Objectives: Fetal growth restriction is defined as a patho-logic decrease in the rate of fetal growth. The most frequentetiology for late onset fetal growth restriction is uteroplacentaldysfunction which is due to inadequate supply of nutrients andoxygen to support normal aerobic growth of the fetus. How-ever, for symmetrical IUGR, fetal chromosomal anomalies,structural anomalies and fetal infections should be carefullyexcluded. Consequent to the uteroplacental vascular malad-aptation of endovascular trophoblastic invasion, there isincreased vascular resistance and decreased blood flow to theplacenta in the choriodecidual compartment.
Conclusions: This under perfusion of the placenta causesvillous damage; that is, total tertiary villous capillary bed isreduced leading to increased placental resistance. Thesechanges can be diagnosed by Doppler and characteristicchanges are seen in the uterine, umbilical, middle cerebralarteries and ductus venosus vessels. In severe cases,delivery of the fetus with optimum intrapartum surveil-lance, or caesarean section, is essential.
Keywords : IUGR, Placental insufficiency, Colour doppler, Low birth weight
Fetal weight is determined by the genetic growth potential,the health of the fetus, the capacity of the mother to supplyadequate quality and quantities of substrates required forgrowth and the ability of the placenta to transport thesenutritional substrates to the fetus. The majority of condi-tions affecting fetal growth are placental or fetal in origin.
The most common placental conditions are alterations inthe uteroplacental and fetal-placental circulations. In themajority of these cases, there is diminished maternaluteroplacental blood flow, caused by insufficient orincomplete trophoblastic invasion of the spiral arteries inthe placental bed.
Causes of Fetal Growth Restriction
The causes can be broadly classified as fetal, maternal andplacental factors.
Fetal causes include chromosomal abnormalities, multiplepregnancies, fetal structural anomalies and fetal infections.
Maternal factors include nutritional deficiencies, espe-cially of vitamin C and E. Maternal infections, especiallychronic infections like tuberculosis and malaria can causefetal growth restriction (FGR).
Medical problems in the mother like hypertension,anemia, diabetes mellitus, chronic lung diseases and heartdisease can cause FGR.
Antiphospholipid antibody (APA) syndrome is associ-ated with first trimester miscarriage, intrauterine death, pre-eclampsia, fetal growth restriction. Antigen–antibodybinding and complement activation increases thrombo-genic potential and leads to widespread endothelial dam-age. Vasculopathy of the spiral arteries leads to placentalinfarcts and thrombosis.
It has been suggested that oxidative stress is one of thecauses of FGR. Karowicz-Bilinska et al. [1] found elevatedvalues of indices of oxidative stress in the serum of preg-nant women with IUGR.
Diagnosis of FGR
In order to diagnose FGR it is essential to estimate gesta-tional age accurately. Although this is usually calculatedfrom the last menstrual period, when known with certainty,the reliability of this estimate is low as timing of ovulationis variable. A first trimester ultrasound can date the preg-nancy more reliably.
In both developed and developing countries and for allracial and ethnic groups, there is a positive relationshipbetween maternal total weight gain and fetal birth weight.Inadequate weight gain(less than 4.3 kg) in early preg-nancy, earlier than 24 weeks is an independent predictor oflow birth weight or SGA.
Serial Fundal Height Estimation
Serial fundal height estimation is a simple technique forassessing fetal growth. The measurement begins from thefundus till the symphysis pubis with a non-elastic tape withits centimeter side facing-down to avoid manipulation.
Biochemical Markers
Coyle and Brown in 1963 reported significantly lowerurinary estriol levels in pregnancies with small babies. Thedevelopment of radioimmunoassay promoted a shift fromurinary to blood estriol. Unfortunately significant day today variability in the urinary excretion level and diurnalvariation in plasma concentration made interpretation dif-ficult. Human placental lactogen was first promoted in thelate 1960s as a marker of placental function. Studies ofnormal and abnormal pregnancies let to the concept of thefetal danger zone which classified plasma hPL concentra-tions below 4lg/ml after 30 weeks gestation as abnor-mally low and indicative of a pregnancy at grave risk.However, as a significant number of fetal deaths couldoccur in association with normal concentrations of hPL, theassay did not find a wide application [2].
Ultrasonographic Biometry
Ultrasound measurements of the biparietal diameter, headcircumference, abdominal circumference and femur lengthare recorded and matched with the 50th percentile of thecorresponding parameter in readymade population charts.Measurements below the 10th percentile are highly suspi-cious of FGR and measurements below 3rd percentile areunequivocal evidence of FGR. Growth in the abdominalcircumference of less than 1 cm over 14 days is alsoindicative of FGR.
Ponderal Index
Estimated fetal weight [3] less than the 10th percentile.Based on the Ponderal index two types of FGR aredescribed:
Amniotic fluid is derived from fetal urine and fromrespiratory tract. In FGR, shunting of blood from thesplanchnic circulation results in reduced renal blood flow,reduced glomerular filtration rate and hence less liquor.The amniotic fluid index is measured by adding the verticaldepth of cord free amniotic fluid pools in each of the fouruterine quadrants. A combined depth of 5 cm or more isnormal. Similarly a single vertical pocket of amniotic fluidof more than 2 cm is considered as normal.
Another clue to the presence of FGR is presence ofplacental calcium deposits, indicating placental senes-cence. A finding of a grade 3 placenta before 36 weeks iscorroborative evidence of FGR [3].
Role of Doppler
Uterine Artery Doppler
The majority of blood flow to the uterus is supplied by theuterine arteries. Throughout gestation, uterine blood flowincreases 10–12 fold due to trophoblastic invasion of thespiral arteries within the myometrium and decidua, and50% increase in maternal blood volume. The shape of the uterine artery Doppler waveform is unique and changes asgestation advances. In early pregnancy, the uterine circu-lation is characterized by high vascular impedance and lowflow, giving a waveform with persistent end-diastolicvelocity and continuous forward blood flow throughoutdiastole. As the trophoblastic invasion and spiral arterymodification proceed, placental perfusion increases and theuteroplacental circulation becomes a high-flow, low-resis-tance system giving a waveform with greater end-diastolicflow.
When the normal trophoblastic invasion and modifica-tion of spiral arteries is interrupted, there is increasedimpedance to flow within the uterine arteries and decreasedplacental perfusion. These pathological processes are keyfeatures common to the development of pre-eclampsia andIUGR.
A prospective trial by Zimmermann et al. [4] evaluatedthe utility of uterine artery Doppler performed between 21and 24 weeks in the prediction of subsequent developmentof pre-eclampsia and IUGR. They identified 175 women athigh risk for developing hypertensive disorders of preg-nancy or IUGR, and 172 low-risk pregnancies. Persistentnotching or elevated RI in the uterine arteries or an ele-vated RI in the uteroplacental arteries were defined aspathological Doppler signs.
Based on the currently available data, there is insuffi-cient evidence to recommend uterine artery Doppler as ageneral screening modality for all pregnancies. Whenperformed in a high-risk population, it does have somevalue in identifying pregnancies that may warrant morefrequent blood pressure assessment.
The umbilical artery (UA) was the first vessel to bestudied by Doppler ultrasonography. By about 15 weeks ofgestation, diastolic flow can be identified in the UA. Withadvancing gestational age, the end-diastolic velocityincreases secondary to the decrease in placental resistance.This is reflected in decreases in the S/D or PI. As the cho-rionic vascular bed undergoes an atherosclerotic-like pro-cess, local ischaemia and necrosis results. The UmbilicalArtery shows increasing impedance that initially bluntsforward flow during diastole, and ultimately reverses it at alater stage. These findings have been associated withadverse perinatal outcome. Once reversal of diastolic flow isidentified, administration of steroids for fetal lung maturityin the premature fetus and delivery must be considered.
Middle cerebral artery (MCA) is another vessel wellcharacterized by Doppler and has been shown to beaffected by IUGR as well. MCA normally exhibits lowamplitude of diastolic flow which increases in the presenceof fetal hypoxia as a marker of cerebral vasodilation. Thismost commonly represents a later stage in the hypoxicprocess and typically occurs after changes in the uterineartery.
Dhand et al. [5] compared MCA Doppler indices withumbilical artery Doppler indices in a prospective study of121 women of which 71 were high risk women with growthrestricted fetuses and 50 women had healthy fetuses. Thepredictive value of Doppler PI for detecting abnormal fetaloutcome was 94% in MCA as against 83% for umbilicalartery. The sensitivity was 71% for MCA versus 44% forumbilical artery. Thus, the authors concluded that MCADoppler indices were a better predictor for fetal outcome inIUGR when compared with umbilical artery in terms ofsensitivity and predictive value.
The sequence of abnormal events that herald adverseperinatal outcome begins with an absence of UA end dia-stolic flow. Later findings include abnormal Doppler pul-satility of the MCA (with decreased PI) and abnormalductus venosus flow (absent or reversed flow during atrialcontraction) and reversed flow in the UA. These changesare significantly associated with perinatal death.
Management of the fetus with abnormal Doppler indicesis gestational age dependant. In the mature fetus, there islittle to be gained by continuing pregnancy and the timecourse to decompensation is generally shorter in thesefetuses, therefore delivery is recommended. Induction oflabour would be reasonable in those with re-assuring fetalheart tracing. In the immature fetus close monitoring isnecessary.
Once absent end-diastolic flow in the UA is demon-strated, the biophysical profile (BPP) and Doppler indicesshould be done twice weekly and daily fetal kick counts isrecommended. Once reversal of flow in the UA or cepha-lisation in the MCA is present, hospitalization with con-tinuous oxygen therapy, bed rest, daily BPP and dailyDoppler are indicated. Steroids for fetal lung maturityshould be administered.
A pulsatile pattern in the DV Doppler is highly sug-gestive of fetal acidemia and is an indication for delivery.A fetus with either reversed end diastolic flow in the UAand/or a pulsatile DV pattern has little reserve and will nottolerate labour most likely.
3-D power Doppler is particularly sensitive for detectinglow velocity flow which is then rendered to give a detailedimage of fine vascular structures. Since tertiary stem villican be visualized, there is a potential for earlier detectionof abnormal placentation to detect pregnancies at high riskfor pre-eclampsia or IUGR, or evaluation of a suspectedplacenta abruption or accreta [6].
Placental MRI in Intrauterine Growth Restriction
Fetal MRI is now established as an adjunct to ultrasonog-raphy in the diagnosis of fetal abnormalities. Damodaranet al. [7] studied MR imaging of the placenta in singletongrowth restricted fetuses. The authors found that there was a significant increase in the placental volume affected bypathology in growth restricted fetuses. The placentalappearance was also thickened and globular, with anincrease in the placental thickness to volume ratio.Although placental volume increased with increasing ges-tation, it remained reduced in the growth restricted fetuses.The authors concluded that MRI appearance of the placentaprovides an indication of the severity of the underlyingdisease process in fetal growth restriction.
Treatment of Fetal Growth Restrictiondue to Placental Insufficiency
Bed rest in hospital or at home is widely advised. Thisallows for close monitoring. However the benefits of bedrest must be balanced with the risk of thrombosis. Gulm-ezoglu and Hofmeyr evaluated the role of bed rest forimpaired fetal growth. The authors compared bed rest withambulatory management for women with impaired fetalgrowth. There were differences in the fetal weights andbirth weights in both the groups but the difference was notstatistically significant [8].
Maternal Dietary Supplementation
Maternal dietary supplementation through balanced caloricintake rather than specific protein supplementation has avariable effect on fetal growth. The effect is small, thoughfetal weights have been shown to increase by 100–300 g.Ramakrishnan et al. [9] conducted a randomized doubleblind placebo controlled study on the effect of docosa-hexaenoic acid supplementation during pregnancy on ges-tational age and size at birth. The authors concluded thatprenatal DHA supplementation of primigravid women mayresult in increased birth size in a population where DHAintakes are low.
Nitric Oxide Donors
L-Arginine improves Uteroplacental blood flow to over-come placental ischemia by increasing Nitric oxide. Thisresults in vasodilation of uterine arteries. Neri et al. [10]evaluated the effects ofL-arginine (ARG) infusion, thenitric oxide substrate on the uteroplacental circulation in thethird trimester. Three groups of nine women each wereinfused with 30 g ARG for 30 min. One group served as acontrol. The remaining two groups had IUGR, one withincreased resistance in uteroplacental circulation and onewithout increased resistance. The authors found no hae-modynamic changes in the utero-umbilical circulation.They found that serum nitrites/nitrates as well as serumgrowth hormone levels were significantly raised by ARG.The authors also reported a significant decrease in resis-tance in the women where the IUGR was due to elevatedresistance. They concluded that ARG infusion affects utero-placental circulation in women with IUGR due to elevatedresistance. Such an action is specific and appears to bemediated by a release of nitric oxide. Rytlewski et al. [11]studied the influence of oral supplementation with low doseof ARG on biophysical profile, feto-placental circulationand neonatal outcome in preeclampsia. This was a ran-domized, placebo-controlled, double-blind, clinical trial.Oral therapy with 3 g of ARG daily or placebo was given asa supplement to standard therapy. The results showed thatL-arginine treatment accelerated fetal weight gain andimproved biophysical profile. Starting from the 3rd week oftherapy, the umbilical artery pulsatility indices values weresignificantly lower in the ARG group. Neonates in thisgroup revealed higher Apgar scores. The authors concludedthat supplementary treatment with oral ARG seems to bepromising in improving foetal well-being and neonataloutcome as well as in prolonging pregnancy complicatedwith pre-eclampsia.
Low Dose Aspirin
The use of low-dose aspirin for the prevention and treat-ment of pre-eclampsia and intrauterine growth restrictionhas been studied extensively. Leitich et al. [12] performeda meta analysis of low dose aspirin for the prevention ofIUGR. The use of aspirin showed a significant reduction inIUGR and a nonsignificant reduction in perinatal mortality.Subgroup analyses revealed that aspirin was effective atlower doses between 50 and 80 mg/day, but that the pre-ventive effect was greater at higher doses between 100 and150 mg/day and among women entered before the 17thweek of gestation. The authors concluded that low doseaspirin should not be used routinely in pregnant women.The indications for the use of low dose aspirin wouldinclude preexisting chronic hypertension, a history ofrecurringpre-eclampsiaandhypertensionpriorto20 weeks and associated autoimmune disorders such asSLE, a positive anticardiolipin antibody test and the pres-ence of lupus anticoagulant. A Multicentric study FLASP(FOGSI Low Dose Aspirin Study) was carried out byFOGSI to assess the effectiveness of low dose aspirin forprevention & treatment of pre-eclampsia & IUGR. Theincidence of IUGR & pre-eclampsia were significantlyreduced in patients who received prophylactic low doseaspirin prior to 16 weeks of gestation. One of the largestcollaborative studies was CLASP—Collaborative LowDose Aspirin studies in pregnancy. This study recom-mended the use of Low Dose aspirin in women to bespecially liable to early onset of pre-eclampsia severeenough to need preterm delivery.
Heparin
Heparin plays an important role in preventing complica-tions of the APA syndrome. Heparin prevents pregnancyloss by inhibiting complement activation on trophoblast inaddition to its anticoagulant effect. Unfractionated heparinor low molecular weight heparin can be used. The maindanger of heparin therapy in pregnancy is osteoporosisbecause its use in pregnancy is prolonged and pregnancyand lactation also cause reversible bone demineralization.Adequate calcium and Vit D3 intake and moderate exerciseis necessary to prevent vertebral collapse. Bone densityimproves once heparin is discontinued.
Low molecular weight heparins (LMWH) have fewercomplications than conventional heparin and are beingmore frequently used in pregnancy safely. LMWH inhibitsfactor Xa and has an antithrombotic effect while heparinhas, in addition, an anticoagulant effect through its actionon antithrombin III and factor IIa. Thus, bleeding compli-cations are few with little alteration of PT and APTT. It canbe given as once daily and has a lower risk of thrombo-cytopenia and osteoporosis. Both heparin and LMWH donot cross the placenta and fetal complications have notbeen reported. Enoxaparin 40 mg per day subcutaneouslyor Dalteparin 5000 units per day is injected from the timeof confirmation of pregnancy until delivery.
Sildenafil Citrate
Sildenafil citrate, a specific phosphodiesterase inhibitor, isincreasingly used for pulmonary hypertension in preg-nancy. Sildenafil is also emerging as a potential candidatefor the treatment of intra-uterine growth retardation and forpremature labour. Maharaj et al. [13] studied the effectsand mechanisms of action of sildenafil citrate in humanchorionic arteries ex vivo. In a series of pharmacologicstudies, the effects of sildenafil citrate in pre-constrictedchorionic plate arterial rings were determined. Their resultsshowed that phosphodiesterase-5-mRNA and protein wasdemonstrated in human chorionic plate arteries. Sildenafilproduced dose dependant vasodilatation. The authorsconcluded that sildenafil citrate vasodilated the feto-pla-cental circulation via a cGMP dependant mechanisminvolving increased responsiveness to nitrous oxide. VonDadelszen et al. [14] studied the role of sildenafil citratetherapy for severe early onset intrauterine growth restric-tion. Women were offered sildenafil citrate 25 mg threetimes daily until delivery if their pregnancy was compli-cated by early onset IUGR (AC\5th centile) and eitherthe gestational age was less than 25 weeks or the fetalweight was\600 g. The authors found that sildenafilgrowth was associated with increased AC growth (oddsratio 12.9) Randomised controlled trial data are required todetermine whether sildenafil improves perinatal outcomefor early onset IUGR patients.
Surveillance of the Growth—Retarded Fetus
Fetal Kick Count
A reduction in fetal movements is a cause for concern andanxiety. Fetal movements follow a circadian pattern andare expressions of fetal well being [15]. Decreased fetalmovements are regarded as a marker for suboptimalintrauterine conditions. The fetus responds to chronichypoxia by conserving energy and the subsequent reduc-tion of fetal movements is an adaptive mechanism toreduce oxygen consumption.
Fetal Heart Rate Monitoring
Fetal heart rate monitoring will show a sequence of chan-ges that correlate with worsening in the fetal situation. Theusual order is lack of accelerations, decreased variability,and onset of spontaneous decelerations. These changes aredependant on the severity of fetal compromise and thegestational age of the fetus. At less than 32 weeks it isunusual to obtain an accelerative pattern even if the fetus isnot compromised.
FHR monitoring is a sensitive indicator of fetal hypoxiaand acidosis but lacks specificity and has a significantnumber of false positive results.
Biophysical Profile
The BPP is a combination of the observation of the fetalbehavior with ultrasound (fetal breathing movements, fetalmovements, fetal tone and amniotic fluid volume) and FHRmonitoring and is a sensitive test to determine exhaustionof fetal reserve.
Delivery of the Growth Restricted Fetus
The optimal management strategy is to avoid delivery ofthe preterm infant that is adequately compensating for theplacental dysfunction and to recommend delivery wheninitial signs of acidemia are detected. The followingchanges are suggestive of beginning of fetal acidemia.
The full-term fetus has a large capacity to tolerate thehypoxic stress of labour. This capacity is substantiallyreduced in fetal growth restriction due to the markeddepletion of energy stores in the liver and subcutaneoustissues. With hypoxia, the energy reserves are rapidlyconsumed and the fetus must switch to anerobic metabo-lism for the generation of energy. Unfortunately, anaerobicmetabolism produces a large number of hydrogen ions, andmetabolic acidosis appears. Thus, intrapartum asphyxia isthe major cause of perinatal morbidity and mortality infetal growth restriction. Therefore, when umbilical Dopplershows absent or reversed diastolic flow, delivery bycaesarean section is indicated. Vaginal delivery may beattempted with close monitoring in patients with increasedresistance in the umbilical arteries but Caesarean deliveryshould be anticipated in a large number of them.
Fetal heart rate should be carefully monitored duringlabour and alterations of the fetal heart rate suggesting fetalcompromise should be followed by caesarean delivery. Thesecond stage of labour requires special attention. In mostcases it is preferable to avoid pushing during the secondstage and let the fetus descend under the exclusive effect ofuterine contractions. It is not recommended to prolong theduration of the second stage for more than 2 h in nullipa-rous and 1 h in multiparous patients [16].
Intrapartum Monitoring
Fetal Heart Rate Auscultation
Intrapartum surveillance is mainly focused upon detectingfetal asphyxia in order to prevent perinatal death or futureneurodevelopmental handicap. Bradycardia, tachycardiaand irregular heart rate are signs of asphyxia.
Electronic Fetal Monitoring
Uterine contractions of labour reduce the uteroplacentalblood flow and/or compress the umbilical cord dependingon its position and the quantity of amniotic fluid. Reductionof blood flow may compromise fetuses which have pre-existing hypoxia. The features of reduced baseline vari-ability, decelerations, absence of accelerations suggesthypoxia in the fetus.
Fetal Pulse Oximetry
Fetal pulse oximetry appears to be a promising new tool inintrapartum fetal surveillance. Not only is it accurate andrapid in its measurement of fetal oxygenation, it alsoaffords direct assessment (rather than indirect assessment,as with FHR monitoring) of fetal oxygenation andperipheral tissue perfusion. Fetal pulse oximeters measurethe fraction of light that is unabsorbed after being passedthrough a pulsatile vascular bed. Sensors are placed on askin surface such as the fetal head or face. Sensor place-ment is not difficult at cervical dilatations of more than2cm[17].
Scalp Blood pH
In 1962, Saling introduced fetal scalp blood samplingduring labour. This is a useful aid to determine fetal aci-dosis when difficulties arise with interpretation of abnor-mal CTG tracings. With CO2accumulation, due to reducedplacental gas exchange, pH decreases as a result of respi-ratory acidosis. Increasing hypoxia leads to anaerobicmetabolism resulting in lactate and hydrogen ion (H?)production. Low pH has been used as one of the bestavailable measures for identification of asphyxia duringlabour and delivery. Although used effectively in manycentres abroad, very few use this method in India.
