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Evaluation and Management of Suspected Fetal Growth Restriction

  • Claartje Bruin
    Correspondence
    Corresponding author.
    Affiliations
    Department of Obstetrics and Gynecology, Amsterdam University Medical Centers, University of Amsterdam, Room H4-205, PO Box 22660, Amsterdam 1105 AZ, The Netherlands
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  • Stefanie Damhuis
    Affiliations
    Department of Obstetrics and Gynecology, Amsterdam University Medical Centers, University of Amsterdam, Room H4-205, PO Box 22660, Amsterdam 1105 AZ, The Netherlands

    Department of Obstetrics and Gynecology, University Medical Center Groningen, University of Groningen, Huispostcode CB20, Hanzeplein 1, Groningen 9700 RB, The Netherlands
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  • Sanne Gordijn
    Affiliations
    Department of Obstetrics and Gynecology, University Medical Center Groningen, University of Groningen, Huispostcode CB20, Hanzeplein 1, Groningen 9700 RB, The Netherlands
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  • Wessel Ganzevoort
    Affiliations
    Department of Obstetrics and Gynecology, Amsterdam University Medical Centers, University of Amsterdam, Room H4-205, PO Box 22660, Amsterdam 1105 AZ, The Netherlands
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      Keywords

      Key points

      • The diagnosis fetal growth restriction (FGR) is made when the fetus has clinical signs of malnourishment and/or hypoxia owing to placental insufficiency.
      • There is no available effective “cure” for FGR, other than delivery.
      • In early-onset FGR (“easy diagnosis, difficult management”), the obstetric challenge lies in timing of delivery, whereas in late-onset FGR (“difficult diagnosis, easy management”), the challenge is the detection of FGR.

      Introduction

      Prenatal care focuses on the early detection of several pregnancy-specific conditions. Impaired fetal growth due to placental insufficiency is among the most important of those conditions because it is a major contributor to adverse perinatal outcomes. In this article, the authors focus first on the evaluation by prenatal care providers that identifies fetal growth restriction (FGR) and potential causes. Second, the authors discuss management options, including potential therapeutic strategies, monitoring modalities, and how to inform the decision for iatrogenic delivery.

      Evaluation

      Primary Assessment

      The evaluation of suspected FGR typically commences when it is observed that the estimated fetal size is below a defined threshold of normality for gestational age, termed small for gestational age (SGA), or when a decline in growth percentile is observed. In optimal conditions, the fetus grows according to its own intrinsic growth potential, determined by genetic and epigenetic factors. A fetus may be small in relation to a population reference or standard, yet be appropriate for its intrinsic growth potential. However, the more significant the deviation from the threshold of normality, the bigger the chance that a pathologic process underlies the observed smallness. This is described in Stefanie E. Damhuis and colleagues’ article, “Abnormal Fetal Growth: SGA, FGR, LGA: Definitions and Epidemiology,” in this issue. The core issue when confronted with a small fetus is determining if the fetal size is appropriate for this fetus. The aim of the clinical approach is primarily to discover if the fetus is compromised by placental insufficiency and at risk for morbidity or mortality.
      For all diagnoses, it is important to first verify if the gestational age was calculated appropriately because this is key to the interpretation of fetal size. In high-income countries, a reliable due date will often be provided by routine first-trimester ultrasound, but this may not be the case in exceptional cases, for example, in (socially) deprived settings. If the gestational age has been reliably set, evaluation proceeds with an ultrasound to confirm the extent of abnormality of fetal size. It is important to understand that fetal size is the result of previous fetal growth. It is advisable to incorporate the results from all previous ultrasounds greater than 18 weeks of gestation in the evaluation to establish the growth pattern. Impaired placental function leads, if long-lasting or severe enough, to a decline in size centiles of biometric measurements plotted on a reference chart to “crossing centiles.” As a screening tool, this is sometimes defined by a decline of 20 centiles or more, and for the diagnosis FGR, a decline of 50 centiles has been determined in consensus.
      • Verfaille V.
      • de Jonge A.
      • Mokkink L.
      • et al.
      Multidisciplinary consensus on screening for, diagnosis and management of fetal growth restriction in the Netherlands.
      ,
      • Gordijn S.J.
      • Beune I.M.
      • Thilaganathan B.
      • et al.
      Consensus definition of fetal growth restriction: a Delphi procedure.
      Also, the medical, obstetric, and family history should be taken to understand if specific other factors contributing to impaired placental function can be identified. The most common are maternal or environmental smoke exposure and medical problems, such as hypertension.
      • Ko T.J.
      • Tsai L.Y.
      • Chu L.C.
      • et al.
      Parental smoking during pregnancy and its association with low birth weight, small for gestational age, and preterm birth offspring: a birth cohort study.

      Placental insufficiency

      The underlying pathologic mechanism of FGR is placental insufficiency, with or without maternal diseases, fetal chromosomal abnormalities, or infection. Pathologic smallness reflects malnourishment as well as hypoxia, as these processes go hand in hand.
      • Dunsworth H.M.
      • Warrener A.G.
      • Deacon T.
      • et al.
      Metabolic hypothesis for human altriciality.
      ,
      • Thilaganathan B.
      Ultrasound fetal weight estimation at term may do more harm than good.
      Many causal placental lesions are known. However, the most common lesion is suboptimal remodeling of uterine spiral arteries (placentation) in early pregnancy; this is termed “maternal vascular malperfusion” (MVM). MVM occurs mostly when uterine artery remodeling is only shallow and the maternal vascular bed thereby retains smooth muscle cell vascular reactivity, which amounts to an incomplete physiologic transformation. High-resistance vessels persist, resulting in high-velocity blood flow into the intervillous space with shear stress and altered villous vascularization.
      • Bell E.
      A bad combination.
      ,
      • Burton G.J.
      • Jauniaux E.
      Placental oxidative stress: from miscarriage to preeclampsia.
      Other well-described FGR-related placental lesions include fetal vascular malperfusion (FVM) and villitis of unknown etiology (VUE).
      • Khong T.Y.
      • Mooney E.E.
      • Ariel I.
      • et al.
      Sampling and definitions of placental lesions: Amsterdam Placental Workshop Group Consensus Statement.
      FVM is most often caused by obstructed fetal blood flow because of thrombosis or other lesions, such as those occurring in the cord (high- or low-coiling index) and hypercoagulability with and without thrombosis. VUE is only considered present when a nonspecific inflammatory process results in villitis.
      • Khong T.Y.
      • Mooney E.E.
      • Ariel I.
      • et al.
      Sampling and definitions of placental lesions: Amsterdam Placental Workshop Group Consensus Statement.

      Antenatal detection of placental insufficiency

      The increased vascular resistance in MVM can be detected by use of Doppler ultrasound to measure the blood flow patterns of both maternal and fetal arteries (Fig. 1). Many vessels, including the uterine artery, umbilical artery (UA), and middle cerebral artery (MCA), can be assessed throughout pregnancy and can provide an indication of actual placental function. Abnormal flow patterns can be used to identify the compromised fetus that is deprived of oxygen and nutrients. It is noteworthy that Doppler abnormalities are not necessarily seen in other placental lesions (Table 1).
      • Kingdom J.C.
      • Audette M.C.
      • Hobson S.R.
      • et al.
      A placenta clinic approach to the diagnosis and management of fetal growth restriction.
      Figure thumbnail gr1
      Fig. 1Different Doppler flow patterns in maternal and fetal vessels relevant to placental function. PVIV, peak velocity index for the vein.
      Table 1Overview of relevant ultrasound parameters and their implications
      Doppler ParametersIndicationAbnormal FindingsIndicative for
      Uterine arteryScreening high-risk FGR pregnanciesUtA-PI >95th centile
      Most often used cutoff for abnormal.
      Risk stratification for development of PE and FGR
      Umbilical artery(Suspected) FGR maternal hypertensive disordersUA-PI >95th centile
      Most often used cutoff for abnormal.


      AEDF REDF
      Very early-onset FGR
      Middle cerebral artery(Suspected) FGRMCA <5th centile
      Most often used cutoff for abnormal.


      PSV
      Fetal adaptation to hypoxemia

      Fetal anemia
      Cerebroplacental ratio(Suspected) FGRCPR <5th centile
      Most often used cutoff for abnormal.
      Fetal redistribution
      Ductus venosusSevere early-onset FGRPVIV >95th centile
      Most often used cutoff for abnormal.


      Reversed A wave
      Fetal cardiac compromise
      Abbreviations: AEDF, absent end-diastolic flow; CPR, cerebroplacental ratio; PE, preeclampsia; PSV, peak systolic flow; REDF, reversed end-diastolic flow; UtA, uterine artery.
      a Most often used cutoff for abnormal.

      Uterine artery

      In normal pregnancy, the uterine arteries, as an indirect measure of resistance in the spiral arteries, demonstrate a transition from a unit of high resistance to very low resistance in the first trimester.
      • Bell E.
      A bad combination.
      The opening of the spiral arteries into low-resistance units causes the upstream resistance of the uterine artery to decrease to levels where the notching of the uterine artery disappears. If this does not occur sufficiently, the notching continues to be measurable, and/or the pulsatility index (PI) remains high. Retained high resistance of the uterine artery in the second trimester of pregnancy is associated with an increased risk for the development of especially early-onset preeclampsia and FGR.
      • Leslie K.
      • Whitley G.S.
      • Herse F.
      • et al.
      Increased apoptosis, altered oxygen signaling, and antioxidant defenses in first-trimester pregnancies with high-resistance uterine artery blood flow.

      Umbilical artery

      Many studies demonstrate the relationship between uteroplacental insufficiency and consequent increased impedance in the UA. Among the earliest phenomenon in early-onset FGR are abnormal UA flow velocity waveforms.
      • Baschat A.A.
      • Gembruch U.
      • Harman C.R.
      The sequence of changes in Doppler and biophysical parameters as severe fetal growth restriction worsens.
      ,
      • Hecher K.
      • Bilardo C.M.
      • Stigter R.H.
      • et al.
      Monitoring of fetuses with intrauterine growth restriction: a longitudinal study.
      It is described quantitatively by increased PI and qualitatively by absent or reversed end-diastolic (ARED) flow. ARED-flow is specific for very-early-onset FGR and less so for term or late preterm FGR.
      • Schreurs C.A.
      • de Boer M.A.
      • Heymans M.W.
      • et al.
      Prognostic accuracy of cerebroplacental ratio and middle cerebral artery Doppler for adverse perinatal outcomes: a systematic review and meta-analysis.
      This phenomenon is merely the “tip of the iceberg” because ARED-flow is only observed when a larger proportion of the placental vascular bed is dysfunctional.
      • Thompson R.S.
      • Stevens R.J.
      Mathematical model for interpretation of Doppler velocity waveform indices.
      In later gestational ages, fetuses have little placental reserve, and UA waveforms do not typically become severely abnormal. Fetal distress in advanced pregnancy can become apparent through reduced fetal movements, abnormal cardiotocogram (CTG), or death before deterioration of Doppler flows, partly because the indication to measure flow patterns is often only small size.
      • Efkarpidis S.
      • Alexopoulos E.
      • Kean L.
      • et al.
      Case-control study of factors associated with intrauterine fetal deaths.

      Signs of redistribution in the fetal circulation

      An early response to placental insufficiency is redistribution of blood flow in the fetal circulation. Blood flow is selectively redirected to the most important organs, including the heart, brain, and, in utero, the adrenal gland. This phenomenon has been dubbed the "brain-sparing effect" and can be expressed in an abnormal ratio between the PI of the UA and the MCA, the so-called cerebroplacental ratio.
      • Flood K.
      • Unterscheider J.
      • Daly S.
      • et al.
      The role of brain sparing in the prediction of adverse outcomes in intrauterine growth restriction: results of the multicenter PORTO Study.
      Other organs may be selectively deprived of blood flow, such as the renal arteries, explaining the phenomenon of oligohydramnios. Asymmetrical measurements of size signify brain growth (biparietal diameter, head circumference) is less affected than the measurements of the other organs (abdominal circumference, femur length). Abdominal growth is heavily influenced by liver size, which is the predominant location of fetal energy storage. In energy-deprived situations, the liver will consequently grow less fast, and the abdominal circumference will be typically smaller relative to cerebral measurements.

      Venous Doppler changes

      Signs of FGR can also be observed in the fetal venous circulation. Both abnormal ductus venosus (DV) measurements and pulsations in the umbilical vein are related to fetal hypoxemia and adverse perinatal outcomes.
      • Hecher K.
      • Bilardo C.M.
      • Stigter R.H.
      • et al.
      Monitoring of fetuses with intrauterine growth restriction: a longitudinal study.
      ,
      • Baschat A.A.
      • Cosmi E.
      • Bilardo C.M.
      • et al.
      Predictors of neonatal outcome in early-onset placental dysfunction.
      Because these changes typically occur late in the sequence of deterioration of placental function, this parameter is more useful for the monitoring strategy to determine timing of delivery rather than for the diagnosis of FGR.

      Serum biomarkers

      Placental dysfunction is also reflected in serum markers; of these, placental growth factor (PlGF) is the best studied and most potentially useful. It has strong associations with early-onset hypertensive disorders of pregnancy and its clinical manifestations, particularly if combined with soluble fms-like tyrosine kinase-1 (sFlt-1).
      • Chappell L.C.
      • Duckworth S.
      • Seed P.T.
      • et al.
      Diagnostic accuracy of placental growth factor in women with suspected preeclampsia: a prospective multicenter study.
      These markers may be useful in identifying FGR fetuses,
      • Benton S.J.
      • Hu Y.
      • Xie F.
      • et al.
      Can placental growth factor in maternal circulation identify fetuses with placental intrauterine growth restriction?.
      ,
      • Calabrese S.
      • Cardellicchio M.
      • Mazzocco M.
      • et al.
      Placental growth factor (PLGF) maternal circulating levels in normal pregnancies and in pregnancies at risk of developing placental insufficiency complications.
      although utility is diluted significantly if SGA is chosen as the endpoint rather than FGR.
      • Griffin M.
      • Seed P.
      • Webster L.
      • et al.
      Placental growth factor (PLGF) and ultrasound parameters for predicting the small for gestational age infant (SGA) in suspected small for gestational age: Pelican FGR study.

      Decreased fetal movements

      When placental insufficiency deteriorates to the extent whereby the fetus experiences hypoxemia, a decline in fetal activity can occur.
      • Arduini D.
      • Rizzo G.
      • Caforio L.
      • et al.
      Behavioural state transitions in healthy and growth retarded fetuses.
      This phenomenon is one that can be recognized by the mother, and as such, can be considered an additional monitoring tool. Although efficacy is uncertain, most authorities recommend additional antenatal testing in cases of decreased fetal movement.

      Differential diagnosis and maternal comorbidities

      Clinicians, when confronted with a suspected small or growth-restricted fetus/newborn, must explore all possible pathophysiologic mechanisms besides and/or relating to placental insufficiency. These mechanisms are, among others, fetal infections, congenital anomalies, syndromes, genetic abnormalities, and maternal diseases. Each of these conditions requires different management and treatment strategies and should therefore be considered.

      Fetal infections

      An uncommon, but clinically important alternative diagnosis underlying SGA is congenital infection. The microorganisms that are the main contributors are toxoplasmosis, rubella, cytomegalovirus (CMV), herpes simplex virus, and malaria, as they have the potential to cause a placental and/or congenital infection.
      Ultrasonographic abnormalities that are associated with these infections are fetal ventriculomegaly, intracranial calcifications, ascites, and hyperechogenic bowel. In severe fetal smallness, screening for CMV infection can be considered because this is the most common congenital viral infection, with a prevalence of 0.2% to 2% (average, 0.65%).
      • Kenneson A.
      • Cannon M.J.
      Review and meta-analysis of the epidemiology of congenital cytomegalovirus (CMV) infection.
      Other infections should only be assessed if there is a specific pattern of ultrasound abnormalities or specific clinical risk factors, because the incidence of these infections in the absence of ultrasonographic abnormalities is very low.
      • Yamamoto R.
      • Ishii K.
      • Shimada M.
      • et al.
      Significance of maternal screening for toxoplasmosis, rubella, cytomegalovirus and herpes simplex virus infection in cases of fetal growth restriction.
      ,
      • Society for Maternal-Fetal Medicine
      • Electronic address pso
      • Martins J.G.
      • et al.
      Society for Maternal-Fetal Medicine Consult Series #52: diagnosis and management of fetal growth restriction: (replaces clinical guideline number 3, April 2012).

      Syndromal abnormalities

      In the case of early-onset FGR, an advanced obstetric sonogram can help to screen for chromosomal abnormalities, especially if other signs of placental insufficiency are absent. Structural anomalies can suggest an underlying syndrome and may justify invasive prenatal testing with amniocentesis or chorionic villus sampling. Noninvasive prenatal testing is currently only useful to screen for a small number of chromosomal abnormalities. Because placental insufficiency is more common in the context of chromosomal abnormalities, diagnostic testing (rather than screening) should be considered in early-onset FGR, especially when other ultrasound abnormalities are seen.
      • Guseh S.H.
      • Little S.E.
      • Bennett K.
      • et al.
      Antepartum management and obstetric outcomes among pregnancies with Down syndrome from diagnosis to delivery.

      Maternal comorbidities

      The presence of maternal comorbidities may increase (or sometimes decrease) the likelihood that the observed fetal smallness is caused by placental insufficiency. Most noticeable are disorders that have impact on endothelial cell function, such as chronic hypertension, diabetes mellitus, renal disease, lupus, and cardiovascular disease, all of which can have an impact on early placental development.
      • Redman C.W.
      • Sargent I.L.
      • Staff A.C.
      IFPA senior award lecture: making sense of pre-eclampsia - two placental causes of preeclampsia?.

      Maternal preeclampsia

      Most of the pathophysiologic processes of hypertensive disorders of pregnancy are similar in FGR. Therefore, some of this knowledge can be extended into the field of FGR. Preeclampsia is a serious complication of pregnancy, characterized by hypertension and proteinuria in the second half of pregnancy because of endovascular inflammation.
      • Tranquilli A.L.
      • Dekker G.
      • Magee L.
      • et al.
      The classification, diagnosis and management of the hypertensive disorders of pregnancy: a revised statement from the ISSHP.
      Poor placentation is particularly associated with the early-onset phenotype of both preeclampsia and FGR. Especially in earlier gestational ages, hypertensive disorders of pregnancy and FGR have a reciprocal association.
      • Groom K.M.
      • North R.A.
      • Poppe K.K.
      • et al.
      The association between customised small for gestational age infants and pre-eclampsia or gestational hypertension varies with gestation at delivery.

      Management

      In this section, the authors discuss potential therapies influencing the root cause of the placental insufficiency. Next, they discuss how the main therapeutic approach remains determining the timing of delivery and how this is different in early-onset FGR and late-onset FGR. In early-onset FGR (“easy diagnosis, difficult management”), obstetric management focuses on timing of delivery, whereas in late-onset FGR (“difficult diagnosis, easy management”), the focus lies on the detection of FGR.

      Therapeutic strategies

      Particularly in early-onset FGR, MVM with retained smooth muscle cell function of the spiral arteries appears to be the predominant pathophysiologic pathway. This suboptimal remodeling of uterine spiral arteries has led to pharmacologic strategies that influence uteroplacental vascular function through the endothelial nitric oxide pathway and vasodilatation, depicted in Fig. 2.
      • Groom K.M.
      • David A.L.
      The role of aspirin, heparin, and other interventions in the prevention and treatment of fetal growth restriction.
      No strategy with established efficacy is currently available. Such an intervention is particularly wanted for the severe phenotype of early-onset FGR, because any option that can prolong pregnancy and decrease the consequences of prematurity after iatrogenic delivery can have a tremendous impact on perinatal outcomes.
      Figure thumbnail gr2
      Fig. 2Possible interventions to treat FGR by site of action influencing the vascular smooth muscle and endothelium metabolism. 5′ GMP, guanosine monophosphate; cGMP, cyclic guanosine monophosphate; GTP, guanosine-5′-triphosphate; HO-1, heme oxygenase-1; NO, nitric oxide; NOS, nitric oxide synthase; PDE5, phosphodiesterase type 5 inhibitor; sGC, soluble guanylate cyclase; TX-A2, thromboxane A2.
      (From Groom KM, David AL. The role of aspirin, heparin, and other interventions in the prevention and treatment of fetal growth restriction. Am J Obstet Gynecol. 2018;218(2S):S829-S840.)

      Sildenafil

      Early evaluations of phosphodiesterase-5 inhibitors (sildenafil) as therapeutic treatment for early-onset severe FGR with high risk of fetal demise appeared promising.
      • von Dadelszen P.
      • Dwinnell S.
      • Magee L.A.
      • et al.
      Sildenafil citrate therapy for severe early-onset intrauterine growth restriction.
      ,
      • Paauw N.D.
      • Terstappen F.
      • Ganzevoort W.
      • et al.
      Sildenafil during pregnancy: a preclinical meta-analysis on fetal growth and maternal blood pressure.
      However, in an international collaboration (acronym STRIDER), randomized controlled trials (RCTs) of antenatal sildenafil citrate for FGR showed no benefit and possible harm.
      • Sharp A.
      • Cornforth C.
      • Jackson R.
      • et al.
      Maternal sildenafil for severe fetal growth restriction (STRIDER): a multicentre, randomised, placebo-controlled, double-blind trial.
      • Groom K.M.
      • McCowan L.M.
      • Mackay L.K.
      • et al.
      STRIDER NZAus: a multicentre randomised controlled trial of sildenafil therapy in early-onset fetal growth restriction.
      • Pels A.
      • Derks J.
      • Elvan-Taspinar A.
      • et al.
      Maternal sildenafil vs placebo in pregnant women with severe early-onset fetal growth restriction: a randomized clinical trial.

      Antioxidants: arginine

      An increasing number of studies on the therapeutic use of antioxidants, such as l-arginine, have become available.
      • Chen J.
      • Gong X.
      • Chen P.
      • et al.
      Effect of L-arginine and sildenafil citrate on intrauterine growth restriction fetuses: a meta-analysis.
      This option is appealing, as it is a nutritional supplement, unlikely to have unexpected unwanted side effects, such as seen with sildenafil exposure in the Dutch STRIDER RCT.
      • Pels A.
      • Derks J.
      • Elvan-Taspinar A.
      • et al.
      Maternal sildenafil vs placebo in pregnant women with severe early-onset fetal growth restriction: a randomized clinical trial.
      A recent cross-species meta-analysis combining all available data from human and nonhuman studies suggests that arginine family supplementation, in particular, arginine and nitrogen carbamoyl glutamate, improves fetal growth in complicated pregnancies.
      • Terstappen F.
      • Tol A.J.C.
      • Gremmels H.
      • et al.
      Prenatal amino acid supplementation to improve fetal growth: a systematic review and meta-analysis.
      Rigorous research in complicated human pregnancies is needed before determining efficacy in the treatment of FGR.

      Gene therapy

      A promising and more radical approach is vascular endothelial growth factor (VEGF) gene therapy, in which adenoviral vectors encoding for proteins, such as VEGF, are introduced to the maternal uterine artery.
      • David A.L.
      Maternal uterine artery VEGF gene therapy for treatment of intrauterine growth restriction.
      In preclinical studies, it has been shown to increase uterine blood flow and reduce vascular contractility. These functional findings correspond with the anatomic findings of vascular remodeling with increased endothelial cell proliferation in the perivascular adventitia of treated uterine arteries. This method is anticipated to be safe, because no vector seems to spread to the fetus, and no adverse effects on either the mother or fetus have been observed. However, this bold strategy still requires many steps, including extensive clinical trials, before it can be implemented into clinical practice. Furthermore, the high cost associated with gene therapy may restrict this option to high-income health care settings.

      Monitoring for delivery in early-onset fetal growth restriction

      Although the term “fetal growth restriction” implies that the fetus suffers most from poor nutritional exchange, sustained starvation is rarely the cause of fetal demise. It is the lack of oxygen supply to the fetus, resulting in chronic or acute hypoxia that leads to perinatal death. Obstetric management aims to minimize the risk of fetal demise. The only management that “treats” placental insufficiency is delivery, which prevents stillbirth but predisposes to postnatal death from prematurity. Despite the fact that early-onset FGR is rare (0.3% of all pregnancies), this extreme phenotype has significant societal and individual impact owing to the aggravated effects of prematurity: death or survival with severe impairment.
      • Spencer R.
      • Rossi C.
      • Lees M.
      • et al.
      Achieving orphan designation for placental insufficiency: annual incidence estimations in Europe.
      All severe morbidities are essentially expressions of underdeveloped organ function, including lungs (bronchopulmonary dysplasia, respiratory distress syndrome), bowels (necrotizing enterocolitis), immune system (sepsis and meningitis), and cerebral blood vessels (intracerebral hemorrhage, periventricular leukomalacia).
      Timing of delivery is therefore based on the estimated balance of the risks of ongoing intrauterine hypoxia versus the consequences of iatrogenic premature delivery. In the previable/periviable period, consideration of expectant management is warranted even when fetal death is expected because delivery often confers near certainty of postnatal death.
      • Gaugler-Senden I.P.
      • Huijssoon A.G.
      • Visser W.
      • et al.
      Maternal and perinatal outcome of preeclampsia with an onset before 24 weeks' gestation. Audit in a tertiary referral center.
      In scenarios whereby severe fetal compromise is present before viability, pregnancy termination should be made available, especially when continued expectant management is associated with maternal risk. Of note is that viability may occur at later gestational ages for fetuses with FGR, and the determination of the moment of esteemed viability depends on the expertise of the obstetric and neonatal staff along with local resources. Once a viable gestation is reached, the main clinical dilemma is which surveillance test should guide the decision on timing of birth: CTG, fetal Doppler ultrasound, and/or serum biomarkers.
      • Hecher K.
      • Bilardo C.M.
      • Stigter R.H.
      • et al.
      Monitoring of fetuses with intrauterine growth restriction: a longitudinal study.
      ,
      • Ganzevoort W.
      • Thornton J.G.
      • Marlow N.
      • et al.
      Comparative analysis of 2-year outcomes in GRIT and TRUFFLE trials.
      ,
      • Lees C.C.
      • Marlow N.
      • van Wassenaer-Leemhuis A.
      • et al.
      2 year neurodevelopmental and intermediate perinatal outcomes in infants with very preterm fetal growth restriction (TRUFFLE): a randomised trial.
      At the moment, published national guidelines on the matter vary considerably.
      • McCowan L.M.
      • Figueras F.
      • Anderson N.H.
      Evidence-based national guidelines for the management of suspected fetal growth restriction: comparison, consensus, and controversy.

      Indication for delivery

      Umbilical Artery

      The finding of ARED flow in the UA in FGR is a telltale sign of severely impaired placental perfusion, and it has been consistently shown to be an indicator of adverse outcomes, including death.
      • Baschat A.A.
      • Cosmi E.
      • Bilardo C.M.
      • et al.
      Predictors of neonatal outcome in early-onset placental dysfunction.
      ,
      • Karsdorp V.H.
      • Van Vugt J.M.
      • Van Geijn H.P.
      • et al.
      Clinical significance of absent or reversed end diastolic velocity waveforms in umbilical artery.
      The use of UA Dopplers as a direct indicator for fetal well-being is supported by recent study results,
      • Morsing E.
      • Brodszki J.
      • Thuring A.
      • et al.
      Infant outcome after active management of early-onset fetal growth restriction with absent or reverse umbilical artery blood flow.
      but a study comparing the use of UA Doppler with a management protocol that remains expectant until other parameters of fetal condition become abnormal is lacking. Currently, UA Doppler is variably part of management protocols as a direct indicator for delivery in the extremely preterm period. The most recent Society for Maternal-Fetal Medicine Guideline for FGR recommends general timing of delivery at 37 weeks’ gestational age in the case of UA Doppler PI > p95, delivery at 33 to 34 weeks if there is absent end-diastolic flow, and delivery at 30 to 32 weeks if there is reversed end-diastolic flow. However, in the case of repetitive late decelerations on CTG tracing, delivery is advised after the fetal viability.
      • Society for Maternal-Fetal Medicine
      • Electronic address pso
      • Martins J.G.
      • et al.
      Society for Maternal-Fetal Medicine Consult Series #52: diagnosis and management of fetal growth restriction: (replaces clinical guideline number 3, April 2012).

      Cardiotocography

      Fetal heart rate (FHR) is a function of the autonomic nervous system. At the onset of hypoxia, FHR variability decreases, whereas progressive hypoxia and acidemia result in spontaneous decelerations. When repeated decelerations occur, unprovoked by uterine contractions, there is strong consensus that imminent delivery is warranted because hypoxia is likely present, and the risk of stillbirth is high.
      • McCowan L.M.
      • Figueras F.
      • Anderson N.H.
      Evidence-based national guidelines for the management of suspected fetal growth restriction: comparison, consensus, and controversy.
      The importance of low FHR variability is less clear. Short-term variation (STV) is a measurement of FHR variability that is calculated by computer analysis, which avoids the high interobserver and intraobserver variability of visual CTG observation.
      • Dawes G.S.
      • Redman C.W.
      • Smith J.H.
      Improvements in the registration and analysis of fetal heart rate records at the bedside.
      It has recently been made available as freeware.
      • Wolf H.
      • Bruin C.
      • Dobbe J.G.G.
      • et al.
      Computerized fetal cardiotocography analysis in early preterm fetal growth restriction - a quantitative comparison of two applications.
      STV has been established as a reflection of fetal acid-base status.
      • Street P.
      • Dawes G.S.
      • Moulden M.
      • et al.
      Short-term variation in abnormal antenatal fetal heart rate records.
      However, no studies exist with sufficient power to detect an association of STV at any threshold with the most important outcomes, stillbirth, and long-term infant health.
      • Pels A.
      • Mensing van Charante N.A.
      • Vollgraff Heidweiller-Schreurs C.A.
      • et al.
      The prognostic accuracy of short term variation of fetal heart rate in early-onset fetal growth restriction: a systematic review.
      In an indirect comparison of visual CTG versus STV assessment with computerized CTG (cCTG) using data from the GRIT and TRUFFLE trials, it was suggestive that monitoring with cCTG improved outcomes.
      • Ganzevoort W.
      • Thornton J.G.
      • Marlow N.
      • et al.
      Comparative analysis of 2-year outcomes in GRIT and TRUFFLE trials.
      Notwithstanding the lack of conclusive comparative evidence, some advocate that cCTG should be the gold standard.
      • Bilardo C.M.
      • Hecher K.
      • Visser G.H.
      • et al.
      Severe fetal growth restriction at 26–32 weeks: key messages from the TRUFFLE study.
      However, clinical practice shows variable implementation: although STV has been adopted as a standard of care in many European centers (but far from all), it has not been adopted in the United States. Because of these firm beliefs and practice variation, cCTG needs to be tested rigorously to determine whether its use improves outcomes compared with visual CTG interpretation.

      Ductus Venosus

      Use of the DV Doppler waveform in addition to CTG to determine timing of delivery appears to improve neurocognitive outcome at the age of 2 among surviving infants, although this finding is nonsignificant when stillbirths and perinatal deaths are included in comparison groups.
      • Lees C.C.
      • Marlow N.
      • van Wassenaer-Leemhuis A.
      • et al.
      2 year neurodevelopmental and intermediate perinatal outcomes in infants with very preterm fetal growth restriction (TRUFFLE): a randomised trial.
      It is likely that intrauterine malnutrition and hypoxia affect some fetal organs before others. In fetuses with early-onset FGR, cardiac dysfunction (as reflected in abnormal DV assessment) can precede cerebral dysfunction (as reflected in low STV).
      • Ganzevoort W.
      • Mensing Van Charante N.
      • Thilaganathan B.
      • et al.
      How to monitor pregnancies complicated by fetal growth restriction and delivery before 32 weeks: post-hoc analysis of TRUFFLE study.
      The combination of CTG and Doppler evaluation of the DV as monitoring modalities to time delivery is likely to be synergistic in achieving optimal results. The findings of the TRUFFLE trial are difficult to generalize to practice settings in the United States, where cCTG has not been widely adopted and Doppler evaluation of the DV waveform has not been endorsed by professional societies.
      • Society for Maternal-Fetal Medicine
      • Electronic address pso
      • Martins J.G.
      • et al.
      Society for Maternal-Fetal Medicine Consult Series #52: diagnosis and management of fetal growth restriction: (replaces clinical guideline number 3, April 2012).

      Biophysical Profile

      The biophysical profile score (BPS) is a crude composite score of a combined assessment of fetal movements, reactivity of the CTG, and assessment of amniotic fluid. The association of an abnormal BPS with the adverse outcomes of interest is not as good as other available parameters.
      • Turan S.
      • Turan O.M.
      • Berg C.
      • et al.
      Computerized fetal heart rate analysis, Doppler ultrasound and biophysical profile score in the prediction of acid-base status of growth-restricted fetuses.
      Nevertheless, in the difficult decision of iatrogenic preterm delivery in the context of borderline abnormal findings of cCTG, the presence or absence of fetal movements may sometimes sway decisions in practice.

      Late-Onset Fetal Growth Restriction: From Diagnosis to Delivery

      In late-onset FGR when placental reserve is already challenged, the interval between the onset of nutritional deprivation and life-threatening hypoxia is typically shorter than in early-onset FGR. In this gestational age period, the concept is “easy to manage, difficult to diagnose.” This concept is reflected in the fact that a significant number of fetuses suffer from the consequences of hypoxia without apparently being challenged in growth, as they are not small.
      • Vasak B.
      • Koenen S.V.
      • Koster M.P.
      • et al.
      Human fetal growth is constrained below optimal for perinatal survival.
      ,
      • Moraitis A.A.
      • Wood A.M.
      • Fleming M.
      • et al.
      Birth weight percentile and the risk of term perinatal death.

      The Small for Gestational Age Approach

      Because the aforementioned signs of placental insufficiency are unlikely to be observed in late-onset FGR, differentiation between FGR (failure to meet growth potential) and SGA (constitutionally small but healthy) is difficult. Despite the low absolute risk, adverse outcomes are devastating and include stillbirth and short- and long-term effects of hypoxia (neonatal intensive care unit admission, hypoxic-ischemic encephalopathy). On the other hand, unnecessary iatrogenic (relatively) preterm birth in women with small but healthy infants also confers low absolute risk of postnatal morbidity but translates into significant societal impact.
      Because serious perinatal morbidity from delivery in the late preterm pregnancy is unlikely,
      • Delnord M.
      • Zeitlin J.
      Epidemiology of late preterm and early term births - an international perspective.
      clinicians may have a low threshold for delivering small fetuses relatively later in gestation. Imperfections with approaches that depend exclusively on assessments of fetal size lead to “undertreatment” of fetuses of normal size but who are affected by FGR and “overtreatment” of fetuses who are small but healthy. The DIGITAT study randomized women with fetuses suspected to have FGR at 37 weeks’ gestation to delivery or expectant management and showed no difference in the primary outcome of short-term perinatal morbidity.
      • Boers K.E.
      • Vijgen S.M.
      • Bijlenga D.
      • et al.
      Induction versus expectant monitoring for intrauterine growth restriction at term: randomised equivalence trial (DIGITAT).
      However, more fetuses in the expectant management were in the lowest birth weight percentile group, and these were the fetuses at risk of later developmental delay.
      • van Wyk L.
      • Boers K.E.
      • van der Post J.A.
      • et al.
      Effects on (neuro)developmental and behavioral outcome at 2 years of age of induced labor compared with expectant management in intrauterine growth-restricted infants: long-term outcomes of the DIGITAT trial.
      This study shows that selection of “the fetus at risk” is still imperfect, and the ideal approach is still not known.

      The individual risk approach

      Further risk stratification is necessary to identify the fetus that should be delivered early.
      • Ganzevoort W.
      • Thilaganathan B.
      • Baschat A.
      • et al.
      Point: fetal growth and risk assessment: is there an impasse?.
      The same variables that are identified in early-onset FGR can be used for an individualized risk approach. The most commonly used marker is the brain-sparing phenomenon.
      • Figueras F.
      • Gratacos E.
      An integrated approach to fetal growth restriction.
      Cohort studies have consistently shown that abnormal MCA Dopplers (low PI) are associated with adverse outcomes.
      • Schreurs C.A.
      • de Boer M.A.
      • Heymans M.W.
      • et al.
      Prognostic accuracy of cerebroplacental ratio and middle cerebral artery Doppler for adverse perinatal outcomes: a systematic review and meta-analysis.
      ,
      • Morris R.K.
      • Selman T.J.
      • Verma M.
      • et al.
      Systematic review and meta-analysis of the test accuracy of ductus venosus Doppler to predict compromise of fetal/neonatal wellbeing in high risk pregnancies with placental insufficiency.
      However, in a recent individual patient data meta-analysis, it was found that, if continuous data of UA and MCA Doppler indices were used, the diagnostic performance of both UA and MCA variables and their ratio (cerebroplacental ratio) was similar.
      • Vollgraff Heidweiller-Schreurs C.A.
      • van Osch I.R.
      • Heymans M.W.
      • et al.
      Cerebroplacental ratio in predicting adverse perinatal outcome: a meta-analysis of individual participant data.
      Ongoing studies are further evaluating these discrepancies and whether UA Doppler velocities that were previously considered normal may actually represent evidence of compromised placental function.

      Management: other aspects

      Prevention of Fetal Growth Restriction/Acetyl Salicylic Acid

      Low-dose aspirin (acetyl salicylic acid 80–150 mg) has long been recognized as effective for reducing the risk of developing preeclampsia, provided it is started in early pregnancy.
      • Bujold E.
      • Roberge S.
      • Nicolaides K.H.
      Low-dose aspirin for prevention of adverse outcomes related to abnormal placentation.
      Considering the fact that preeclampsia and FGR share risk factors with MVM as the most common pathologic underlying lesion, these data have been extrapolated to FGR by some. Its use in decreasing the risk of FGR is studied with mixed results
      • Bettiol A.
      • Lombardi N.
      • Crescioli G.
      • et al.
      Pharmacological interventions for the prevention of fetal growth restriction: protocol for a systematic review and network meta-analysis.
      and will be reviewed in more detail in Nathan Blue and colleagues’ article, “Recurrence Risk of Fetal Growth Restriction: Management of Subsequent Pregnancies,” in this issue. Also, the risk of SGA infants is reduced with low-dose aspirin, although this was assessed as a secondary outcome in most studies. One approach is to offer it to women with the highest risk of developing the disorder, using algorithms provided by the Fetal Medicine Foundation algorithm, or US Preventive Services Task Force.
      • LeFevre M.L.
      • Force USPST
      Low-dose aspirin use for the prevention of morbidity and mortality from preeclampsia: U.S. Preventive Services Task Force recommendation statement.
      ,
      • Rolnik D.L.
      • Wright D.
      • Poon L.C.
      • et al.
      Aspirin versus placebo in pregnancies at high risk for preterm preeclampsia.

      Mode of Delivery

      Severe fetal compromise often affects mode of delivery planning. In situations where it is unlikely that the fetus will be able to withstand the challenges of uterine contractions, a cesarean section without a trial of labor should be considered. If it is estimated that the placental reserve will allow vaginal delivery, continuous fetal CTG is warranted. Because it can be difficult to accurately predict whether a fetus will tolerate labor, shared decision making is critical.

      Corticosteroids and Magnesium Sulfate

      Once it is estimated that the antenatal risks surpass the neonatal risk and intensive monitoring is underway with the intent to deliver a fetus, it is also important to optimally anticipate imminent delivery. The benefit of a single course of antenatal corticosteroids to accelerate fetal lung maturation for spontaneous premature delivery has been unequivocally established remote from term.
      • Roberts D.
      • Brown J.
      • Medley N.
      • et al.
      Antenatal corticosteroids for accelerating fetal lung maturation for women at risk of preterm birth.
      Whether this is also valid in the context of severe early-onset FGR is uncertain, as these high-risk pregnancies were often excluded from trials included in meta-analyses. Nonetheless, it is appropriate to offer this potentially potent preventive therapy, as it is endorsed by professional societies.
      • Society for Maternal-Fetal Medicine
      • Electronic address pso
      • Martins J.G.
      • et al.
      Society for Maternal-Fetal Medicine Consult Series #52: diagnosis and management of fetal growth restriction: (replaces clinical guideline number 3, April 2012).
      A serendipitous finding from studies assessing magnesium sulfate for prevention of eclamptic seizures was a reduction in the risk of cerebral palsy, and several studies have since confirmed that magnesium sulfate has a neuroprotective effect and can reduce the incidence of cerebral palsy when given to women at risk of early preterm (<32 weeks) birth.
      • Altman D.
      • Carroli G.
      • Duley L.
      • et al.
      Do women with pre-eclampsia, and their babies, benefit from magnesium sulphate? The Magpie Trial: a randomised placebo-controlled trial.
      • Doyle L.W.
      • Crowther C.A.
      • Middleton P.
      • et al.
      Magnesium sulphate for women at risk of preterm birth for neuroprotection of the fetus.
      • Crowther C.A.
      • Middleton P.F.
      • Voysey M.
      • et al.
      Assessing the neuroprotective benefits for babies of antenatal magnesium sulphate: an individual participant data meta-analysis.

      Postnatal Pediatric Care

      The need for specialized pediatric care is self-evident if birth is very preterm. Given the potential for the need of specialized postnatal pediatric care, clinicians should be prompted to consider referral to a center where such specialized care is available. Specific attention should be given to the problems associated with long-standing metabolic challenges, such as an increased risk of necrotizing enterocolitis and difficulties in achieving full enteral feeding. However, if growth restriction is suspected in a neonate born at term, transitional problems above and beyond those associated with preterm birth should be anticipated. These problems include neonatal hypoglycemia and jaundice.

      Summary and future perspectives

      Currently, there is no proven therapeutic option in FGR other than timed delivery. In early-onset FGR, Doppler assessment of UA, MCA, and DV, along with visual or computerized CTG assessment can be used to guide delivery timing. However, the optimal combination of how to use these modalities remains unclear. Some may be indicative in themselves (recurrent FHR decelerations) but most seem to be interdependent. In the future, the integration of these variables in decision support tools is likely to be of great value. The development of such tools would require a collaborative effort to analyze prospectively collected data that include all known prognostic factors: cCTG, fetal sex, gestational age, Doppler measurements of fetal (UA, MCA, DV) and maternal (uterine artery) blood vessels, and maternal characteristics (age, body mass index, blood pressure) as well as serum biomarkers (PlGF, sFLT). In the development of such a model, several sources of bias, including intervention bias and competing risks, need to be accounted for. Moreover, before implementation of decision support, the approach needs to be prospectively evaluated with a randomization element with outcomes that include long-term neonatal follow-up.
      In late-onset FGR, identifying the fetus that is at risk for immediate hypoxia and benefits from expedited delivery is the challenge. In most cases, available parameters have imperfect correlation with important outcomes, particularly when considered dichotomously and as stand-alone prognosticators. It is likely that studies in the next decades will provide evidence on how to use estimated fetal size in combination with other identifiers of placental insufficiency in risk models that include these identifiers as continuous variables.

      Clinics care points

      • The most common mechanism in fetal growth restriction is suboptimal remodeling of uterine spiral arteries, leading to smooth muscle cell vascular reactivity of the maternal vascular bed, resulting in high-resistance placental circulation without a constant large amount of low-velocity maternal blood flow into the intervillous space.
      • Doppler ultrasound of the uterine artery, umbilical artery, and middle cerebral artery can be measured throughout pregnancy and provides an indication of placental function.
      • The main obstetric decision for fetal growth restriction remains timing of delivery. In early-onset fetal growth restriction, management hinges on weighing the risk of prematurity versus the risk of fetal hypoxia; in late-onset fetal growth restriction, the clinical challenge is the correct diagnosis of the fetus at risk for hypoxia.

      Disclosure

      The authors S. Gordijn and W. Ganzevoort report the in-kind contribution of study materials from Roche Diagnostics for investigator-initiated studies. The authors C. Bruin and S. Damhuis have nothing to disclose.

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