CURRENT TOPIC

Causes and consequences of fetal acidosis

Catherine S Bobrow, Peter W Soothill

The fetus depends on the mother for placentalexchange of oxygen and carbon dioxide. Thisin turn relies on adequate maternal blood gasconcentrations, uterine blood supply, placentaltransfer and fetal gas transport. Disruption ofany of these can cause fetal hypoxia, which,despite compensatory mechanisms, may leadto acidosis. When severe and acute (lastinghours), but especially if prolonged (days orweeks), hypoxia and therefore acidosis, areassociated with significant morbidity and mor-tality with potential long term sequelae.Whether this damage is primarily due toreduced cell energy availability, as a result ofhypoxia, or secondary to cell poisoning, as aresult of acidosis, is unclear and indeed acido-sis could simply be a marker of the cause andseverity of the hypoxia.

The very diVerent aetiologies of acute vschronic acidosis and the possible consequenceswill be reviewed, whether directly caused by theacidosis or indirectly by the hypoxia

What is acidosis?Acidosis means a high hydrogen ion concentra-tion in the tissues. Acidaemia refers to a highhydrogen ion concentration in the blood and isthe most easily measured indication of tissueacidosis. The unit most commonly used is pH,which is log to base 10 of the reciprocal of thehydrogen ion concentration. Whereas bloodpH can change quickly, tissue pH is morestable. The cut oV taken to define acidaemia inadults is a pH of less than 7.36, but after labourand normal delivery much lower values com-monly occur in the fetus (pH 7.00), often withno subsequent ill eVects. Studies looking at thepH of fetuses from cord blood samples takenantenatally and at delivery have establishedreference ranges. Other indices sometimesused to assess acidosis are the base excess orbicarbonate. Neither of these is measured byconventional blood gas machines but is calcu-lated from the measured pH and pCO2.

The major sources of hydrogen ions in thefetus are carbonic and lactic acids from aerobicand anaerobic metabolism, respectively. Theremoval of CO2 (and so carbonic acid) from thefetus depends almost entirely on the placenta.Unlike in sheep, lactate does not normallyseem to be an important substrate for thehuman fetus and lactic acid is usually eitherfurther metabolised or excreted transplacen-tally. The latter has been shown by analyses of

arterial and venous cord blood samples fromhuman fetuses with low blood oxygen contentdue to anaemia secondary to severe Rhesusisoimmunisation. Lactate concentration washigher in the umbilical artery than the umbili-cal vein. The increased lactate is explained byincreasing production from anaerobic metabo-lism and the diVerence in concentrationbetween the umbilical artery and vein suggeststhat the placental circulation clears lactatefrom the fetal blood so helping to “repay” afetal oxygen debt.1

The causes of fetal hypoxia and thereforeacidosis can be divided into maternal, placen-tal, or fetal. The consequences of acidosisdepend on its severity and duration and alsothe condition of the fetus before the insult, andwe classify the causes of fetal acidosis intoacute (hours) or chronic (days). In postnatalmedicine acidosis is often described as respira-tory (predominantly due to increased pCO2) ormetabolic (predominantly due to increasedlactic acid). However, while acute fetal acidosisis almost always initially respiratory, this isquickly followed by mixed respiratory andmetabolic acidosis if there is no improvementin oxygenation. Furthermore, the chronicacidosis of fetal life is also mixed,2 (fig 1) andwe therefore prefer to use the terms acute andchronic.

AetiologyACUTE

MaternalAnything that causes hypotension or hypovol-aemia such as haemorrhage, a vasovagal attack,or epidural anaesthesia will reduce the mater-nal blood supply and so oxygen delivery to theuterus. Uterine contractions can also interruptthe uterine blood flow by a pressure rise and ifprolonged, as in hypertonus, may causehypoxia and so acidosis.

PlacentalAbruption can disrupt the utero-placentalcirculation by separating and so tearing theuterine spiral arteries from the placenta.

FetalBlood flow from the placenta to the fetus isoften aVected during labour and delivery byumbilical cord compression and this can some-times happen before labour if there is reducedliquor or a true knot in the cord. Animal

Arch Dis Child Fetal Neonatal Ed 1999;80:F246–F249F246

Fetal MedicineResearch Unit,University of Bristol,Department ofObstetrics, StMichael’s Hospital,Bristol BS2 8EGC S BobrowP W Soothill

Correspondence to:Professor Peter Soothill.

group.bmj.com on April 22, 2018 - Published by http://fn.bmj.com/Downloaded from

experiments have shown that there is signifi-cant reserve because the fetus can compensateby increased oxygen extraction,3 meaningblood flow to the fetus must be reduced by atleast 50% to cause hypoxia.4

CHRONIC

MaternalMaternal causes of chronic fetal acidosisinclude reduced oxygenation of maternalblood, such as in severe respiratory or cardiacdisease, or reduced blood flow to the placentaas in connective tissue diseases—for example,systemic lupus erythematosus—and pre-eclampsia.

PlacentalAntenatal fetal blood sampling by ultrasoundguided needle aspiration from the umbilicalcord (cordocentesis) in pregnancies with fetalgrowth restriction (FGR) has shown hypoxia asa result of impaired placental transfer ofoxygen.5 This is thought to result frominadequate trophoblast invasion of the myo-metrium in early pregnancy,6 leading toreduced perfusion of the intervillous spaces. Inanimal experiments, like acute cord compres-sion studies, utero-placental blood flow alsoneeds to be reduced by at least 50% to producefetal hypoxia.7 This indicates that the reductionin placental transfer seen in human FGR mustbe substantial to produce the hypoxia and aci-dosis found at cordocentesis in such cases.

FetalEven with normal placental function, condi-tions within the fetus can cause acidosis. Anae-mia from rhesus disease, parvovirus infection,á-thalassaemia or feto-maternal haemorrhage,when severe enough to reduce fetal haemo-

globin concentrations below 40 g/l (equivalentto an oxygen content below 2 mmol/l), can leadto a fall in pH.8 9 Arterio-venous shunting infetal tumours, serious cardiac structural abnor-malities, or arrhythmias are other conditionswhich can lead to chronic acidosis by decreasedoxygenation as a result of reduced feto-placental blood flow.

Diagnosis of acidosisANTENATALLY

The use of ultrasound imaging to assess fetalsize and wellbeing, Doppler studies of the fetalcirculation, and cordocentesis have helped usto understand some of the mysteries of lifebefore birth. During the 1980s cordocentesiswas used to study the acid base status of thefetus and create reference ranges for umbilicalarterial and venous blood gases in the secondand third trimesters (fig 2).2 10 These studiesprovided the first direct evidence of chronicacidosis.5 However, cordocentesis carries aprocedure related risk of 1% and cannot there-fore be used routinely or repeatedly formonitoring. To overcome this, fetal medicinespecialists have searched for non-invasive tech-niques to detect acidosis.

In acute situations where severe hypoxia andacidosis are suspected, the non-invasive tech-niques used are fetal heart rate monitoring orbiophysical profile score (fetal breathing/movements, gross body movement, tone andamniotic fluid volume). However, in pregnan-cies with placental dysfunction before labour,the onset of hypoxia and acidosis is moregradual and results of these tests are often nor-mal until a preterminal stage11 where urgentdelivery is required to prevent an intrauterinedeath.

An important breakthrough in antenatalsurveillance was the demonstration that in-creased resistance in placental vasculature inpregnancies with hypoxia and acidosis due to

Figure 1 Relations between umbilical venous hypoxaemia(pO2) and umbilical hypercapnia (pCO2),hyperlacticaemia (blood lactate), or acidosis (pH); these areall expressed in multiples of SD from the appropriate meanfor gestational age). Reproduced with permission fromNicolaides et al. Am J Obstet Gynecol;1989;161:996-100.

2

–2

–6

–10

–14

–18

5

Umbilical venous hypoxaemia

Aci

do

sis

25

15

5

–5Hyp

erla

ctic

aem

ia

–2 –1 0 1 2 3 4

16

12

0

4

8

–4

Hyp

erca

pn

ia Key points+ The causes and consequences of acute

(minutes or hours) and chronic (days orweeks) fetal acidosis are diVerent

+ In the past much attention has been paidto acute acidosis during labour, but inpreviously normal fetuses this is rarelyassociated with subsequent damage

+ In contrast, chronic acidosis, which isoften not detected antenatally, is associ-ated with a significant increase in neu-rodevelopmental delay

+ The identification of small for gestationalage fetuses by ultrasound scans and theuse of Doppler waveforms to detectwhich of these have placental dysfunctionmean that these fetuses can be monitoredantenatally

+ Delivery before hypoxia has producedchronic acidosis, may prevent subsequentdamage and good timing of deliveryremains the only management option atpresent.

Causes and consequences of fetal acidosis F247

group.bmj.com on April 22, 2018 - Published by http://fn.bmj.com/Downloaded from

placental dysfunction caused abnormal flowpatterns in the umbilical artery, demonstrableusing Doppler ultrasonography. Umbilical ar-tery Doppler velocimetry is a sensitive and spe-cific non-invasive way of detecting chronicacidosis. This was confirmed by the demonstra-tion of significant associations between umbili-cal artery Doppler waveforms and blood gases atdelivery.12 13 Further work has also shown acharacteristic pattern of redistribution of bloodflow to the most essential organs at the expenseof the peripheral ones. This occurs with increas-ing acidosis, and is followed by progressive car-diac dysfunction, leading to abnormal venousblood flow patterns. Doppler is now the mostwidely used technique to detect chronic acidosisin expert UK clinical practice.

INTRAPARTUM

Fetal heart rate monitoring during labour cangive us an indication of fetal hypoxia andacidosis, but although sensitive, this method isnot very specific. Measurements of acid basestatus intrapartum obtained from samplingfetal blood from the presenting part after cervi-cal dilatation and rupture of membranes helpdecrease operative deliveries following falsepositive fetal heart rate traces.14 In contrast toantenatal blood gas results, the value of a singleresult in labour is limited as the acid baseinteractions are dynamic and may changequickly, and repeated samples are oftenneeded. Several methods of continuous bloodgas monitoring using an electrode attached tothe fetus sub- or transcutaneously have beentried for pO2,

15 pCO2, and pH.16 Intrapartumfetal oxygen saturation monitoring by pulseoximetry is being developed and seems to be agood predictor of pO2 and acid base status,17

and this has important implications for moni-toring in labour.

Fetal pH falls during normal labour but thisis found earlier in pregnancies aVected bycomplications such as pre-eclampsia andgrowth restriction.18 We believe this result isnot only because of “reduced reserve” for

labour but that some of these cases are acidoticbefore labour onset (as described above).

AT DELIVERY

Studies of acid base status in cord blood atbirth have provided normal ranges.19 As inlabour, neonates from pregnancies with ante-natal (growth retardation) or intrapartum(meconium staining) complications, are morelikely to be hypoxic20 and acidotic at birth. Inour view the important distinction is whetherthe acidosis resulted from chronic (presentbefore labour) or acute hypoxia. The differencein umbilical artery and vein gases may give fur-ther information on its duration. In placentaldysfunction where hypoxia is due to reducedplacental transfer, umbilical artery and veinvalues will both be abnormal and similar,whereas in acute cord compression or fetalbradycardia the hypoxia and acidosis will bepredominantly in the umbilical artery, leadingto a large arteriovenous diVerence. This isbecause a slow passage of blood through theplacenta allows time for maximum gas ex-change despite reduced total blood flow.

Consequences of acidosisAcidosis occurs as a result of tissue hypoxia andit is unclear whether the consequences of thisprocess are due primarily to the acidosis or thehypoxia. What has become clear over the pastdecade is that the consequences of hypoxia/acidosis are very diVerent, depending onwhether this is acute or chronic. The normalhuman fetus is adapted to survive labour andhas compensatory mechanisms that allow it towithstand even severe hypoxia and acidosis forshort periods of time. Several studies havelooked at the neurological outcome of neonateswho were severely asphyxiated at delivery.21–24

Although the cutoV of pH used to define severeacidosis and the age at follow up varied,conclusions were similar from all the studies:although mortality may be slightly increased,the predictive value of acidosis at birth forneurological sequelae, especially in term ne-onates, is poor.

In contrast, the fetus exposed antenatally tochronic hypoxia and acidosis is much more atrisk of associated long term morbidity. In 1994Low et al reported a study of neonates follow-ing respiratory or metabolic acidosis atdelivery.25 Umbilical arterial buVer base wasused and they found that complications werenot increased with a pure respiratory acidosisbut they were with metabolic acidosis, andthese neonates were more likely to have passedmeconium and have had instrumental deliver-ies. An increased proportion of undiagnosedchronically acidotic fetuses in this group couldexplain this. In a large study of the antecedentsof cerebral palsy in 1986 Nelson et alconcluded that antenatal events were muchmore important than intra- or postpartumones.26 This was supported by a study byAdamson et al in 1995 where all term, singletonneonates born over an 8 month period with awell defined diagnosis of encephalopathywithin the first week of life were identified pro-spectively and matched with a well neonate.27

Figure 2 Reference ranges (mean and 95% confidence intervals), of umbilical venous andarterial pH with gestation. Dots represent pH values from FGR fetuses, many with chronicacidosis. Reproduced with permission from Nicolaides et al. Am J Obstet Gynecol. 2

18 20 22 24 26 28 30 32 34 36 38

7.5

7.4

7.3

7.2

7.1

7.0

6.9

Gestation (weeks)

Umbilical vein Umbilical artery

Feta

l blo

od

pH

18 20 22 24 26 28 30 32 34 36 38

F248 Bobrow, Soothill

group.bmj.com on April 22, 2018 - Published by http://fn.bmj.com/Downloaded from

Antenatal and intrapartum factors in bothgroups were compared and only 6% of caseshad intrapartum risk factors alone. Theyconcluded that in most of their cases intra-partum acidosis was not the cause and eventsoccurring in the antenatal period were moreoften implicated. Further evidence for thisassociation comes from a follow up study ofinfants with acid base status assessed as fetusesby cordocentesis. To remove the complicationsof extreme prematurity only cases deliveredafter 32 weeks were studied. Neurodevelop-mental assessment showed a reduction indevelopmental quotient following chronic fetalacidaemia (fig 3).28

ConclusionPrevention of severe acute acidosis depends ongood labour ward monitoring and care. Pre-vention of chronic fetal acidosis, which is prob-ably a much more common cause of damage,depends on detection of placental dysfunctionantenatally by clinical fetal growth assessment,ultrasound scanning and Doppler ultrasonog-raphy. There is still no overall consensus on thebest balance between keeping the fetus in anhypoxic/acidotic environment or very prema-ture delivery.29 In fetuses with abnormalDoppler waveforms delivery should usually beby Caesarean section to avoid acute on chronicacidosis. Much current research is concentrat-ing on improving placental transfer to developa future in utero treatment for this group.

1 Soothill PW, Nicolaides KH, Rodeck CH, Clewell WH andLindridge J. Relationship of fetal haemoglobin and oxygencontent to lactate concentration in rH isoimmunised preg-nancies. Obstet Gynecol 1987;69:268-71.

2 Nicolaides KH, Economides DL and Soothill PW. Bloodgases, pH, and lactate in appropriate- and small-for-gestational-age fetuses. Am J Obstet Gynecol 1989;161:996-1001.

3 Clapp JF. The relationship between blood flow and oxygenuptake in the uterine and umbilical circulations. Am JObstet Gynecol 1978;132:410-13.

4 Itskovitz J, LaGamma EF and Rudolph AM. The eVect ofreducing umbilical blood flow on fetal oxygenation. Am JObstet Gynecol 1983;145:813-18.

5 Soothill PW, Nicolaides KH, Campbell S. Prenatal as-phyxia, hyperlacticaemia, hypoglycaemia and erythroblas-tosis in growth retarded fetuses. BMJ 1987;294:1051-3.

6 Khong TY, De Wolf F, Robertson WB, Brosens I.Inadequate maternal vascular response to placentation inpregnancies complicated by pre-eclampsia and by small-for-gestational age infants. Br J Obstet Gynaecol1986;93:1049-59.

7 Wilkening RB, Meschia G. Fetal oxygen uptake, oxygena-tion and acid-base balance as a function of uterine bloodflow. Am J Physiol 1983;244:H749-55.

8 Soothill PW, Nicolaides KH and Rodeck CH. EVect ofanaemia on fetal acid-base status. Br J Obstet Gynaecol1987;94:880-3.

9 Vandenbussche FPHA, Van Kamp IL, Oepkes D, HermansJ, Bennebroek G, Kanhai HHH. Blood gas and pH in thehuman fetus with severe anaemia. Fetal Diagn Ther1998;13:115-22.

10 Soothill PW, Nicolaides KH, Rodeck CH, Campbell S.EVect of gestational age on fetal and intervillous blood gasand acid base values in human pregnancy. Fetal Ther1986;1:168-75.

11 Ribbert LS, Visser GH, Mulder EJ, Zonnerveld MF, Mors-sink LP. Changes with time in fetal heart rate variation,movement indices and haemodynamics in intrauterinegrowth retarded fetuses: a longitudinal approach to theassessment of fetal well being. Early Hum Dev1993;31:195-208.

12 Tyrell S, Obaid AH, Lilford RJ. Umbilical artery Dopplervelocimetry as a predictor of fetal hypoxia and acidosis atbirth. Obstet Gynecol 1989;74(part 1):332-7.

13 Arduini D, Rizzo G, Capponi A, Rinaldo D, Romanini C.Fetal pH value determined by cordocentesis: an independ-ent predictor of the development of antepartum fetal heartrate decelerations in growth retarded fetuses with absentend –diastolic velocity in umbilical artery. J Perinat Med1989;24:601-7.

14 Saling E. Cardiotocography with or without fetal bloodanalysis. Geburtshilfe und Frauenheilkunde 1985;45:190-3.

15 Huch A, Huch R, Schneider H, Rooth G. Continuous tran-scutaneous monitoring of fetal oxygen tension duringlabour. Br J Obstet Gynaecol 1977;84(suppl 1):1-39.

16 Nickelsen C, Thomsen SG, Weber T. Continuous acid-baseassessment of the human fetus during labour by tissue pHand transcutaneous carbon dioxide monitoring. Br J ObstetGynaecol 1985;92:220-5.

17 Dildy GA, Clark SL, Loucks CA. Intrapartum fetal pulseoximetry: Past, present and future. Am J Obstet Gynecol1996;175:1-9.

18 Bretscher J, Saling S. pH values in the human fetus duringlabour. Am J Obstet Gynecol 1967;97:906.

19 Yeomans ER, Hauth JC, Gilstrap LC, Strickland DM.Umbilical cord pH, pCO2 and bicarbonate followinguncomplicated term vaginal deliveries. Am J Obstet Gyne-col 1985;151:798-800.

20 Low JA, Pancham SR, Worthington D, Boston RW. Clinicalcharacteristics of pregnancies complicated by intrapartumfetal asphyxia. Am J Obstet Gynecol 1975;121:452-5.

21 Dweck H, Huggins W, Dorman L, Saxon SA, Benton JW,Cassidy G. Developmental sequelae in infants havingsevere perinatal asphyxia. Am J Obstet Gynecol1974;119:811-15.

22 Ruth VJ, Raivio KO. Perinatal brain damage: predictivevalue of metabolic acidosis and the Apgar score.BMJ1988;297:24-7.

23 Dennis J, Johnson A, Mutch L, Yudkin P, Johnson P. Acid-base status at birth and neurodevelopmental outcome atfour and one-half years. Am J Obstet Gynecol,1989;161:213-20.

24 Fee SC, Malee K, Deddish R, Minogue JP, Socol ML.Severe acidosis and subsequent neurologic status. Am JObstet Gynecol 1990;162:802-6.

25 Low JA, Panagiotopoulos C, Derrick EJ. Newborn compli-cations after intrapartum asphyxia with metabolic acidosisin the term fetus. Am J Obstet Gynecol 1994;170:1081-7.

26 Nelson KB, Ellenberg JH. Antecedents of cerebral palsy. NEngl J Med 1986;315:81-6.

27 Adamson SJ, Alessandri LM, Badawi N, Burton PR,Pemberton PJ, Stanley F. Predictors of neonatal encepha-lopathy in full term infants. BMJ 1995;311:598-602.

28 Soothill PW, Ajayi RA, Campbell S, Ross E, Nicolaides KH.Fetal oxygenation at cordocentesis, maternal smoking andchildhood neuro-development. Eur J Obstet Gynecol ReprodBiol 1995;59:21-4.

29 The GRIT Study Group. When do obstetricians recom-mend delivery for a high-risk preterm growth-retardedfetus? Eur J Obstet Gyneacol Reprod Biol 1996;67:121-6.

Figure 3 Fetal blood pH (expressed in multiples of SDfrom the normal mean) at cordocentesis in chromosomallynormal small for gestational age fetuses and subsequentGriYths neurodevelopmental quotient (DQ); r= 0.41, n= 65, p= 0.0008. Squares indicate three children withcerebral palsy. Reproduced with permission from Soothill etal. Eur J Obstet Gynaecol Reprod Biol, 1995;59:21-4.

2

0

–2

–4

–6

–8

–10

–12

–14130

Griffiths developmental quotientp

H (

SD

)70 80 90 100 110 120

×

× ×

×

×

×

××

××

×

××××

×

××××

××

×

×××× ××

×

××

××××××××

××××

××

×

×

××

× ××

×

×××

×

×

××

Causes and consequences of fetal acidosis F249

group.bmj.com on April 22, 2018 - Published by http://fn.bmj.com/Downloaded from

Causes and consequences of fetal acidosis

Catherine S Bobrow and Peter W Soothill

doi: 10.1136/fn.80.3.F2461999 80: F246-F249 Arch Dis Child Fetal Neonatal Ed

http://fn.bmj.com/content/80/3/F246Updated information and services can be found at:

These include:

References http://fn.bmj.com/content/80/3/F246#ref-list-1

This article cites 29 articles, 3 of which you can access for free at:

serviceEmail alerting

box at the top right corner of the online article. Receive free email alerts when new articles cite this article. Sign up in the

CollectionsTopic Articles on similar topics can be found in the following collections

(637)Radiology (diagnostics) (692)Radiology

(393)Immunology (including allergy) (720)Clinical diagnostic tests

(929)Epidemiologic studies (291)Metabolic disorders

Notes

http://group.bmj.com/group/rights-licensing/permissionsTo request permissions go to:

http://journals.bmj.com/cgi/reprintformTo order reprints go to:

http://group.bmj.com/subscribe/To subscribe to BMJ go to:

group.bmj.com on April 22, 2018 - Published by http://fn.bmj.com/Downloaded from