The Significance of Fetal Acidosis

THE SIGNIFICANCE OF FETAL ACIDOSIS IRWIN

H. KAISER,

M.D., MINNEAPOLIS, MINN.

(From the Department of Obstetrics and Gynecology, The Medical School, University of Minnesota)

F

ETAL acidosis, defined simply as an increase in the hydrogen ion concentration in umbilical cord blood, has been known for over twenty-five years to be associated with neonatal difficultiE>s. Recently, a considerable body of information about the control of fetal pH and its related variables has become available, making it possible to review and extend our understanding of the significance of changes in fetal blood pH. Present-day concepts of acid-base regulation and electrolyte distribution developed largely in the second and third decades of the twentieth century. ·williamson/ in 192!3, was probably the first to apply these concepts to the study of the mother and newborn infant in human pregnancy. Oard and Peters2 later presented a very meticulous analysis of the maternal changes, to which ver·y little has been added sinee. In 1926, Levy-Solal and his coworkers3 published, in addition to other observations, the first measurements of pH in the blood of mother and fetus, based upon samples obtained at cesarean sertion in 2 patients. Bock, 4 in 1927, reported the first extensive study of the changes in pH of maternal blood with advancing pregnancy and labor. Blair Bell and his cowul'ket·s,·' having become interested in V{arburg's hypothesis that malignant eh11nges in cells were a consequence of metabolic alterations due to hypoxia, studied the fetus as a rapidly growing, relatively hypoxic mass of tissue. They dearly established, in H)28, that the pH of fetal blood is lower than that of maternal blood. At that time, the glass electrode was just coming into usc for the measurement of pH in body fluids, and its usc was beset with technical difficulties. It is clPar now that the values found by Levy-Solal and Blair Bell are too low. In 19;30, Haselhorst and StT·omberge1-," who Wl're primarily interested in distributions of gases across the placenta, reported values for pH of fetal and maternal blood based upon samples obtainrd in 4 patients at cesarean section. These values were calculated from the measured gas contents and a series of equations, a method with a larger inherent error than that of direct measurement. In 3 of their cases the fetal pH was lower and in one higher than that of the mother. Eastman, 7 in 1932, using the glass electrode, added one further case studied at cesarean section. and 7 cases at normal delivery in which fetal blood pH was lower than maternal. 573

\Ill.

f.

.

Ob~t. & Gvnf'l

1·brch. ·lq;q

Noguchi, 8 also using the glass eleetrode. in 19::7 reported findings in a larger series of infants and mothers whose blood was obtained at the monl(mt of' delivery. He took pains to compare the blond pH of those infants who harl and thosp who had not initiated respirations, hut as Eastman had pointed out. neither group r·ould really be take11 to r·r·Jn'('S(•llt frtal c•mHlitions. In general, Noguehi found, as hacl Eastman, that tht• pH of umbilir·al blood. was lnwpr· than that of mat<~mal blood. With valm•s nxailablP for· <'11111JHII'ison 011 only :-; infants sampled in uteJ'o, that is, at c•P:mrean seetion,"· "· 7 it was not possihk to state how thesf' values n·laterl to f'l'tal r·onditions. Pur'tlwnrwrP, it was already wf'll known that an<'sthcsia r·ould markvdly ehang<~ adult aeid-IHIS<' distributions, and that ohstdl'i<"al an<·sthesia. eould affed: the f<'tns. 1t is of some int<·1·est that wh<"n BaJ·<·t·oft" rnvi<~wed th<' snhjP<"t ol' n·lative ft-tal ancl matl:'rnal pH in hi~ monogmph on pl'<•natal life in 1~)46, h<> ns<'d only tlw data of Hasf'lhorst and Ntrmnlwr·gc·r, an
I.

Tu~: NoRMAl.

pH

o~· 'l'lm l1llfH!LlCAJ, BLoOD m· 'l'JH; Il11MAX r'~;·rrs Al'W ,N'~]WBOI\1\

(~OMPARBD \VI'l'H THAT f)f' T'l'ii l\fO'!'HER :\TA'l'~;RKAL '

-~-~--~~-""

--·--

Eastman,< 1932 Noguchi,s 1937 Kaiser,Ja 1953 Goodlin ani! KnisPt·,H HJ5i

)[

f<·X·

l+t _, 1'"

V}~J)f

/.:l(1

7.:Hi i.:P\ i.:li

7.:ln i.:lll

i.:t:! i

i.:l:!

i.:!li 7.2R

*Inelu<·al an ..stlwsh and !1.11 samples prior to el'fec .ive respiration. ill\facKinney ant! eo-workers" rep
In thr early ';jQ's, Uraham and his group 11 at the University of 1\Iiehigan prt-sented their observations of the changes in aeid-base homeostasis and electrolyte distribution whi<·h o<~em· in the infant in the :.!4 hour p<~riod aftn birth. Although th<•y dis, ohtainnd ideally hy withdrawal of blood from a pulsating cord prior to any respiratory efforts, and neonatal sampl<•s must. therpfore. bt' sharply maintained. 12 In 195:3, determinations of pH hy tht' glass cleetroclr on 12 tnw fetal blood samples, ohtaiiwd from thP um hili<·al <·ord at the timv of <·Psarenn section undC't' l hy(hog<·n iou <·otH'l'lltnrtion of umhili<'al art<>I"Y hlood it~ highPr than that in the umhilieal

\-(.~lnme

575

SIGNH'lCANCE OF FBTAL AClDO::ilS

77

Nnmher _:_

vein, and in the umbilical vein higher than in the maternal veins. These observations have since been extended and confirmed. Jt is elear that normal labor and delivery under loeal anesthesia do not alter the pH of fetal blood.' 1

Fetal Blood pH in Animals 'J'hcre is now also a considerable body of information about fetal pH in experimental animals. The need for relatively large blood samples for thl· aN•nrate determinations of blood pH has limited these studies to the species whieh pr·oduec large fetuses. f;'ur·thermore, sin<·e tho physiologists who have wor·kod with laboratory animals havr; been f·hiefiy interested in blood gas distl'ihutions, detailed data on blood pH have appeari'd only recently. Keys/ 0 in 1934, made observations on four fetal kids which indicated thal in the goat the fetal blood pH is higher than that of the mother. In 19fl7. Bart·on and Mesehia 15 published blood pH values on three fetal kids which do not confirm Keys' measurements. They suggest that the rapid changes in maternal alkali reserve which occur under anesthesia might account for Keys' findings. Another recent study,"1 hasr>d upon a large number of goats and their kids at 69, 106, and 139 days of pregnancy, also indicah's that conditions in the goat arc essentially the same as those in other species. Another· species on which thert• is a large body of data is the sheep, and het'(' again the fetus is found to have a lowt>r blood pH than the mother at all stages of pregnancy. 17 Essentially the same observation has been made in the l'abhit by Young/ 8 although, as she states, her measureuwnts are affected by the very small quantities of blood nvailable. One study on the domestic pig"1 late in pregnancy suggests that in this species the pH of umbilical vein blood may he slightly above that of the maternal utel'inc win. The need for heavy anesthesia in pigs, in contt·ast to the possibility of ohtaining samples undl'l' lo<'al anesthrsia in sherp, goats an!l humans. reqnirps that this ronelnsinn he lw I <1 sub jurlire. Thrse ohsi'rvations are gathrre<1 in Tahle n. whi(•h is hasPd on data ohtained in onr own lahorator,v, exe<'pt. as noted. 'l'ARLE

H.

pH

RELATIONSHII'S OF 1\iATERl\AT. Al\1) U~iBIT.JCAL BLOOI1 IX SEVERAL RPJ<:Clf.S, AT VARIOl'S R1'A«ES Ol' PREGNAN\'Y

RR

(;oa{IH

Halohitt

106 1:!4 H:J (iil ]0:! l :w J:l3·40t 23-31 33-:H

106

14 16 11

21 16 l'',,

7.:17

Ill

i.:l5

R 3

7

7 .:~~;

1.43 7.40 7.42 IAI i.:ix

f)

i.-111 iAO

i.:lX

f)

j'

1.46 I.H 1.+7 7.+;}

3

i.+:!

:I 6

i.JO

]:!

*Duration of pregnancy· at term: pig 110 to 114 days. tBarron an
7.+11

7.311 ~heep

7.35

-;. :~:{

/ ..17 7.:16 7.:!4

i .:11 7.:!;}

7.:11

7.:H) i.:n

7.:1:! 7.:H

7.:Vl

+I

7.37 7.34

10 12

and. goats 147-150

7.:{fi 7.3:1

7.41 7.36

1~

7.37 days,

rabbit

ANIMAL

7.34

:n

dayg,

and

lt can be concluded unequivocally from these data that in all species tltw,; fat· studied, the hydrogen ion concentration of fetal blood is higher in th1• umbilieal artery than in the vein, and that the mean pH of normal fetal

KAlt:il:l{

57()

\Ill.

I.

hlootl ito: lowel' than the mean pll of maternal blood. The qtwstion nmy lw r·aisNl as to whPther a tetm sueh as aeidosis, whieh has pathological implieations, can properly be used to refer to this situation. If the pH of normal adult arterial blood lw used as a point of rt•fPI'PnCf\ then the f<:'tus is in rf'latin: acidosis. Indeed, if the sen1·al normal par·amders of adult hloorl pli an· <'Ollsidered, tht~n the f(•tlu; is in I'Piatin· rt·spiratot-y aeidosis, silwe its pCO~ is higher than that in th<• rulnlt. On tht• other hand, as will be denloped below, thc·n• is no evidPnN' that this is a pathological t•ondition. and it would mtdouhtedly be better, if thesP terms an• used at all, to indicate that they at·<~ l'Plative only. The pt'O}Wt' hasP line i'oJ' t~onsitlt>ring altpr·ations of aeid-base equilibria in tht' fetus is, of cout·s<·, th<· noi·mal fetal state and not the adult state·.

Buffering of Blood 1'h<' pH of the blood is subjPet to tlw ll<:tion of tiH• blood buffer systems oprr·ate in th(• fptus as tlwy do ill tlw adult. The phosphate buffer syskm is not of much significanc(• lweausc· of the relatively low concentration of phosphate ions in blood, in t hP Yieinity of :; m Eq. per liter. Rimilarly, the protdn system is not vc•J'Y signifieant, (•nn though the eoneentration of protein is higher than that of phosphat(·, bP<·aus<' of the fad that the normal range of hlood pH is well ahov(• the isot•lrd !'i(• point of blood prot<:" ins. ·whi(~h

The buffering· effPet of thP hi<·arlwnatP syst!•tll. which iH important, is Je]H'IHlent upon the disstwiation of thP wt•nk add. carhonic acid. to hydrogen ions and bicarbonatP ions. as follows: (l)

Tlw t(•1H1Pncy for this dissociation to take plaee is related, by the law of mass nction, to th(• concc•ntration of hy(hogen ions in the sysh•m. The exp1·rssion of this relationship is refer'l'rd to as thP H<•nd<•t•son-Hasselbalch t'quat.ion which, with (•<:'rtain reservations. holds fnr· all biologieal fluidR. This equation can lw stated as: pH

pK' + log 1II(JO{) (H,CO")

(:3)

where K' is the first dissm·iation f~onst~mt o t' carhonie acid, whi(·h is a m<'asm·e of the tf'lHlPm•y of <'qnation J to pr·nePe(l to the right. FurthernHH'<\ shlf'(' thc•J'f' is a \'('l'Y strif•t relationship ht>tWPI'll the lJl'PSSUr<' of CO~ as a gas and thP roneentration of ll~CO:: in <111 aqneons system, and ~
, p !'\., -. I o:.; IHCO.,•)

(3)

~ow, since pK' is a ('Onstant, this l'Clationship makes clear that as pCO" in('t'eases. if (HCO::') is constant, thP value of' pH must decrease. Rimilarl;v·. if HC0 3 • for· any rNtson dccl'ea:;;ps while pf'0 2 is constant, pH must derrease. The three values are thPn intimately intPnelatNl. Consequently, for given changes in pC0 0 , the changes in pH will he in proportion to changes in the fraction of which pCOe is a part, that is, the hlood will he buffered. The operation of this buffer system in blood is, howPver, in the final analysis dependent upon tJw funrtioll of tlw l'N1 e!'ll in (;()~ transpOI't. 'J.'his works in a number of' wa;.·s. 'l'he hydration of C0 2 to H 2 C0:1 is a relatiYely slow reaction. The adul1 red cell contains the enzyme carbonic anhydrase, which markedly speeds up this

Volumr 77 ~umber 3

SfGNIFTCANC:E: OF FETAL ACIDOSIS

577

reaction, thereby greatly accelerating the conversion of C0 2 as such to bicarbonate. In all likelihood this enzyme is absent from fetal red cells20 • 21 but, 1-!ince there is no lung in the fetal s.vstem, exchangr of gases ocrurs entirely in an aqueous medium and the absence of carbonir anhydraRe may not be of crnrial importanee. H cmoglohin is, of eom·se, a IH'otein and can funetion directly as a buffer. :-iime, for example, concentration of hemoglobin in fetal blood is at least 15 Gm. pPl' (•Pnt, Hnd fetal blood hcmatocJ·it is about flO per cent, it follows that the eoneent1·ation of hemoglobin inside the red cell is at least 30 Gm. per eent, whirh is, of eourse, many times that of protein in the plasma. This amount of protein ean achieve signifieant degrees of buffering, by its effect within the red cell. Furthermore, undissociated amino groups in the lwmoglohin molecule ean J'Pa<'t with C0 2 to form carhamino comp(nmds as follows: R-NH, +CO,= R-NHCOO' +II+

(4)

The hydrogen ions thus formed contl'ibutc to the pool of hydrogen ions from other sources but they do not alter the pH in the 1·ed cell appreeiahl~· for two reasons: ( 1) the high buffering capacity and high concentration of hcmoglohin in the red cell and (2) only a small fraction, lPsR than onP-fifth, of t lH• co~ hl the blood l'C'aets arcording to l'C'action 4.

Relations of pH to Oxygen It is essential to bear in mind that the r0actions involving C0 2 are affcctrd by and affect the oxygenation of the hemoglobin. Oxyhemoglobin is a somcwhat stronger acid than l'educecl h0moglobin. 'l'his means that as blood is oxygenatcd, reaction 1 will tend to go to the ldt, and the carbonie aeid thus fomwd will tend to he dehydrated into C02. '!'his gas in the adult will rea(lily be exerrted in the expired ail', and. in the fetus, move aeross the placenta into the maternal blood stream. Oxyg<•nation of hPmoglohin will have the samP effl•ct on equation 4, also liberating· C0 2 • There arc also shifts in ion distribution. as consideration of <'qnations 2 and :1 will malu• clear, hut thcse nN•
=

oxyhemoglobin total hemoglobin

-,---,-.c,-,--"--,,---,--;-

(5)

~otP, however, that equation 5 docs not include the ox~·gen pressure, although the movement of oxygen within tissues and across membranes is related to its pressure and not to the hemoglobin saturation with oxygen. Consideration of the relationships between pH and pC02 and oxygen saturation as outlined in the preceding paragraphs will make it clear that:

A. If pH and pC0 2 are held eonstant, oxygen saturation will decrease as p0 2 decreases. Expressed graphieally, this is the familiar dissociation curve of oxyhemoglobin. B. If p0 2 is held constant, as either hydrogen ion eoncentration or pCO~ is increased, oxygen saturation will deerease. This is known as the Bohr effect. At present it is not entirely established whether the pH effeet is separate from the pC0 2 effect, sinee, as equation :3 demonstrates, they are intimately related. This influence of pH and pCO~, however, is of great importance in oxygen transport. It makes more readily understandable that at the lung or placl'nta,

I\ A IHEH whCl'l\ CO~ l'rmorP, tlwsP d'feds at·e to a <'<'rtain PXtent ind to fetal blood. Ind(ePtL the wt>ll-known difft•renee in oxygen affinity lwtw(•en fetal and adult blood shon ld sCl"Yl~ as warning that tlH•rc may ht> similar rliffet'Pll<'l'S in rrgard to tlH' Bohr

('ff('f't. :;:;

Placental Exchange Complex as these relations may lw, t lwy heeonw even more so when tht• effeet of placent~tl exchange ii-i <'OilsidPt'Pd. All the i-inbstan<·('l-i mentioned above, with the exception ol' the hwnoglobin within t·ed eells, move more or less readily across the interfaeP hl't.ween tlw maternal and fetal blood streams. Since they move in proportion to thdr gTadi(·nts, cxC'hange will depend upon the flow of blood past the interfact•. Bol'll, Hawes and l\1ott 2 :' have demonstrated that in the fetal lamb under N•J·tain eonditions of acute hypoxia thPre is an increase in fetal heart rate and a (~otwomitant inerease in placental blood flow. \Vhether sueh a eomp(•nsatory lll<'<·hanism Fxists in othf'r s1wcil's is not known. Gases move across the plaeenta with eonsidel'able rapidity. Dieckmann/" in 1944, using a technique of multiple sampling of human cord blood at cesarean section, demonstrated signifieant changes in 0 2 and COz content within fi minutes of ehanging matPrmll inioipin·d ail· to 100 per <•ent oxygen. On thf' other hand, changes in matemal pH, without signifieant alterations in gas pressures, are refleeted in the fptus only in a mattPJ' of hours, in both human and sheep.U· u• 'l'he adult tends to n;ainta.hl pH <'oHstant by altering the respiratory rate, taking advantag(~ of rapid gas movt'llll'llt either tn raise ot· lower pC0 2 and thereby, as in equation 3. hold pH fixed. If, as suggested, th~: fetal equivalent of inereased respirations, v,rhieh wonlfl he incrrased p]aeental flow, is not sensitive to pH ot· pC'O:; chang1\S. 2 '' plar·(·ntal adjustment of pH might indeed be slow. 'l'he regulation of the function of the placenta as a kidney to maintain pH is little understood. Ions can be expeet.eu to move across the placenta IPSN readily than the electrically neutral gases. Furthel'more, steep placental gr·adients of such ions as C'hlol'ide, laetat.P, and [Jyt·uvate haY(' !wen ohserv••d under a variety of conditions. 111 • 2 (;, 27 • " 8 In regard to some ions, active tt·ansport rather than movement by diffusion gradient alone certainly occurs. How sueh aetivP transpor·t might t·espontl 1o an inet·eas<· of lactate in the ])J'esetw•· of severe fetal hypoxia for examplP is not known. If lactate accumulates, i1 tends t.o replace biearbonat(; in th<· anion totals. alld, as <'an be sl'en in equation 3, this lowers pH. In considering fetal hypoxia, it is important to (•onsid<·r simultan(•ous ehanges in fetal pC0 2 • 1n any interferenee with placental gas exchange, fetal pC0 2 dses as pO~ falls, and this donhle-hatTt'lP
\'IJllliiJC

77

SIGNIFlCANCE OF FE'L'AL

~ Uinber ~ 1

ACIDOi:lJ~

pH. If, however, oxygen exchange alone is disturbed. the changes in pH and pC02 can be expected to be less marked, and oxygen saturation of hemoglobin maintained at a higher level. As is well known, the sensitivitv of the adult 1·r~piratory center to pC0 2 changes is much greater than to ox);gen saturation (•hangeR. That hypoxia, as compared with hrpoxia and h~·per<>apnia c<)lnbined, is less deleterious to the fetus has not been demonstratrd, hut thr experiencP of Crosf! and assoeiates 29 with the use of 15 per cent oxygen atmospheres for tlw nrwborn suggests that this is the ease. Finally, it is possible to reduce both p0 2 an(l pC02, and this appeal'S to he eompatihle with survival at Yery seYerc> drgrees of h~·poxia, with maintenance of normal pH relationships."' ,Tames and eo-workers 20 have now reported studies which add considerably to an understanding of these changes. Thev examined rord blood obtained from infant~ at the moment of birth and rompai·ed tht>ir findings with sroring of th!' status of the infant by the Apgar method. Depressed infants were fonnd to h~nJ depressed pH in umbilical artcr? blood. Many vigorous infants also exhibited lowering of pH, however, which ,Jamrs and his assoeiates attributn to transitory interferrnces with plac~ental exchange due to cord obstruction. maternal posture, anesthesia, and labor. 'l'hr depressed infants exhibit a lowering of blood buffer basr, however, as evidence of a metabolic as well as a respiratory type of acidosis.

Occurrence of Low Fetal pH Depression of fetal or immediate neonatal pH has been observed in both spontaneous and experimental cireumstancrs. In rach instance it is im po1-tant to consider whethrr this is depr
Eastman7 Noguchis James et al.3o

III. pH

A}:[D pCO, OBSERVED

6 7 9-12

7.32

!}:[

1NFAK1'8 WI'l'H ASPHYXIA NEONATORUM

27.6

7.04

7.24

7.04*

61.6 40.4 82.0*

Ul 6.6 6.3*

•TTmbilical artery samples.

Asphyxia neonatorum was the first naturally occurl'ing eondition in which rlepression of fetal blood pH was drscrihcd. Niner nn infant must hr hom hrfore it can have asphyxia n<•muttorum, the stucli<•s summarized in Table III, reported by Eastman 7 and Noguehi, 8 are nec-essarily based upon blood obtained at birth, hut in all eases the samples were ohtainrd immediately and so reflect intrauterine conditions late in labor. Comparison of these figures with those in 1'able I makes elear that two factors are operating. Difficult labor itself I'esults in acidosis in the mother, as can be seen in :."' oguchi 's mean mate mal value of 7.32. In the two instames in which maternal values were reported by Eastman, the blood pH's were• 7.18 and 7.20. The mother ordinarily com]J(•nsates for· this in part by hyprr·vEmtilation, and iml••e1l the sever·e hyp(•rventilation in the seeo!Hl staj.(·e of dvstod<· labor l'ltn r<>:·mlt in markP•l dropk in pCO~ as Noguchi's mean value (;f 27.() makes clE'at•. This may lw ('Xag·ger·ated by inereasf's in body temperature, which fnrthc·e dee1·eases pCC\. In addition, however, in these eases of asphyxia neonatorum the pH gradient lwtween maternal blood and fetal blood is increased over normal. The gradient found by Noguchi in normal eases was 0, although later studirs have indicated that tlw normal gradh•nt is 0.0!) to 0.06 pH unit (Tahle 1). The maternalfetal pH gradient for Noguchi's asphyxiated infants is 0.08 unit, and for tho

580

,\m. ). Oh'L & Gyncc. March, 19S'l

KA11"\EH

:! eaf.lcs of Eastman's wh<•re maternal Yah!t'S are reported, 0. l:l and 0.1-t unit. Associated with this there h; a mark(·d intn;ast in p( '( )" awl a d<"<·rease in oxygrn eontrnt to sneh a degnw that the p0 2 ean lw presUttH'rs abo han· a dP<'t'('HS<·d blood pH. ThPy ohser·ved a <·on<·-

lation of elinieal outcome with the J>rPst·nce of this pH n pointed out11 that tht'('C of the mothrr·s itt Lown·y'H seriPs reeeiYed ammonium ehlor·i(h•, whidt pr·odtH'<·;; at'idmds. and ihHt pH ndm•s on tht•s<; mothers WPl'l' not obtained. (i'urth<·rmore. the :; infants hom to these motlwr:-; cxhibitw1 low blood pH vahws hut had JH; m•onatal diffkultil's. A suhsnqul'nt study of a SOllll'\Vhat Jat•gt•J' gt·oup of llPW!JOI'Jl infant;.; of diaJwtie 1110thei'S ~ has, howeyrr<, r·onfimw
TABLE

lV. pH

oF

BL

Lowrey et a1.,a1 1954 Kaiser and Goodlin,:<2 195H et al.,H 1957


7.:l-t

7.1'/t i.08t

*Sorne 1notherR were not te::.tp, I tl'mbiJi<,al art~ry at tlw tinw of delivPry. Xnrmal ( Tablt.c 1 l 7.28. tUmbilkal <1 r·tery. Normal in thi" stu
That these ehangt•s in the 11ewbor·n of diabetie '\volnen are not due tu maternal changes e.an lw seen fr·om the data in Tab]\' IV. ( 'arringtou,'H studying the prediabetic statn, in whi<·h tht• blood pH ot' tht• mother· ean be assumed to be normal, founs resemhling thosP

of the infants of diabctie mothers. It must he noh•d that these bio(•he111ical dumges (•m, however, that dystocia severely aggravates thes(' a hnormalit.ies, since extrrnw values were observed in the infants who suffered a difficult deliverv. Changes in fetal blood pH not associated with either asphyxia or diabetes have been observed. In one such case, 14 •nd 35 , oa.e 99 maternal pH was also depressed, and blood laetates wore elevate(l. .A met.aholi(~ acidosis of unknown rtiology affected not only the mother but hrr fetus. ln an other case/ 3 a fetal umbilical vein pH of 7.01 >vas found in the peesenee of matrmal venous pH of 7.:J6. Detailed J'(•vicw of this ease at the time and subsequently has failC'd to disclose any explanation of this finding. 'l'hc observations of Carrington and his associates"* may prnvidr this nxplanation. At pres(~nt, however, it is not possible to state the expected ineidenr(' of such UBJH'edict.able abnormalities of fetal hlood plf. Depression of blood pH associated with increase of hlood lactates has been observed in spontaneously and severely anemic fetallmnhs. 36 It is not known whether such changes occur in anemic states of the human fetus. The acidbase status of infants with erythroblastosis fetalis has been studied only in

SIGNll:'ICANCE OF FE'L\L M'fDOI'JS

;)~

1

conneetion with exchange teansfusiou, 37 Bv the time such transfusion is undertaken the infant has haa 1inw fot· r·p~piratory eompensation of fl'tal abttormalitics. Bxperimentally, depr·0ssion of fPtal pH has lwt>n pt·odneed hy administration of ammonium chloride to the preg·nant humanH· :l:; and pregnant rabbit,'' 8 with essentially i(lentical results. Impetus was giwn to tho human study by tht> observation of J,owroy and eo-workers" 1 of blood pH depression in the infants of diabetic mothers who had received ammonium chloride. This drug has been used widely in medicine as a diuretic and in obstetrics, in addition, in the treatment of hydramnios but then• was no study of its effect on the fdus. It was found that, as maternal blood pH dropped, fetal blood pii dr·opped with it, maintaining f>Ssentially the normal gradient. In some cases. moee marked changes were observPd, and some newborn infants were found to have not only markedly depressed blood pH values, but also very high pCO~ all ease with the diabetic infants. tlwsr artifactitious changes were not associated with the kind of morbid coui·se ohserYecl in the infants whose blood pH depression was the result of dystoeia and the attendant asphyxia neonatorum. Although some of the infants whose mothers had recdn~d ammonium chloridC' were strikingly cyanotic at birth. they aU C'stablishC'd respirations without diffic·ulty and nonP had a morbid eourse. Of smm· interest in this study was the ohsNvation that depn•ssion of fetal blood pH appeared to lag behind dcpt'Pssion of maternal blootl pH when uncoated ammonium chloride was used to produce maternal acidosis ravhlly, and that recovery of fC'tal pH to normal h•vels also lagged when administration of the drug was disenntinned. A similar lag ph(•nomf'non has been observed by Barron and 1\fesehia'" in sheep. The other experinH'ntal c·ondition in which depression of fetal blood pH has been produced is the exposur·t' of prC'gnant sheep to chronic existence at much diminished pressnrl's in an altitude c·hamber. 27 The simulated altitwks USf'i1 W('l'f' suffieif'llt to eausc· Sl'\Tt•re distress, and the death of one ewC' awl :1 fetnsrs of the 8 JH'egnant ewes employed. All of the survivors exhibited ma t·ked lowering of both p( ~(\ and pO~ mH1 large rises in hemoglobin coneentration. All of thP ewt'S which wer·e eal'l'ying living fetuses had normal hlood pH values, hut one of the 5 fetuses was found to have a marked pH deJH'{•ssion eomparetl with thc• normal. with the other fetuses, and with its own mnthc·r. This was assoeiatC'd with a vm·y low umbilical artery oxygen content aml a p(\ in the bloocl of that Ycssd of 9 rrnn. Jig. In addition the fetus had a plasma lactate conePntr·ation of ;J4.5 mEq. per lite1·, as compared with a normal of :1.5 mEq. per liter. and a chloride concentration of 81.5 mEq. per lit<•r·. This fetus, then. exhibited the biochemical stigmas of a true metabolie aeint of fetal pH wh<•n rapid shifts in mat0rnal pH occur. hut this i;;; an unstahl0 condition whic•h inedtahlv conPets itself toward the norma I i\•tal-maternal pH gradiPnt. · Tn the mother, if pC0 2 rises. nr tends to rist', and the pH to fall with it. hyperventilation ordinarily oecnrs and eompensation is thereby achieved. There is no evidenee at present that the fetus has any compensatory mechanism lih hyJH'rvPntilation availahk to it. ThC' increasrs h1 frtal blood flow through

1\.\ 11-\I<:Jt

\IIi. ).

the placenta, whieh Da Wl'S aud his <·o-wo rk<•t'i'e· han· •~h:-;c·t·Y<·d uw kr <'l'rt a ill eonditions of a<;utP hypoxia in the fi'i a I Ia Hl h. t·atuwt lH' maintaitH•d for Y<·t·.'· long-. 'rher·n is no evidPlH'l' of :->twh a JH'O('\'SH in tht· human fPtus. Hi;.;•· in fPtal p( '0 2 ant.l contomitant fall in pll, will. by tht• Bohr effect, 1t•tH1 to tkpn·s;.; oxygen saturation even if thl' pO" is <'Ullstant. ~inc<" the mov<'mPnt of oxyg<•ll in tissues dep!'nds on its pt'(•sstm• atHl not on tht• hemoglobin satut·ation, this depression will not lw of impot·tanct• until VPI',\' low I<'VPls of satut·ation ar·p reached. As far· as tlw twwhorn stah· is eon<·<•rtwd, it has been shown 1hat the newborn respiratory eenh·r it~ refractory to large increa~ws in p(~( l~. Om·<· pulmonary t•ompemmtion of ehang£•s snl'h HX thrst~ is availahh· 1o tlw l'l'tus. it can t>vidently estahliHh nm·mal <;onditions r·atlwr· l'apidly. Only if tnw hypoxia has cwc·ur·r·c·d awl ('anspd (Ia nrH ge a J'P tlws(~ altf~ra.thms i 11 pii and p< '0~ really nwaningful.

Hydrogen Ion Relationships Across the Placenta [t may be profitable at this time to eonxider the basic relationship nf blood pH and earbon dioxide aeross the plaeenta. Equation::. the Hc·nderRonHasst'lhalch relationship, (·;m he rt•arr·anged to read: pE'

pH

i.HCO,-) - pCO,.

If the placenta is considered a semipermeable membr"anc which is fr·e1•lv permeable to hoth HCO"' and CO~. thPil, since for· rmtctical purposes pK' is the same on both sidex of thr placenta, W<' Nm state· I

HC
(ill

'l'his can be fm·ther l'<'HITHBgiHl to xtate: (6tt)

'J'hen, if pHm pHt is positive, that is, if the hydrogen ion cmu·entration of the mother is lowel' than that of the fetus: (HC0 3'.,.1

1 HC0/,1

> .·---~""-~

(7)

Tn the ordinary placental relationships, thP pr·essm·c of ( ·o~ on the ft'tal sidr exceeds that on tht' maternal. Under these drcumstanees, the relationship in ( 7) provides for a much smaller diff('rcnce in biearbonate concentra· tion between mother and fetus than if fetal blood pH exceeded maternal. Since maternal bicarbonate is buffered, this nwans that with fetal blood pH lower than maternal, the fetal bicarbonate tends to be similarly buffered, and in the presence of changes in carbon dioxide pressure in either mother or fetus the necessary corresponding shifts in ionic distribution are minimized. This can be illustrated with the use of the normal concentrations of these substances. If maternal bicarbonate is about 22 mEq. per liter and maternal pC0 2 , expressed in millimols per liter is about 1.1, then fetal pCO~ must be more than 1.1. vVe can set it at 1.3 a}l(1 substitute in (7) : 2::!

--> 1.1

I HCO,'f) ~-~-~;-;;:--

In this case, fetal bicarbonate must he lPss than 2fi mEq. pm· litt•r and the

diffeJ·pnce hetwet?n fetal and matt?rnal bi(•arbonatc less than 4 mEq. per liter.

Volumr 77 \ilJtHher 3

HIGNU'JCANn: OF r'E'l'AL

ACIDO~I~

?\ow, ir we use the same Ya hws. hut snlmtitnte in tht• l't'V<'l'S(' t·dationship or that in (7), we obtain: ~:!

~-

1.1

<

( HUOi l

in whieh case fetal bicarbonate must be more than 26 mEq. pf•t· liter and tlw tlifferencc between fetus and mother more than 4 mEq. per liter. In other words, it can be stated that, assuming that fetal pCO~ rxc·<·Nls mater·mtl, the mor<' closely the fdal eleetrolyt<' pattem approaches that of th(· moth<'l', th<• greatrr wi1l be the depression of fdal blood pH below matf•r·nal blood pH. l•'E>tal "aridosis" thus w•rves thr ]nu·pos<'S of elN·trolyte honwostasis. 'l'hf're is something in the maternal diahdie stat!• whieh r!'sults in n obsPrv<>d in the infants of p1w1iabetie m othrrs. :' 4 \Vlwn, in th<· course of dystocic labor, thrre is intuferelwP with placl':'ntal exchange, very s<•vrre hiochrmiral changes can be prod nerd in fetal blood. 3 " I\'far·ked blood pH
What then is the meaning of a depression of fetal blood pH-fetal aeidosis? In all likelihood, it is a finding much like an elevated whitP blood cPll count. It may be entirely incidental and without pathological significancf', a.lthough this is distinctly unusual. It may he the responsP to an exogenous stimulus sueh as ammonium chloride, and well within thf' allaptive eapaeitks nf the newborn. Finally, it may reflect a serious morbid state. Only an estimation of the clinieal state in which the lowered fetal pH is found, and a dl:'ter·mination of the other variables, which arf' inc•xtricably relatPd to it in rPspirator;' r.hemistry, can make possible a proper eYaluation of its signifieance. References 1. Williamson, A. C.: AM. J'. 0BST. & GYNEC. 6: 263, 1H23. 2. Oard, H., and Peters, J.: .T. Biol. Chem. 81: H. lfl2!J. 3. Levy·Solal, Weissmann-Netter, and Dalsace, .T.: Com pt. rend. Soc. de hiol. 95: 185, IH26. -t Bock, A.: Arch. Gynak. 131: 468, 1H27. :3. Blair Bell, ·w., Cunningham. L., Jowett, ~f., Millet, H., and Brooks, .1.: Brit. i\f. .r. 1: 126, 1929. !}. Haselhorst, G-., and Stromberger, K.: Ztschr. G-ebmtsh. u. G~·niik. 98: 49, Hl!ll!. 7. Eastman, N.J.: Bull. Johns Hopkins Hosp. 50: 39, 1932. 8. Noguchi, M.: Jap. J. Obst. & Gynec. 20: 348, HJ37. !!. Barcroft, ,T.: Researches on Pre-natal Life, London and Oxford, lfl46, Blackwell fki<-ntific Publications, Ltd., p. 1~0. 10. Keys, A. B.: J. Physiol. SO: 491, 1934.

584

KAI~RH.

\m . .L Obst. & Gynct·. ::\brd1, J
11. Graham, B. JJ., Wi!Ron, .J. L., '!'suo, .1\L ll., Baumann, M. L., ant! Brown, 1:-\.: Pediat riex 8: m;,, J!cli'il. 1:!. MaeKinney, L. 0., Gultlberg, ]. ll., Ehrlieh, F. E., and Freyman, K. I!.: Peiliatrir•s 21: 555, 195S. 1:1. Kaiser, l. H.: Science 118: :!H, 1!15:l. 14. Goodlin, R. C., and Kaiser, I. H.: Am. J ..M. 1':\c. 233: ii6:!, W57. 15. Barron, D. H., and Meschia, G.: Yale J. Bioi. & Mecl. 29: 41lO, l~i5i. 16. Kaiser, f. H., and Cummings, ,J. N.: Am. ;J, Physiol. 195: 481, l!l5il. 17. Kaiser, I. H., and Cummings, .1. N.: .1. Appl. Physiol. 10: 484, 1\if\7. LH. Young, I. M.: Am. J. PhyHiol. 170: 4il±, 1!.152. Hi. Cummings, J. N., and Kaiser, 1. H.: AM .•J. 0BST. & GYNEU. 77: 10, 185~1. 30. Meldrum, :x·. U.~ and Houghton, :E,. J. \~r.: ,J. PhysioJ. 80: 113, J~a;-L 21. Berfenstam, R.: .Etudes neo-natales 2: 21, lP5:l. 22. Manwell, C.: Science 127: i05, 1\15.~. 23. Born, G. V. R., Dawes, G. I:!., and Mott, ,J. C.: J. Phy~iol. 134: 14li, l!15ti. 24. Dieckmann, W. ;r., and Kramer S.: Proc. 1':\oc. Exper. Bioi. & Med. 55: 242, 1!.14-L 25. Miller, H. C.: Pediatrks 14: 1114, 1954. 26. Kaiser, I. H., and Cummings, ,J. N.: Am . .r. Physiol. 193: !i:J7, 1P5K. 27. Kaiser, 1. II., CnrnrningH, J. N .. Rr,ruol(h;, H. R. J\1.~ and Marbarger, .J.: (T. Appl. Ph.ysiol. 13: 171, ]!151:-i. :JS. Eastman, N. J., and McLane, C.M.: Hull. ,Johns Hopkins Hosp. 48: 2ill, 1831. 29. Cross, K. W., 'l'izard, .r. P. M., ano·natales 7: 27, 1958. :17, Graham, B. D., and Heyn, H. JVL: Pediatrics 15: 241, Hl55. ilS. Dancis, J., Worth, M., .Ir., and Scht•indau, P. B.: Am . .T. Physiol. 188: 535, 1!157. illi. Heijkenskjiild, P., and f+emzell, C. A.: Acta paediat. 46: 74, lfl57.

:n.