations.4,11
The placenta plays an essential role in the maintenance of fetal acid-base balance
when metabolic acidosis develops. As mentioned earlier, fetal metabolic acidosis
most frequently occurs when abnormal uteroplacental function or blood flow results
in fetal hypoxemia. Fetal hypoxemia then causes a shift to anaerobic metabolism
and large quantities of lactic acid accumulate. As hydrogen ions are buffered by the
extracellular and intracellular buffering systems of the fetus, pH drops as plasma
bicarbonate decreases. Because of the unhindered diffusion of carbon dioxide through
the placenta,12 restoration of normal fetal pH initially occurs through elimination of
the volatile element of the carbonic acid-bicarbonate system via the maternal lungs.
However, as lactate and other fixed acids cross the placenta more slowly,4 the onset
of maternal renal compensation of fetal metabolic acidosis is delayed. In addition,
if fetal oxygenation improves, the products of anaerobic metabolism are also metabolized by the fetus.
Because there is no physiologic significance to respiratory compensation of
metabolic acidosis in utero, the finding that the respiratory control system in the
fetus is much less sensitive to changes in pH than in the neonate13 has little practical importance. Yet, a decrease in the fetal pH stimulates breathing movements in
the fetus.14,15
Finally, as for the role of the fetal kidneys in the maintenance of acid-base
balance, available evidence indicates that the fetal kidneys excrete both inorganic16–18
and organic acids19 and are also able to reabsorb bicarbonate.20,21 Studies in fetal
sheep have found age-dependent increases in glomerular filtration rate (GFR) and
urinary titratable acid, ammonium, and net acid excretion.16 A positive relationship
also exists between changes in GFR and bicarbonate, sodium, and chloride excretions.16,18 Yet, the adaptive capacity of the fetal kidney to changes in fetal acid-base
balance is limited. In fetal sheep the hydrochloric acid infusion-induced metabolic
acidosis results in increases in titratable acid, ammonium, and net acid excretion
without significant changes in GFR or renal tubular bicarbonate absorption.18 However,
as mentioned earlier, under certain conditions, such as volume depletion20 or recovery
from mild hypocapnic hypoxia,21 the fetal kidney has the ability to increase bicarbonate
reabsorption. It is also important to note that the vast majority of these data have
been obtained in animal models and that there is only very limited information
available concerning renal acidification by the human fetus.22 In addition, the physiologic importance of the adaptive fetal renal responses is limited compared with that
in the postnatal period because the acid load excreted in the fetal urine remains
within the immediate fetal environment and needs to be eliminated by the placenta
or metabolized by the fetus.
Indeed, amniotic fluid acid-base status and electrolyte composition have been
shown to affect the fetus. When the effects of amnion infusion of physiologic saline
with those of lactated Ringer were compared in the fetal sheep, significant increases
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Perinatal Mineral, Electrolyte, and Acid-Base Homeostasis
in fetal plasma sodium and chloride concentrations were noted only in the physiologic
saline infusion group.23 In addition, fetal arterial pH decreased in the physiologic
saline group and the change in the fetal pH was directly related to the changes in
plasma chloride concentrations. However, despite the significant changes in plasma
sodium and chloride concentrations and pH, fetal plasma electrolyte composition
and acid-base balance remained in the physiologic range, leaving these findings with
little clinical significance.23
B
Postnatal Elimination of Metabolic Acid Load
The most frequent causes of increased anion gap (lactic acid) metabolic acidosis in
the neonate are hypoxemia or ischemia secondary to perinatal asphyxia; vasoregulatory
disturbances and/or myocardial dysfunction caused by immaturity, sepsis, or asphyxia;
severe lung disease with or without pulmonary hypertension; certain types of structural
heart disease; and volume depletion. Severe metabolic acidosis caused by a neonatal
metabolic disorder is rare but should always be considered. Preterm neonates frequently
present with a mild to moderate normal anion gap acidosis, which almost always is
the consequence of the low renal bicarbonate threshold of the premature kidney.24–27
However, the use of carbonic anhydrase inhibitors28 and parenteral alimentation, as
well as the maturation-related decreased sensitivity to aldosterone, have also been
suggested to contribute to the development of normal anion gap acidosis in the
neonate.29–32
As mentioned earlier, in metabolic acidosis caused by the accumulation
of lactic acid, hydrogen ions are buffered by the intracellular and extracellular
buffering systems and plasma bicarbonate concentration decreases and pH drops.
Restoration of pH toward normal initially occurs through elimination of the volatile
element of the carbonic acid–bicarbonate system via the lungs. This process may be
severely compromised in the sick preterm and term neonate with parenchymal lung
disease.
The principle mechanism of the renal compensation is the regulation of renal
tubular bicarbonate and acid secretion in response to changes in extracellular pH.
Although full activation of this system requires at least 2 to 3 days, changes in renal
acidification may be seen as early as a few hours following the development of the
acid-base disturbance. Although renal compensation is the ultimate mechanism that
adjusts the hydrogen ion content of the body, this compensatory function is also
affected by the immaturity of the neonatal kidneys.27,33 Both renal hemodynamic and
tubular epithelial factors play a role in the limited renal compensatory capacity of
the newborn.
Renal blood flow (RBF) significantly increases after the immediate postnatal
period, and some of the renal vasodilatory mechanisms are functionally mature as
early as the 24th week of gestation.34 Similar to RBF, GFR is also low in the immediate
postnatal period and increases as a function of both gestational and postnatal age.35–37
Indeed, the low GFR is considered the primary hemodynamic factor limiting the
ability of the neonate to adequately handle an acid load.27,33
In addition, net renal acid excretion is regulated by several tubular epithelial
functions.38 In the proximal tubule the following major transport mechanisms regulate
active acid extrusion and transepithelial bicarbonate reabsorption: the H+-ATPase, the
Na+,K+-ATPase–driven secondary active Na+/H+ antiporter in the apical membrane
and the electrogenic Na+/3HCO3− cotransporter in the basolateral membrane, and
the Na+,K+-ATPase–driven tertiary active Na+-coupled organic ion transporter.39
Because approximately 80% of the filtered bicarbonate is reabsorbed in the proximal
tubule,40 the function of these proximal tubular transporters determines the renal
threshold for bicarbonate reabsorption. The bicarbonate threshold is approximately
18 mEq/L in the premature and approximately 21 mEq/L in the term infant,24,41 and
it reaches adult levels (24–26 mEq/L) only after the first postnatal year.25,26 However,
in the extremely low gestational age neonate the renal bicarbonate threshold may
be as low as 14 mEq/L. Because renal carbonic anhydrase is present and active
during fetal life42 and because its activity is similar in the 26-week-old extremely
immature neonate to that of the adult,43 a developmentally regulated immaturity
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Acid-Base Homeostasis in the Fetus and Newborn
89
of the function of the previously described proximal tubular transporters is most
likely responsible for the low bicarbonate threshold during early development.
Indeed, both the activity and the hormonal responsiveness of the proximal tubular
Na+,K+-ATPase are decreased in younger compared with older animals.44 Moreover,
similar to the decrease in bicarbonate reabsorption in the proximal tubule,45 the
activity of Na+/H+ antiporter is also decreased to approximately one-third of the
adult level.46
In addition to immaturity, medications used in critically ill neonates may also
affect proximal tubular bicarbonate reabsorption. For example, via inhibition of the
proximal tubular Na+/H+ antiporter, dopamine may potentially decrease the low
bicarbonate threshold of the neonate.47–49 Carbonic anhydrase inhibitors also decrease
proximal tubular bicarbonate reabsorption by limiting bicarbonate formation and
hydrogen ion availability for the Na+/H+ antiporter.50 By acting on several transport
proteins along the nephron, furosemide directly increases urinary excretion of titratable
acids (phosphate and sulfate salts) and ammonium.51 On the other hand, by inhibition
of the activation of aldosterone receptors, spironolactone indirectly decreases hydrogen
ion excretion in the distal tubule.
Under physiologic circumstances, the thick ascending loop of Henle and the
distal tubule reabsorb the remaining filtered bicarbonate via transport mechanisms
similar to those of the proximal tubule. In addition, by transporting bicarbonate
across the membrane,39 the distal nephron-specific HCO3−/Cl− antiporter located in
the basolateral membrane contributes to the reabsorption of bicarbonate.
Hydrogen ions are excreted in the urine in the form of titratable acids (phosphate
and sulfate salts) and as ammonium salts, which are formed by the combination of
hydrogen with ammonia.39 Because the major constituent of titratable acid in the
urine is H2PO4−, drugs that decrease proximal tubular phosphate reabsorption and
thus increase the delivery of phosphate to the distal nephron may increase the renal
acidification capacity of the neonate. Indeed, by inhibiting proximal tubular phosphate
reabsorption, dopamine has been shown to increase the excretion of titratable acids
in preterm infants.52 Furthermore, net hydrogen ion secretion in the distal nephron
continues after the reabsorption of virtually all bicarbonate by active extrusion of
hydrogen and via the ability of the distal tubular epithelium to maintain large
transepithelial concentration gradients for hydrogen and bicarbonate.39
Urinary excretion of titratable acid and ammonium increases as a function of
gestational and postnatal age.27,37 However, because effective urinary acidification
is usually acquired by the age of 1 month, even in premature infants, postnatal
distal tubular hydrogen ion secretion is inducible independent of the gestational
age at birth.53,54
Aldosterone is one of the most important hormones influencing distal tubular
acidification. By affecting the function of several different transport mechanisms,
aldosterone stimulates net hydrogen ion excretion in the distal nephron.39 Of note is
that the premature neonate has a developmentally regulated relative insensitivity to
aldosterone.30,32
In summary, the renal response to metabolic acidosis in the immediate postnatal
period consists of attenuated increases in GFR, proximal tubular bicarbonate reabsorption, and distal tubular net acid secretion. However, a significant improvement
in the overall renal response occurs after the first postnatal month even in the
premature infant.33,53,54
Regulation of Acid-Base Homeostasis
Respiratory Alkalosis
Correction of Fetal Respiratory Alkalosis
Rather than causing fetal respiratory alkalosis, acute maternal hyperventilation may
lead to the development fetal hypoxia and metabolic acidosis.55 The fetal acidosis
under these circumstances is thought to be the consequence of the acute decrease in
placental blood flow caused by the maternal hypocapnia-induced significant uterine
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Perinatal Mineral, Electrolyte, and Acid-Base Homeostasis
vasoconstriction.56 In these cases, restoration of maternal carbon dioxide levels rapidly
corrects both the abnormal uterine blood flow and the acid-base abnormality in
the fetus.
The physiologic hyperventilation of the pregnant woman causes a compensatory
decrease in her serum bicarbonate concentration to approximately 22 mM4 without
any apparent effect on the fetus (see earlier).
B
Correction of Postnatal Respiratory Alkalosis
Neonatal respiratory alkalosis occurs most often in the febrile nonventilated neonate
or in cases with iatrogenic hyperventilation of the intubated preterm or term infant.
Rarely, respiratory alkalosis may be the presenting sign of a urea cycle disorder
during the first days of postnatal life because the rising ammonia level may initially
stimulate the respiratory center in the brain. As for the renal compensation of respiratory
alkalosis, both urinary bicarbonate reabsorption and distal tubular net acid excretion
decrease and thus extracellular pH tends to return toward normal. This renal compensation plays an important although somewhat limited role in neonatal respiratory
alkalosis.
Regulation of Acid-Base Homeostasis
Metabolic Alkalosis
Correction of Fetal Metabolic Alkalosis
Although metabolic alkalosis is a very rare fetal condition, it may occur in hyperemesis
gravidarum. As a result of the significant and lasting hydrogen chloride losses, maternal
renal compensation results in retention of bicarbonate to maintain maternal anionic
balance. Because bicarbonate is transported slowly across the placenta, the development
of fetal metabolic alkalosis lags behind that of the mother. On the other hand, the
maternal respiratory compensation (hypoventilation with the ensuing hypercapnia)
tends to restore normal pH in the fetus as carbon dioxide is rapidly transported across
the placenta.
Correction of Postnatal Metabolic Alkalosis
Metabolic alkalosis most frequently develops in the preterm neonate receiving prolonged
diuretic treatment for bronchopulmonary dysplasia. Although there is little evidence
that chronic diuretic management results in improved medium- or long-term pulmonary
outcome, many neonatologists use this treatment modality, at least intermittently. If
total body chloride and potassium content is not appropriately maintained during
chronic diuretic administration, severe metabolic “contraction” alkalosis may develop,
which also results in poor growth. The respiratory response is a decrease in the rate
and depth of breathing to increase carbon dioxide retention. This response may be
interpreted as a sign of worsening pulmonary condition in the ventilated preterm
neonate and may inappropriately trigger an increase in ventilatory support. Thus
respiratory compensation of metabolic alkalosis may be ineffective if the intubated
neonate is subjected to iatrogenic overventilation on the mechanical ventilator. As
for the neonatal renal compensation for metabolic alkalosis, urinary bicarbonate
reabsorption and distal tubular net acid excretion fall, resulting in a return of the
extracellular pH toward normal.
Finally, metabolic alkalosis can also result from a nondiuretic administration–
related loss of extracellular fluid containing disproportionally more chloride than
bicarbonate. During the diuretic phase of normal postnatal adaptation, preterm and
term newborns tend to retain relatively more bicarbonate than chloride.57 The obvious
benefits of allowing this physiologic extracellular volume contraction to occur clearly
outweigh the clinical importance of a mild contraction alkalosis developing during
postnatal adaptation. Thus no specific treatment is needed in these cases, especially
because with the stabilization of the extracellular volume status and the renal function
with time, acid-base balance rapidly returns to normal.
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Acid-Base Homeostasis in the Fetus and Newborn
91
Normal Acid-Base Balance and Growth
Growth is most accelerated during fetal life. The normal fetus grows from a weight
of 0.22 g at the eighth week of gestation to 3400 g at 40 weeks’ completed gestation.58
The estimated energy density of each gram of body weight gained (or lost) is 23 kJ
(5.6 kcal). However, in premature infants, especially if they are critically ill and/or
growth retarded, the energy density of the new tissue is estimated to be higher than
5.6 kcal/g.59 For instance, in small-for-gestational-age infants at approximately 5
weeks after birth, the total energy expenditure is estimated to be 20% greater than
in appropriate-for-gestational-age controls.60
Fetal growth can be negatively affected by several fetal and placentomaternal
conditions. Proven fetal conditions affecting fetal growth include certain genetic
conditions and infection of the fetus.61 Placentomaternal conditions with demonstrated
influence on fetal growth are primary placental insufficiency and maternal diseases,
nutritional status or substance abuse leading to secondary placental insufficiency,
decreased fetal nutrient availability or direct fetal toxicity, or a combination of these
harmful effects on fetal well-being.61
Although direct evidence demonstrating an impact of chronic fetal acid-base
abnormality on fetal growth is very limited, a mild shift in the fetal acid-base status
has been suggested as the primary pathologic factor for intrauterine growth restriction
caused by placental insufficiency of any etiology.62 From 18 weeks’ postconception,
growth-retarded fetuses exhibit a greater degree of mild acidemia than their appropriately
growing counterparts.63 This acidemia is attributed to the reduced perfusion and mild
hypoxemia the growth-retarded fetus faces as a result of the placental insufficiency.
According to the above hypothesis, the small initial reduction in the pH negatively
affects nitric oxide production in the fetus, and it is the decreased availability of
nitric oxide that then plays a major role in the ensuing growth restriction.62
The following findings are in support of this hypothesis. Because locally formed
nitric oxide regulates tissue perfusion and thus oxygen delivery and tissue growth
itself, it has been suggested to play a pivotal role in regulation of growth in the
fetus.61,62 In addition to its effect on oxygen delivery to the tissues, nitric oxide is an
anabolic factor. Indeed, it is necessary for normal growth of several tissues, including
the bone and muscle, and for the action of different hormones, such as the parathyroid
hormone, vitamin D, and estrogen, known to be of importance in fetal growth and
development.64,65
Interestingly, the enzyme responsible for generating nitric oxide from L-arginine,
the constitutive nitric oxide synthase (cNOS), is sensitive to changes in pH, and its
activity decreases even with a mild shift in the pH toward acidosis.66 Thus a vicious
cycle may develop in growth-retarded fetuses because the initial decrease in blood
flow and pH caused by placental insufficiency may lead to decreased cNOS activity
and thus nitric oxide production. Decreased nitric oxide production, in turn, leads
to further decreases in tissue perfusion and thus in pH, exacerbating the decrease in
local nitric oxide production.62
In addition to being the source of locally generated nitric oxide, L-arginine also
serves as the source of polyamines and L-proline. These compounds are generated
by the arginase enzyme and are important when growth and tissue repair processes
predominate. The function of this enzyme is also pH dependent,67 and the proposed
decrease in its activity in the growth-retarded fetus may contribute to further impairment
of fetal growth.
Based on this information, it seems that elevating the pH in the fetus toward
normal and supplementing L-arginine to the mother may be a plausible approach to
attenuate the impact on fetal growth of the placental insufficiency–induced decreased
fetal oxygen delivery. However, due to the inherent difficulties associated with attempts
to effectively control fetal pH, no clinical trial has as yet attempted this combined
approach.
As for the neonate, the syndrome of late metabolic acidosis of prematurity is
an example how postnatal growth can be affected by alterations in the acid-base
balance. This entity was first described in the 1960s, in which otherwise healthy
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B
Perinatal Mineral, Electrolyte, and Acid-Base Homeostasis
premature infants after a few weeks developed mild to moderate anion gap acidosis
and decreased growth rate. All of these infants were receiving high-protein cow’s
milk formulas and demonstrated increased net acid excretion compared with controls.
This type of late metabolic acidosis is now rarely seen, probably because of the use
of special premature formulas and the changes made to regular formulas now containing
a decreased casein-to-whey ratio and lower fixed acid loads.
The diuretic administration–induced hypochloremic metabolic alkalosis is another
example of the impact of acid-base balance on postnatal growth. This phenomenon
is also associated with growth failure and may be a contributing factor of poor
outcome in infants with bronchopulmonary dysplasia.68 Indeed, in addition to mild
chronic hypoxemia and inadequate nutrition, the decrease in cell proliferation and
diminished DNA and protein synthesis in response to intracellular alkalosis may
contribute to the growth failure of infants with severe bronchopulmonary dysplasia.69
Chronic decrease in total body sodium resulting in a negative sodium balance may
further hinder the growth of these infants.70 Aggressive chloride and potassium
supplementation with relatively limited sodium supplementation decreases the risk
for the development of clinically significant severe contraction alkalosis associated
with chronic diuretic use in these patients.
Obstetrical Management and Fetal and Neonatal
Acid-Base Balance
Evidence has accumulated on the impact of certain aspects of obstetrical management
of labor and delivery on fetal and neonatal acid-base homeostasis. These effects are
transient, and it is unclear whether they have an independent impact on clinically
relevant neonatal outcome measures.
Maternal betamethasone administration has been associated with a transient
decrease in fetal movements including fetal breathing71 and fetal heart rate variability.71,72
Although the exact pathomechanism of these effects of antenatal betamethasone
administration is unclear, animal73 and human74 data suggest that transient fetal acidosis
following maternal steroid administration may, at least in part, explain the findings.
It has been suggested that fetal acidosis is a consequence of the demonstrated fetal
cardiovascular, endocrine, and metabolic effects of maternal steroid administration.74,75
However, in growth-restricted fetuses, cardiovascular responses to maternal steroid
administration differ from those of fetuses with normal growth76,77 and may lead to
significant acidosis and poor outcome.76
Delayed cord clamping also appears to have an impact on neonatal acid-base
balance immediately after delivery, resulting in changes consistent with mixed acidosis
during the first 45 seconds followed by primarily a metabolic acidosis by 90 seconds
with delayed cord clamping.78 The metabolic acidosis immediately after delivery
likely occurs because the normally produced and accumulated anaerobic metabolites
in nonvital organs during labor and delivery are washed out faster in the larger blood
volume of neonates with delayed cord clamping, and thus they exert a smaller effect
on blood pH in these infants later on.78 Because the potential clinical relevance of
fetal and immediate postnatal acidosis depends on the severity of hypoxemia and
the associated acidosis, it may have importance only in the neonate with prolonged
labor and difficult delivery.79 Observations in preterm infants suggest that delaying
clamping of the cord even for 30 seconds is associated with a decrease in metabolic
acidosis shortly after birth.80
Finally, the type of anesthesia during delivery via C-section also appears to have
an impact on the fetal acid-base status. Findings of a meta-analysis of 27 studies
found lower cord pH and larger base deficit in newborns of mothers who received
spinal anesthesia compared with those who received general and epidural anesthesia.81
A more recent prospective observational cohort study examined the relationship
between the type of anesthesia provided during C-section and fetal acid-base balance
and neonatal condition upon delivery in 900 women with uncomplicated singleton
pregnancies.82 The study found that epidural anesthesia was associated with higher
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Acid-Base Homeostasis in the Fetus and Newborn
93
venous cord pH (7.30 ± 7.26–7.34) than general (7.25 ± 7.21–7.26) or spinal (7.23 ±
7.19–7.26) anesthesia and that neonatal well-being was negatively affected primarily
by general anesthesia. These findings highlight the importance of taking the type of
anesthesia into consideration when evaluating a neonate with metabolic acidosis in
the immediate postnatal period following delivery via cesarean section.
Summary
This chapter has reviewed the available information and the gaps in our knowledge
on how fetal and neonatal acid-base balance is regulated and the impact of alterations
in acid-base balance on some aspects of fetal and postnatal growth, as well as how
selected obstetrical management approaches affect fetal and neonatal acid-base balance.
In the future, a better understanding of the role of growth factors and their interaction
with the fetal acid-base status may result in improved early management of the
growth-retarded fetus. This, in turn, may decrease the negative impact of growth
retardation on brain and other organ development.
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