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Intrauterine growth restriction is associated with signifi-cant reductions in uteroplacental blood flow, which occurs in response to vascular disease1,2 and/or pregnancy-induced hypertension.3 Animal studies have also clearlydocumented that reductions in uteroplacental blood flowproduced by maternal placental embolization4,5 or me-chanical reduction6 leads to significant fetal growth re-striction. Additionally, studies in sheep have shown thatreduction of umbilical blood flow (UmbBF) by emboliza-tion of the fetal placenta7,8 or ligation of one of the twoumbilical arteries9,10 significantly impedes UmbBF andultimately leads to fetal growth restriction. Maternal andfetal embolizations, as well as umbilical vessel ligation, areassociated with blockage of arterioles and cessation of

uterine or UmbBF that leads to local tissue death andnecrosis.

Clapp et al5 have demonstrated that embolization ofthe maternal uteroplacental circulation results in a sig-nificant reduction in UmbBF within days of maternal placental embolization. The mechanism by which reduc-tions in uterine blood flow (UBF) can lead to reductionsin UmbBF remains unknown, but in the embolizationmodel, this is most likely due to shunting UmbBF awayfrom necrotic and hypoxic areas of the fetal placenta.11

Recent studies from our laboratory have produced amodel of significant fetal growth restriction by long-termmechanical reduction in UBF, which is not associatedwith placental necrosis.6 Therefore, this study was de-signed to evaluate the cardiovascular adaptation in fe-tuses exposed to chronic reduction in UBF, which was notassociated with placental damage or altered fetal oxy-genation. Thus, the present study determined the effectof chronic restriction of UBF in late-term pregnant sheepon UmbBF, umbilical vascular resistance (UmbVR), fetalblood pressure, heart rate, and PaO2 levels from days 115to 138 of gestation.

Methods

Surgical preparation. Sheep with singleton pregnan-cies (Thomas Morris, Inc, Reisterstown, Md) and a bodyweight between 45 and 60 kg were instrumented on ges-

From the Department of Obstetrics and Gynecology, Justus-Liebig Uni-versity Giessen,a and Division of Maternal-Fetal Medicine, Departmentof Obstetrics and Gynecology,b and Division of Biostatistics, Departmentof Environmental Health,c College of Medicine, University of Cincin-nati.Supported in part by NIH and Deutsche Forschungsgemeinschaft grantsHD-18370, HD-20748, HL-49901, and DFG La 660/4-1.Received for publication October 9, 2001; revised December 12, 2001; accepted January 9, 2002.Reprint requests: Kenneth E. Clark, PhD, Department of Obstetrics andGynecology, University of Cincinnati College of Medicine, 231 Albert B.Sabin Ave, Cincinnati, OH 45267-0526.© 2002, Mosby, Inc. All rights reserved.0002-9378/2002 $35.00 + 0 6/1/122849doi:10.1067/mob.2002.122849

Fetal umbilical vascular response to chronic reductions in uteroplacental blood flow in late-term sheep

Uwe Lang, MD, PhD,a R. Scott Baker, BS,b Jane Khoury, MS,c and Kenneth E. Clark, PhDb

Giessen, Germany, and Cincinnati, Ohio

OBJECTIVE: The present study was designed to determine the effects of chronic reduction in uterine bloodflow (UBF) on umbilical blood flow (UmbBF) and fetal cardiovascular hemodynamics and oxygenation.STUDY DESIGN: Sixteen sheep with singleton pregnancies were instrumented on gestational day (GD) 110;an externally adjustable vascular occluder was placed on the common internal iliac artery. UBF in control animals rose from 867 ± 61 mL/min on GD 115 to 1520 ± 158 mL/min (n = 8) on GD 138, whereas UBF inrestricted animals was maintained at 750 ± 50 mL/min (n = 8).RESULTS: UmbBF in control animals increased from 472 ± 25 mL/min to 744 ± 58 mL/min over the studyperiod from GD 115 to GD 138. This was associated with normal gestational increases in fetal arterial pres-sure and significant reductions in calculated umbilical vascular resistance. Although restricted animals ini-tially had a similar UmbBF on GD 115, UmbBF rose only to 545 ± 43 mL/min over the study period (controlvs restricted, P < .008). Although fetal arterial pressure showed normal gestational changes, umbilical vascu-lar resistance failed to decrease over gestation in restricted animals as it did in control animals. Fetal heartrate and oxygenation showed normal changes in both groups.CONCLUSION: Chronic reduction in UBF prevents umbilical vascular resistance from undergoing normalgestational decreases, leading to significantly lower UmbBF. This altered umbilical perfusion pattern wouldbe expected to significantly affect fetal delivery of oxygen and nutrients and ultimately fetal growth. (Am J Obstet Gynecol 2002;187:178-86.)

Key words: Fetus, placental mass, umbilical blood flow, growth restriction, sheep

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tational day (GD) 110 (term being approximately 145days). Before surgery, food and water were withdrawn for48 hours and 24 hours, respectively. Ewes were sedatedwith a 15 mg/kg bolus of pentobarbital sodium and re-ceived spinal anesthesia by intrathecal injection of 15 mgof tetracaine hydrochloride. Ewes were intubated andkept under general anesthesia with 1% to 2% isofluraneand oxygen during surgery. Anesthetized animals werefixed on the table in a recumbent position and cleanedand sterilely draped. The maternal femoral artery andvein were dissected free through a 3- to 4-cm incision inthe left groin and ligated distally. After vascular incision,polyvinyl catheters (0.05 � 0.09 in, Tygon Microbore;Norton Plastics, Akron, Ohio) were inserted in the vesselsso that the catheter tips reached into the vena cava andthe abdominal aorta. Ewes received 1 L of glucose (5%)during surgery.

After the abdominal midline incision was made, an externally adjustable vascular occluder (Dimensional-Designs Inc, Cincinnati, Ohio) was placed around thecommon internal iliac artery of the ewe. The ovarian ar-teries on both sides and the right, left, and middle sacralarteries were thoroughly ligated to avoid collateral circu-lation.6,12 The uterus was opened after palpation of theleft fetal hindlimb. The hindlimb was exteriorized, andthe uterus and amniotic membranes were temporarily“marsupialized” to avoid excessive drainage of amnioticfluid. After administration of local anesthesia with lido-caine (2%), indwelling vessel catheters (0.03 � 0.05inches, Tygon Microbore) were implanted and advancedthrough the femoral artery and vein of the fetus into theinferior vena cava and the descending aorta. The fetuswas mobilized in utero and placed in the uterine incisionin a way that allowed access to the caudal left pre-verte-bral region of its body. An incision of 3 cm was made par-allel to the spinal column and approximately 2 cmanterior to the fetal hip. After the common umbilicalartery was dissected free, a (6-mm) transit time flowprobe (Transonic Systems, Ithaca, NY) was placed aroundthe vessel immediately below the aortic bifurcation, butbefore the umbilical bifurcation, so that total UmbBFcould be continuously measured. The fetal skin was su-tured, and 1 g of ampicillin was instilled into the amnioticfluid. Next, the membranes and then the uterus werecarefully closed in layers around the catheters and theflow probe cable. Finally, electromagnetic flow probes (4-6 mm; Dienco, Los Angeles, Calif) were implanted onboth main uterine arteries.

Maternal and fetal catheters, the occluder cable, andflow probe connections were then brought to the left ab-dominal wall of the ewe and exteriorized through a sub-cutaneous tunnel to the ewe’s left flank. Catheters werewrapped in alcohol-soaked gauze and stored in plasticbags within a canvas pouch on the ewe’s skin. Allcatheters were flushed daily with heparin to maintain pa-

tency (1000 IU/mL maternal, 500 IU/mL fetal). Sheepreceived analgesic prophylaxis and antibiotic prophylaxiswith 1 g of penicillin G (Hanford’s United States Veteri-nary Products, Syracuse, NY) 1 day before surgery, theday of surgery, and 3 days after surgery; they received 80mg of gentamicin (Elkins-Sinn, Inc, Cherry Hill, NJ) onthe day of surgery. The animals had free access to waterand food (Rumilab; Ralston Purina, St Louis, Mo). Mea-surements and experimental studies were not begun be-fore the 5th postoperative day to allow for recovery fromsurgery. All procedures were approved by the Universityof Cincinnati, Institutional Animal Care and Use Com-mittee and conducted within facilities approved by theUS Department of Agriculture.

Experimental protocol. After surgical preparation onGD 110, experiments began 5 days later on GD 115. Afterfetal blood gas analysis was performed, animals with arte-rial pH above 7.30 and arterial PaO2 >18 mm Hg were randomized into 2 groups. A control group (C) was al-lowed the normal physiologic increase in uterine perfu-sion throughout the observation period up to GD 138.The experimental group (R) of animals was restricted toa uterine perfusion of approximately 750 mL/min fromGD 115 to GD 138, which produced brain-sparing (asym-metric) growth restriction.6 The first adjustments to UBFin the experimental group took place on GD 115 afterbaseline measurements were obtained for 60 minutes.After these first adjustments were made, both the controlgroup and the experimental group were checked at thesame time each day, and readjustments of the occluderwere made if necessary in the experimental group.

UmbBF was measured daily by using a Doppler transittime flow probe (Transonic Systems) connected to aTransonic T101 flowmeter, which has a maximal error of±10%. UBF was measured daily with electromagnetic flowprobes on both uterine arteries connected to Dienco RF2100 flowmeters (Dienco, Los Angeles, Calif), which havea maximal error of ±10%. After the animals were killed,uterine and UmbBF values were determined to verify thatbaseline flow registered zero. Fetal blood gases were mea-sured before blood flow reduction on day 115 of gesta-tion, 2 hours after reduction, and on days 117, 124, 131,and 138 before animals were euthanized. Samples weretaken in heparinized syringes, placed on ice, and imme-diately analyzed by using a blood gas analyzer (model288; Ciba-Corning, Norwood, Mass). Maternal and fetalarterial blood pressure and heart rate were obtained onday 115, 117, 124, 131, and 138 of gestation from the fetalaortic catheter by using a Micron MP-15 pressure trans-ducer (Micron Instruments, Simi Valley, Calif) and a Sen-sorMedics cardiotachometer (Sensormedics Corp, YorbaLinda, Calif). All measurements were recorded with an 8-channel SensorMedicsR612 recorder.

Experiments were terminated on GD 138 (term = GD145) to ensure the uniformity and comparability of mor-

180 Lang et al July 2002Am J Obstet Gynecol

phometric data. Ewes received a lethal dose of pentobar-bital sodium, and the fetal body weight and length weredetermined after the fetus had been dried. The fetal pon-deral index was calculated by using the Rohrer formula13:PI = [Fetal Weight (g) � 100]/ [Fetal Length (cm)] 3.The placental weight was determined by taking both thematernal and fetal part of the caruncle cotyledon com-plex (placentome) without separating the fetal portionfrom the maternal portion to have an assessment of theweight of the “perfusion unit” as a whole.

Statistical analysis. Statistical analysis was performedwith SAS software (SAS Institute, Cary, NC) at the De-partment of Biostatistics of the University of Cincinnati.Longitudinal comparisons were done by analysis of vari-ance in a repeated-measures design with Wilks crite-rion.14 Correlations, partial correlations, and univariateand multivariate regression analyses were also applied asappropriate.15 Group differences at the beginning and atthe end of the experimental period were examined bymeans of the unpaired Student t test with P values <.05considered significant. Data are given as mean ± SE of themean.

Results

Sixteen animals were examined throughout the exper-imental period (GD 115-138). Eight animals had beenrandomized to the control group, and another 8 animalshad been randomized to the flow-restricted group inwhich UBF was restricted to approximately 750 mL/min.

Baseline values at GD 115. Baseline UBF in animals thatwere randomized to the control group was 867 ± 61mL/min, and baseline UBF in the animals randomized tothe restricted group was 911 ± 74 mL/min on GD 115.Uterine vascular resistance was calculated as blood pres-sure divided by UBF and equaled 0.095 ± 0.007 mmHg/mL per minute in controls versus 0.094 ± 0.007 mmHg/mL per minute in restricted animals. UmbBF in con-trols was 472 ± 25 mL/min, and UmbBF in restricted ani-

mals was 459 ± 28 mL/min on GD 115. UmbVR was 0.098± 0.005 mm Hg/mL/min in controls and 0.104 ± 0.007mm Hg/mL/min in restricted animals. Maternal meanarterial pressure (79 ± 2 mm Hg vs 82 ± 2 mm Hg) andmaternal heart rate (107 ± 3 beats/min vs 102 ± 5beats/min), as well as fetal mean arterial pressure (46 ± 1mm Hg vs 47 ± 2 mm Hg) and fetal heart rate (198 ± 5beats/min vs 199 ± 5 beats/min) exhibited no differencesbetween the two groups on GD 115. None of these car-diovascular parameters were significantly different be-tween groups. Fetal PaO2 was similar between the 2groups on GD 115, being 20.9 ± 0.8 mm Hg in the controlgroup and 21.9 ± 0.6 mm Hg in the restricted group.

On GD 115, after a 60-minute baseline recording ofUBF, animals in the restricted group had their UBF ad-justed to approximately 750 mL/min. In these 8 animals,this amounted to an average UBF reduction of approxi-mately 18%, and none of the animals had to have UBF re-stricted by more than 30%. The decrease in UBF in therestricted flow animals had no effect on fetal blood gases,with PaO2 values equal to 21.8 ± 0.7 mm Hg 2 hours afterreduction in blood flows (Table). Cardiovascular vari-ables for ewes and fetuses determined 2 hours after theinitial UBF adjustment period showed that uterine perfu-sion was lower and calculated uterine vascular resistancehad increased in restricted animals, whereas all othervariables remained unchanged (Table).

UBF from GD 115 to GD 138. After adjustment of UBFin the restricted group on GD 115, uterine perfusion de-veloped differently in both groups (Fig 1). Control ani-mals experienced the normal physiologic increase ofUBF from 867 ± 61 mL/min on GD 115 to 1520 ± 158mL/min on GD 138 (P < .001). In the restricted group,uterine perfusion was kept stable throughout the obser-vation period. Two days after the initial adjustment, UBFin the restricted animals was 695 ± 22 mL/min (GD 117)and was just 745 ± 49 mL/min on GD 138. During thefirst 4 to 5 days after restriction, UBF had to be adjusted

Table. Cardiovascular data in the restricted group before and 2 hours after the primary adjustment of uterine bloodflow on gestational day 115

Before restriction After restriction(n = 8) (n = 8) P value

MMAP (mm Hg) 82 ± 1.6 83 ± 1.9 NSMHR (beats/min) 102 ± 4.7 104 ± 3.8 NSUBF (mL/min) 911 ± 74 756 ± 18 .05UVR (mm Hg)/(mL/min) 0.094 ± 0.007 0.111 ± 0.004 NS (.07)FMAP (mm Hg) 47 ± 1.5 48 ± 1.9 NSFHR (beats/min) 199 ± 4.5 200 ± 3.9 NSUmbBF (mL/min) 459 ± 28 466 ± 27 NSUmbVR (mm Hg)/(mL/min) 0.104 ± 0.007 0.104 ± 0.008 NSFetal PaO2 (mm Hg) 21.9 ± 0.6 21.8 ± 0.7 NS

Data are given as mean ± SE. MMAP, Maternal mean arterial pressure; NS, not significant; MHR, maternal heart rate; UBF, uterineblood flow; UVR, uterine vascular resistance; FMAP, fetal mean arterial pressure; FHR, fetal heart rate; UmbBF, umbilical blood flow;UmbVR, umbilical vascular resistance.

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daily because it tended to return toward control values.After the initial period, adjustment was generally not re-quired because UBF remained constant. All of the UBFvalues collected from GD 117 onward were significantlylower than the corresponding values in the control group(P < .001).

UmbBF from GD 115 to GD 138. UmbBF of control an-imals rose from 472 ± 25 mL/min on day GD 115 to 744± 58 mL/min on GD138 (Fig 2). The increase in umbili-cal perfusion was significant (P < .002) in the control an-imals. In the restricted group, UmbBF actually decreasedfrom 459 ± 28 mL/min on GD 115 to 444 ± 30 mL/min(not significant) on GD 116, and by GD 117, remainedsignificantly lower than that of controls, reaching only545 ± 43 mL/min on GD 138 (P < .008).

In control fetuses UmbBF was increased by 35% fromGD 117 to GD 138, whereas fetuses of flow-restricted ewesonly showed an increase of approximately 15%. UmbVRwas not significantly different in the 2 groups on GD 115(Fig 3). Although UmbVR of control animals showed asignificant (P < .01) gestation-related decrease, UmbVRin the restricted blood flow group did not appear tochange over the period from GD 115 to GD 138 (Fig 3).However, the 2 groups were significantly different fromeach other over gestation (P < .01). Fetal PaO2 in the con-trol and restricted groups were constant over the periodfrom GD 117 to GD 138, never being <20 mm Hg duringthe study period (Fig 4).

Maternal and fetal blood pressure and heart rate. Nosignificant differences were observed in maternal bloodpressure or heart rate between controls and restricted an-imals at any time during the study. Fetal mean arterialpressure showed a significant increase in both groupsthroughout the observation period (P < .03), going from46 to 55 mm Hg over the study period. However, therewas no significant difference between the control and re-stricted groups (Fig 5). Both control fetuses and fetusesof flow-restricted mothers experienced a decrease inheart rate throughout the observation period from 190beats/min on GD 117 to 153 beats/min on GD 138 (P < .001). Although this drop in heart rate is significantfor both groups, there were no differences between thetwo groups.

Fetal growth. The chronic reduction in UBF resultedin asymmetric growth restriction. Fetuses exposed to re-duced uteroplacental blood flow (n = 8) weighed 2857 ±217 g compared with control fetuses (n = 8), whichweighed 4562 ± 164 g on GD 138 (P < .0001). The pon-deral index was significantly decreased from 3.41 ± 0.07to 2.43 ± 0.06 (P < .0001). The placentas were examinedfor gross signs of disease and appeared normal in bothgroups, and the number of cotyledons was almost identi-cal (79 ± 4 for the control group vs 80 ± 4 for the restricted group), whereas total placental weight was sig-nificantly reduced from 457 ± 46 g to 274 ± 21 g (P = .003), as was average cotyledon weight (5.86 ± 0.71 g

Fig 1. Uterine blood flow in control and restricted UBF animals at GDs 115 through 138. UBF is significantly higher incontrol animals (P < .001).

182 Lang et al July 2002Am J Obstet Gynecol

vs 3.47 ± 0.30 g, P < .007). Morphometric data for these 16animals, as well as 23 additional animals without umbili-cal instrumentation, has previously been reported else-where.6

Comment

The present experiment was conducted to study the ef-fect of chronic reductions of UBF on UmbBF, UmbVR,and blood pressure and heart rate in fetuses with growthrestriction. In this model no placental necrosis occurredand fetal PaO2 values remained normal. UmbBF failed torise, as occurs normally in gestation. The resultant de-crease in UmbBF would be expected to have significanteffects on delivery of oxygen and nutrition to the fetus,and ultimately, on fetal growth.

In addition to the changes that occurred in the um-bilical circulation after reduction in UBF, the uteropla-cental circulation also attempted to adapt in restrictedanimals. Although it was stable for the first 2 hours afterreduction, UBF tended to return toward pre-reductionvalues within 24 hours. In this model, all major collat-eral arteries were ligated (ie, ovarian arteries and all 3sacral arteries), and thus the return of UBF toward base-line is thought to represent a form of uteroplacental au-toregulation that is much slower than that whichnormally occurs in organs such as the kidney. Within 4to 5 days, this daily need to adjust UBF to 750 mL/min

in the restricted group disappeared, and uteroplacentalblood flow was stable until the animals were killed onGD 138. It is not currently clear what the underlyingmechanism of this autoregulatory vasodilation is in theovine uterus, but it is most likely the local release of a va-sodilator such as nitric oxide.

Chronic reduction in UBF had no effect on fetal meanarterial blood pressure or heart rate over the period ofstudy (GDs 115 to 138). In contrast, as indicated previ-ously, UmbBF was lower in restricted animals than in con-trols as early as 24 hours after the initial adjustment inUBF. UmbBF did not decrease (vasoconstriction) butrather failed to rise as much over the period from GD 117to GD 138. Because fetal pressures were identical, thechronic reduction in UBF decreased the normal gesta-tion-related reductions in UmbVR.

The observation of reduced UmbBF in this study isconsistent with the results of other studies, in whichchronically reduced uteroplacental blood flow resultedin fetal growth restriction.5,16 However, in our modelthere is no primary placental injury (eg, necrosis after mi-crosphere injection, etc). Thus, the failure of UmbVR todecrease over time suggests a compromise in either an-giogenesis or a vasodilator system. In the present study,placental weight at GD 138 was significantly lower in flow-restricted animals when compared with controls. Addi-tionally, a clear relationship exists between UmbBF and

Fig 2. Umbilical blood flow versus gestational age. Controls show an increase in UmbBF from gestational day (GD) 115to GD 138 (P < .002). UmbBF is significantly higher in controls than in fetuses of flow-restricted ewes, beginning onGD 117 (P < .008).

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Fig 4. Fetal PaO2 levels in control and restricted animals on gestational days 115, 117, 124, 131, and 138. No significantdifferences were seen between control and restricted animals on any day.

Fig 3. Umbilical vascular resistance on gestational days 115, 117, 124, 131, and 138. Umbilical vascular resistance wasequivalent in both groups on GD 115. Although it decreased in control animals from GD 117 to GD 138, it remainedconstant in the uterine blood flow–restricted animals during the period from GD 117 to GD 138 (P < .01).

184 Lang et al July 2002Am J Obstet Gynecol

UBF, placental weight, and fetal body weight on day 138of gestation (Fig 6). The reduction in placental mass is anespecially interesting observation because placental massin the sheep is known to reach its full size before the timeat which animals were instrumented in the presentstudy.17

The decrease in placental mass together with the fail-ure of umbilical flow to increase substantially could lead

to a significantly reduced placental and fetal perfusion.However, in the restricted UBF group, UmbBF increasedon a per-gram placenta basis, suggesting an attempt atcompensation, that is, hyperperfusion, to counter the po-tential reduction in uterine oxygen and substrate deliveryexperienced by the uterine flow–restricted animals.Growth-restricted fetuses were perfused at 190 ± 19mL/min per kilogram of body weight, whereas control fe-

Fig 5. Fetal mean arterial pressure and fetal heart rate in control and restricted animals on gestational days 115, 117, 124,131, and 138. Mean arterial pressure showed a significant increase with gestation (P < .01), whereas fetal heart rateshowed a significant decrease (P < .001). No significant differences were seen between control and restricted animals onany day.

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tuses were only perfused with 163 ± 10 mL/min per kilogram of body weight. A similar tendency to hyperper-fusion was seen in the placenta, with restricted fetuseshaving perfusion of 200 ± 20 mL/min per 100 g of pla-centa and control fetuses having 169 ± 15 mL/min per100 g of placenta. However, these differences did notreach significance. Because the transfer of oxygen andsubstrate depends on uterine perfusion, umbilical perfu-sion, and placental exchange surface area, the increasedperfusion per gram of tissue may be considered a fetal

compensatory reaction to maintain vital functions andfetal homeostasis in the environment of chronically re-duced UBF and its associated reduction in uterine oxy-gen and substrate delivery.

The observation in the present study that UmbVRfails to decrease in animals exposed to reduced utero-placental blood flow suggests that either a normal va-sodilator system in the umbilical vasculature has failedor that angiogenesis was decreased in the placenta. Themechanism by which this occurs is not currently clear. It

Fig 6. Correlations between umbilical blood flow and uterine blood flow, placental weight, and fetal body weight at ges-tational day 138 (P < .01 for all three).

186 Lang et al July 2002Am J Obstet Gynecol

is possible that the synthetic enzymes of a vasodilator sys-tem (eg, nitric oxide) could fail to be expressed in theplacental vasculature in this altered environment. Someevidence exists to suggest that this is actually not thecase; for example, Myatt et al18 have shown in thehuman placenta that intrauterine growth restriction isassociated with a significant upregulation of nitric oxidesynthase in the placenta. This may be a compensatory ef-fort to increase perfusion; however, it may not be bene-ficial because increased placental nitric oxide synthasecould lead to large intercellular increases in nitricoxide, which in turn increases the amount of peroxyni-trites formed, resulting in endothelial cell damage orplacental apoptosis.19 Endothelial cell damage couldhave significant effects on angiogenesis and the devel-oping vasculature. It is also possible that reduction inUBF could reduce the expression and production ofplacental angiogenic factors and/or growth factors,such as insulin-like growth factor, or their binding pro-teins, which could decrease or prevent vessel growth inthe placenta. If this occurs and circulating angiogenicand/or growth factors are decreased in the fetus, itseems reasonable to speculate that many of the otherfetal organs, which are undergoing neovascularizationat this time, could be permanently affected. The lack ofadequate development of vasculature in the heart andkidneys could ultimately give rise to heart and renal dis-ease in adolescence and adulthood.

In conclusion, chronic restriction of uterine perfusionin the last third of pregnancy is accompanied by reducedplacental mass, reduced UmbBF, and intrauterine growthrestriction in the instrumented sheep. Although fetalheart rate and fetal blood pressure of fetuses exposed tochronic reduction in UBF do not differ from those incontrols, UmbBF fails to exhibit the usual progressive ges-tational rise and is significantly lower in absolute num-bers than that in controls. However, perfusion per gramof placental mass tends to be increased in these fetuses.This could indicate a potentially important adaptivemechanism for the fetus that is faced with an environ-ment of chronically restricted oxygen, nutrient, and sub-strate delivery. The lack of increase in umbilical flow isreflected in a failure of UmbVR to decrease in UBF-re-stricted animals. It seems reasonable to speculate thatsimilar changes in critical organs such as the heart andkidneys could lead to an increased incidence of cardio-vascular disease after intrauterine imprinting. A failure ofthe fetus to adapt or exhaustion of the adaptation mech-anism in this altered environment in utero could lead tofetal death. These observations lead us to speculate that ifangiogenesis is impaired in response to chronic reduc-tion in UBF, then the increase in cross-sectional area ofthe placental vascular bed that normally occurs during

pregnancy cannot take place, resulting in elevatedUmbVR.

We thank Brian Fisher and Angella Friedman for theirtechnical assistance.

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