j. perinat med. fetal kidney volume and urine production in cases of fetal growth 15(1987)

Deutinger et al, Fetal renal system and fetal growth retardation 307

j. Perinat Med. Fetal kidney volume and urine production in cases of fetal growth15(1987)307 retardation

Josef Deutinger, Wolfgang Bartl, Christian Pfersmann, Julius Neumark1, andGerhard Bernaschek

Second Department of Obstetrics and Gynecology and department of Anes-thesia, University of Vienna, Austria

1 Introduction

Studies regarding the function of the fetal renalsystem could be performed only by employmentof radiologic methods or radioactive substancesprior to the introduction of ultrasound investi-gations into obstetrics. VAN GEUNS [8] instil-lated labeled creatinine into the amniotic fluid.From the decrease of the known creatinine levelin the amniotic fluid, he determined the glom-erular filtration rate. Sonographic measure-ment of the fetal urine production was firstdescribed by CAMPBELL et al. [4]. This methodrepresented the first non-invasive method toobserve the physiological filling and emptyingof the fetal urinary bladder as well as to investi-gate the amount of fetal urine production.The amount of amniotic fluid is determined bya dynamical balance of membrane productionand resorption and by fetal excreting and swal-lowing. A reduction of the amount of amnioticfluid can be obtained not only in cases of mal-formations of the fetal urogenital system butalso in cases of growth retardation.The aim of our study was to investigate thehourly fetal urine production rate (HFUPR)and the growth of the fetal kidneys in cases offetal growth retardation and to evaluate itsmeaning for the origin of oligohydramnios inthose cases.

Curriculum vitae

JOSEF DEUTINGER was bornin 1954 in Salzburg, Aus-tria. He studied medicineat the University of Viennaand was graduated fromthere in 1980. From 1980to 1982 he worked at sev-eral hospitals in Salzburg.Since 1982 he has beenworking at the 2nd Depart-ment of Obstetrics and Gy-necology, University ofVienna. His main fields of interest are ultrasound andsterility.

2 Patients and methods

Our investigations were performed on 79 preg-nant women between the 28th and 40th weekof pregnancy (table I). The study group con-sisted of 27 patients with fetal growth retarda-tion. Criteria for acceptance into this studygroup were: confirmed gestational age by ultra-sound in early pregnancy, E-3 and/or HPLlevels less than the 10th percentile in maternalserum and sonographically estimated retarda-tion (figure 1). Standard values of HFUPR andgrowth of the fetal kidneys were also evaluatedin a control group consisting of 52 patients withan uncomplicated pregnancy. For our control

1987 by Walter de Gruyter & Co. Berlin · New York

308 Deutinger et al, Fetal renal system and fetal growth retardation

Table I. Maternal data of patients, reference, control and study group.

Reference group Control group Study group

Number (n)PrimiparaeMultiparae

Age at delivery (years)Weight before pregn. (kilogram)Weight at delivery (kilogram)Delivery (week)

768273495

25.4 + 5.549.8 + 1.859.5 + 6.240.0 + 1.2

521834

26.3 ± 4.148.6 + 2.458.7 + 5.339.6 ± 1.4

271116

23.4 + 4.650.2 + 2.157.8 + 4.936.0 ± 2.8

feb

3500-

3000-

2500-

2000-

1500-

1000-

500-

Hohenauer diagram( mean values)

28

study group( mean values)

30 32 34 36WEEKS OF GESTATION

Figure 1. Birthweights of the study group in relation to gestational age and to the Hohenauer diagram indicatingnormal fetal birthweights.

group we selected the two patients with conse-cutive numbers and uncomplicated course ofpregnancy after each patient with fetal growthretardation who was accepted into the studygroup. Pregnancy was defined to be uncompli-cated, if blood pressure remained below 140/90 torr, no proteinuria, infectional diseases ordiabetes mellitus occured during pregnancy.Patients with multiple pregnancy, blood pres-sure > 140/90 torr on one investigation duringpregnancy or dilatation of the fetal renal pelviswere excluded from the control group [6]. Ifpatients did not agree to participate or if thepregnancy was complicated, the next consecu-tive patient was chosen.

As a reference group for the control group, the768 pregnancies which were delivered duringthe study interval were studied. All patientswith blood pressure > 140/90 torr on one in-vestigation, proteinuria, diabetes mellitus, mul-tiple pregnancy, infectional disease, delivery be-fore 37th week of gestation and a newbornweight > 2500 g were excluded from the refer-ence group. The data of all patients were storedin a data base (WAMIS), and evaluation ofthose data were performed employing BMDP.In regard to maternal age, weight before preg-nancy and at delivery, week of pregnancy atdelivery and newborn weight, no differenceswere noted between the control group and the

J. Perinat. Med. 15 (1987)


clinical parameters of 768 uncomplicated preg-nancies of the reference group (table I). Fetalweights did not demonstrate a difference be-tween the control and reference groups (3367.5± 389.8 : 3351.9 ± 363.4) (mean values ±SD). By this means it could be proved that ourcontrol group is representative for uncompli-cated pregnancies.The ultrasound investigations were performedwith a sector probe with 4.0 MHz (Combison

320, Kretztechnik, Zipf, Austria). The criterionused to diagnose oligohydramnios ultrason-ographically was the apparent near absence ofamniotic fluid with only snail pockets of fluidpresent around the fetal extremities. A longi-tudinal scan of the maternal abdomen wasmade, so that a sagittal section of the fetus wasobtained. Scanning over the lower part of thefetal body revealed the bladder outline andthe largest diameter was determined (figure 2).

Fig. 2 a

Fig.2bFigure 2. Fetal bladder before and after miction, longitudinal section.



Then several transverse scans over the fetalbladder at right angles to the axis of the fetalspine were performed until the largest trans-verse and anterior-posterior section of the fetalbladder was obtained. Because of the ovoidshape of the fetal bladder calculations of thevolume could be performed by means of theformula 4/3 χ II a/2 χ b/2 χ c/2. Measure-

ment of the three diameters of the fetal bladdertook about one minute. Calculation of its vol-ume was done between four and eight consecu-tive times in 15 minutes intervals. Intervals oc-cupied by emptying of the bladder were ex-cluded. In order to standardize the investiga-tion, all sonographical explorations were donebetween 10 and 12 o'clock a.m.

Fig. 3 a

Fig.3b

Figure 3. Sonographic imaging and measurement of fetal kidneys; a: longitudinal section, b: cross section.



The average increase of the fetal bladder vol-ume from the minimum value to the maximumvalue converted to one hour yields the hourlyfetal urine production rate (HFUPR). Then themaximum values of the three diameters of thefetal kidneys were measured (figure 3) and thevolumes were calculated by means of the abovementioned formula. In order to compare theresults of HFUPR and fetal kidney volumeobtained at different gestational ages of normaland growth retarded fetuses, we calculated re-gression gradients. Regression lines and their90% confidence limits were calculated for bothgroups. Data were also tested by employinganalysis of variance in order to prove coinci-dence as well as parallelism of the regressionlines.

3 Results

In 66 cases, all three diameters of both kidneysof the 79 fetuses could be measured, in 13cases the volume of only one kidney could becalculated. The volumes of the kidneys did notshow a significant difference between right and

left. In the control group the volume increasedfrom 5.1 cm3 (mean value) in the 28th week ofgestation to 17.6 cm3 in the 40th week nearlylinearly. In instances of fetal growth retarda-tion, the reduction of the increase of renal vol-ume was statistically evident (from 4.2 cm3 inthe 28th week to 16.1 cm3 in the 40th week),while the increase of volume with advancingage was comparable with the control group(figure 4). The test for hypothetical coincidenceof the two regression lines yielded a significantdifference with p - 0.004 (F = 5.7; 2 and DF2= 141), but the hypothesis of parallelism wasnot rejected (p = 0.85; F = 0.27; DPI = 3and DF2 = 140). That indicates, that between28th and 40th gestational week, the fetal kid-neys were significantly smaller in the studygroup than in the control group, but the volumeincreased during advancing age at the same ratein both groups.The HFPUR of the 52 normal pregnancies in-creased from 5.9 ml (mean value) in the 28thweek of gestation to 26.8 ml in the 40th week.The increase was nearly linear. The increase ofthe HFPUR in the 27 patients with growth

25

20

15

10

Prediction limits (a)

Prediction limits (b)

Regression line (a)Regression line (b)



WEEKS OF GESTATION

Figure 4. volumes of fetal kidneys in uncomplicated pregnancies and in cases with placental insufficiency, bothwith their 90% prediction bands (a = control group, b = study group).



retardation was reduced significantly (from 4.7ml to 15.4 ml) between the 28th and the 40thweek of gestation (figure 5). The test for hypo-thetical coincidence of the two regression linesyielded a highly significant difference with p =

0.0000000007 (F = 28.1; DPI = 2 and DF2= 77). The hypothesis of parallelism of the tworegression lines also had to be rejected withhigh significance (p = 0.000004; F = 11.2;DPI = 3 and DF2 = 76) (figure 6). The latter

40 r


Regression line (a)



Regression line (b)


WEEKS OF GESTATION

Figure 5. Hourly fetal urine production rate (HFUPR) in uncomplicated pregnancies and in cases with placentalinsufficiency, both with their prediction bands (a = control group, b = study group).

40

35

30

20

15

10

Confidence limitsRegression lineConfidence limits

Confidence limits

Regression line

Confidence limits

WEEKS OF GESTATION

Figure 6. HFUPR — regression lines and 90% confidence limits of the control group (dotted) and the study group,proving the lack of parallelism.



demonstrates that with advancing gestationalage HFUPR increases significantly less inpatients with growth retardation.In two third of the patients with fetal growthretardation, we found an obviously reducedvolume of amniotic fluid. Unfortunately only in6 cases were the results of placental histologicalinvestigation available. In all cases trophoplas-tic hypertrophy, intervillous fibrin deposits,hemorrhagic necrosis and extended fibrosis wasdemonstrated.

4 Discussion

The effect of placental insufficiency in the lasttrimester is an asymmetrical growth retarda-tion. The fetal abdomen is affected earlier andmore pronounced than the head [10]. This kindof retardation was designated "late flattening"by CAMPBELL [5], which indicates that a reducedincrease of the fetal biparietal diameter occursin the last weeks of pregnancy. Abdominal dia-meters as well as biparietal diameters are com-monly used as a screening method for retarda-tion. Many sonographically detectable signs ex-ist in pregnancies with fetal growth retardationsuch as reduced fatty layers including the sub-cutaneous layer of the abdomen, in the perire-nal area, lack of detectable Wharton's jelly inthe area of the umbilical cord, alternations ofthe structure of the placenta, and reduction ofthe amount of amniotic fluid. In case of lateretardation a reduced increase of the cell vol-ume is evident histologically, while the numberor cells is not affected [13]. Internal organs ofabdomen and thorax are affected primarily;whereas, the fetal brain shows a significantlyhigher weight in comparison to the body. Thefavored nutrition of head and brain is causedby special features of fetal blood circulation.The reduced increase of the cell numbers wasproven in pathological-anatomical studies onthymus, lung, liver, spleen, kidney and suprare-nal gland [9].Because retardation is evident especially in thearea of the abdomen and the kidney can bemeasured best in this region sonographically, it

is suggested to investigate the kidney in casesof growth retardation. The volume of the fetalkidney increases constantly in the second halfof pregnancy [1] and opens even the possibilityto estimate the fetal weight [2]. In our study wefound a significant difference between normalpregnancies and those with fetal growth retar-dation.

In cases of placental insufficiency, the reducedperfusion of the whole fetus is the reason forgrowth retardation. Also evident is a reducedperfusion rate of the fetal kidney. In cases ofgrowth retardation the glomerular filtrationrate is responsible for the reduction of theHFUPR, which is influenced by the perfusionrate of the fetal kidneys. The tubular functiondoes not seem to be affected [11, 14]. Recentlypulsed doppler equipments have been employedfor the non-invasive determination of the fetalblood flow. This method allows only measure-ment of flow velocity with sufficient accuracy;whereas, the measurement of blood flow vol-ume is affected too much by the diameter ofthe blood vessel. Even a small error in measure-ment may lead to altered results [7]. Determina-tion of the HFUPR refers not only to alreadyexisting fetal malnutrition, but also may bepossibly helpful to detect early fetal hypoxia.Our results exhibited significantly lower valuesin cases of fetal growth retardation in compari-son to the control group. A significant differ-ence between the study group and controlgroup occurs after the 31st week of gestationwhen the confidence limits of both groups areseparated (figure 6). Confidence limits were cal-culated for illustrating our results.

The origin of amniotic fluid has been investi-gated in several studies. A relation to the perfu-sion rate of the fetal kidney and to the fetalurine output is obvious [3, 15]. In cases withrenal agenesis, no anhydramnis is evident occa-sionally. In such cases with distinct malforma-tions, other mechanisms may become more im-portant for the production of amniotic fluid atleast, including perhaps an altered exchangerate of fluid at the chorio-amnion [12]. It cannot yet be answered, if in addition to fetal urine



output and chorionic exchange, other struc-tures may be responsible for the origin of amni-otic fluid [16]. The fact, that in two-thirds ofour patients a diminution of amniotic fluidwas evident, emphasizes the role of fetal urineoutput for the origin of amniotic fluid.

Sonographically determined reduced biometri-cal dates of the fetus in case of growth retarda-tion refer to a longer existing malnutrition.They do not include diagnosis of the actual

fetal condition. Sonographic investigation doesnot allow the determination of subacute oracute potential of hypoxia. Cases with acutefetal distress may be easily diagnosed by em-ploying cardiotocography. Due to the fact thatHFUPR is a dynamical parameter and has apositive correlation to the perfusion of fetalkidneys, determination of this parameter mayhelp to detect subacute distress and emerge asa warning of a fetal distress condition in caseof biometrical proven fetal malnutrition.

Summary

The amount of amniotic fluid has a close correlation tothe function of the fetal renal system. In many cases offetal growth retardation oligohydramnios is obvious.The aim of this study is the investigation of the hourlyfetal urine production rate (HFUPR) and the growth offetal kidneys during pregnancy in cases of fetal growthretardation and to evaluate the renal participation inthe origin of oligohydramnios in cases of growth retar-dation.In 52 healthy pregnancies and 27 cases with known fetalgrowth retardation, the volume of the fetal kidneys wasmeasured sonographically and the hourly rate of fetalurine production was determined. Two third of the

patients with fetal growth retardation had obvious oli-gohydramnios. In cases of fetal growth retardation thevolume of the fetal kidneys was significantly smallerwhen compared to the control group, and the volumeof fetal urine production was significantly lower. Thereduced perfusion of the fetal kidneys in those caseswith fetal growth retardation may be the reason for thereduction of the HFUPR. Due to the fact that HFUPRis a dynamical parameter and in close relationship tothe perfusion of the fetal kidneys, the identificationand measurement of this parameter may help to detectsubacute and imminent fetal distress in cases of son-ographically proven fetal growth retardation.

Keywords: Amniotic fluid, fetal kidney volume, fetal urine production, growth retardation, ultrasound.

Zusammenfassung

Fetale Nierenvolumina und Harnproduktion in Fällen vonfetaler WachstumsretardationDie Fruchtwassermenge steht in engem Zusammenhangmit der Funktion des fetalen uropoetischen Systems.Fälle mit fetaler Wachstumsretardierung gehen häufigmit einer Verminderung der Fruchtwassermenge einher,in zwei Drittel unserer Patientinnen mit Plazentainsuffi-zienz konnte eine Oligohydramnie nachgewiesen werden.Ziel unserer Untersuchung war es, den Faktor der feta-len Harnproduktion und den des Wachstums der fetalenNieren in Fällen von Plazentainsuffizienz näher einzu-grenzen und seine Rolle in der Genese des Oligohydram-nions bei Wachstumsretardation zu ermitteln.Bei 52 klinisch unauffälligen Schwangerschaften und27 Schwangerschaften mit Plazentainsuffizienz wurdesowohl das Volumen der fetalen Nieren sonographischvermessen als auch die Änderung des fetalen Harnbla-senvolumens registriert und dadurch die stündlich pro-duzierte fetale Harnmenge ermittelt. Die Volumensbe-stimmung der fetalen Harnblase erfolgte bei Ausschluß

einer zwischenzeitlichen Harnblasenentleerung bis zu 8mal in Abständen von 15 Minuten. Die durchschnittlicheZunahme des fetalen Harnblasenvolumens vom Mini-malwert zum Maximalwert bezogen auf die volle Stundeergab die stündlich produzierte Harnmenge. Das Volu-men der fetalen Nieren lag in Fällen von Plazentainsuffi-zienz unter dem von unauffälligen Schwangerschaften.Signifikant geringer war ebenfalls, verglichen mit demNormalkollektiv, die stündlich produzierte fetale Harn-menge bezogen auf die Schwangerschaftswoche. DerGrund für die bei Wachstumsretardierung auftretendeverminderte fetale Harnproduktion ist in der Minderper-fusion der Nieren zu sehen. Die Bestimmung der fetalenHarnproduktion als dynamischen Parameter, welcher inKorrelation zur Perfusion der fetalen Nieren steht,könnte geeignet sein, bei biometrisch nachgewiesenerPlazentainsuffizienz auch subakute bzw. sich abzeich-nende akute Gefahren der fetalen Versorgung zu erfas-

Schlüsselwörter: Fetale Harnproduktion, fetales Nierenvolumen, Fruchtwasser, Plazentainsuffizienz, Ultraschall.



Resume

Volume du rein foetal et production d'urine au cours duretard de croissance intra-uterinII existe une relation etroite entre la quantite de liquideamniotique et la fonction du Systeme uropo'ietique dufoetus. En cas de retard somatique intra-uterin on con-state souvent une diminution du liquide amniotique.Chez deux tiers des patientes presentant une insuffisanceplacentaire, on a pu constater un oligoamnios. Nosrecherches ont pour but de definir le facteur de produc-tion d'urine et de la croissance des reins foetaux dans lescas d'insuffisance placentaire, et de determiner son roledans la genese de lOligoamnios dans les cas de retardde croissance.Au cours de 52 grossesses normales et de 27 avec insuffi-sance placentaire nous avons, ä aide de Fechographie,mesure le volume renal foetal ainsi que les modificationsde volume de sä vessie et nous en avons deduit laquantite d'urine produite par heure par le foetus. Pour

obtenir ce resultat nous avons repete l'examen jusqu'ähuit fois en 15 minutes tout en excluant une evacuationvesicale intermediaire. La quantite d'urine produite enune heure resulte de la moyenne entre le minimum et lemaximum de croissance du volume de la vessie, rapportesur la duree d'une heure.Le volume des reins foetaux est plus reduit dans lescas d'insuffisance placentiare qu'au cours des grossessenormales: de meme, on constate une diminution de laquantite d'urine produite par heure en rapport avec leterme. La reduction de la production d'urine foetale dansles cas de retard somatique a pour cause une diminutionde perfusion renale. En definissant la production d'urinedu foetus comme parametre dynamique, mis en correla-tion avec la perfusion renale, on pourrait parer auxdangers subaigus ou potentiels qui menacent Falimenta-tion du foetus dans les cas d'insuffisance placentairedetermines de fagon biometrique.

Mots-cles: Echographie, insuffisance placentaire, liquide amniotique, production d'urine, volume des reins foetaux.

References

[1] BERNASCHEK G, A KRATOCHWIL: EchographischeStudie über das Wachstum der fetalen Niere inder zweiten Schwangerschaftshälfte. GeburtshilfeFrauenheilkd 40 (1980) 1059

[2] BERNASCHEK G, A KRATOCHWIL: Die Möglichkeitder intrauterinen Gewichtsschätzung aus dem fet-alen Nierenvolumen. Ultraschall l (1980) 223

[3] BIGGS JS, RO DUNCAN: Production rates and sour-ces of amniotic fluid at term. J Obstet Gynaecol BrCommonw 77 (1970) 326

[4] CAMPBELL S, JW WLADIMIROFF, CJ DEWHURST: Theantenatal measurement of fetal urine production.Br J Obstet Gynaecol 8 (1973) 680

[5] CAMPBELL S: The assessment of fetal developmentby diagnostic ultrasound. In: MILUNSKI A (ed): Thepregancy at risk. Clin Perinatol 1/2 (1974) 507

[6] DEUTINGER J, R SPERNOL, G BERNASCHEK: Könnenfetale Nierenbeckenerweiterungen physiologischsein? Geburtshilfe Frauenheilkd 44 (1984) 441

[7] PENDEL H, M PENDEL, R WARNKING:Fehlermöglichkeiten der gepulsten Dopplerme-thode zur Blutflußmessung am Feten. Z Geburt-shilfe Perinatol 187 (1983) 83

[8] GEUNS HJ VAN: Cretinine en Vruchtwater. Thesis,p 68. Vrije Universiteit Amsterdam 1973.

[9] GRUENWALD P: Chronic fetal distress and placentalinsufficiency. Biol Neonate 5 (1963) 215

[10] HANSMANN M, H BAKER, S FABULA, H MÜLLER-SCHOLTES, HJ NELLEN, U VOIGT: Biometrische Da-ten des Feten. Ergebnisse einer modifizierten Me-thodik der Ultraschalldiagnostik. In: SALING E, JW

DUDENHAUSEN (eds): Perinatale Medizin, vol III,p 136. Thieme Verlag, Stuttgart 1972

[11] KURJAK A, P KIRKINEN, V . , D IVANKOVIC:Ultrasonic assessment of fetal kidney function innormal and complicated pregnancies. Am J ObstetGynecol 141 (1981) 266

[12] OTTERO LC VAN, JW WLADIMIROFF, HCS WALLEN-BURG: Relationship between fetal urine productionand amniotic fluid volume in normal pregnancyand pregnancy complicated by diabetes. Br J ObstetGynaecol 84 (1977) 205

[13] WINICK M: Cellular growth in intrauterine malnu-trition. Pediatr Clin North Am 17 (1970) 69

[14] WLADIMIROFF JW, S CAMPBELL: Fetal urine produc-tion rates in normal and complicated pregnancy.Lancet I (1974) 151

[15] WLADIMIROFF JW, LC VAN OTTERLO, HCS WALLEN-BURG, AC DROGENDIJK: A combined ultrasonic andbiochemical study of fetal renal function in the termfetus. Eur J Gynecol Reprod Biol 6 (1976) 103

[16] WLADIMIROFF JW: Studies of fetal physiology bysonography. Handbook of Clinical Ultrasound,p 203. Wiley & Sons, New York 1978

Received February 21, 1986. Revised June 6, 1986. Ac-cepted June 18, 1986.

Dr. Josef Deutinger2nd Department of Obstetrics andGynecologySpitalgasse 23A-1090 Wien, Austria


j. perinat med. fetal kidney volume and urine production in cases of fetal growth 15(1987)

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