Intrauterine growth restriction

Editor's Notes

• #3 Fetal weight is determined by the genetic growth potential, the health of the fetus, the capacity of the mother to supply adequate quality and quantities of substrates required for growth, and the ability of the placenta to transport these nutritional substrates to the fetus. The genetic growth potential varies from race to race and from individual to individual and this variation is evident in population studies of healthy term newborns showing a symmetrical distribution curve of their birth weights. Normal fetuses at either extreme of this normal biological distribution curve will be combined with others whose growth has been restricted or accelerated due to pathological influences The most important are oxygen, glucose, and amino acids.Oxygen crosses the placenta by simple diffusion and is necessary for the formation of chemical energy in the form ofadenosine triphosphate (ATP). Glucose crosses the placenta by facilitated diffusion and its concentration in the fetusis determined by the maternal plasma glucose levels.Glucose is utilized in the production of energy and in the provision of carbon-building blocks for the synthesis of lipids, glycogen, nucleotides, and other molecules. Amino acids cross the placenta by active transport and are essential for the synthesis of proteins. Any persistent decrease inthe availability of these substrates will limit the ability ofthe fetus to reach his/her growth potential, and a severe substrate deficiency may threaten the ability of the fetus to survive. The availability of substrates necessary for fetalgrowth may be limited by pathological conditions affecting the placenta, the fetus, and the mother. 
• #7 Maternal conditions associated with PFGR interfere with fetal growth by one of the three mechanisms:1. Causing or aggravating placental vascular insufficiency2. Limiting the availability of substrates required for fetal growth and development or3. Transferring to the fetus substances that affect the fetal growth 
• #9 The most common causes (75–80% of the cases) ofPFGR are abnormalities of the placenta, affecting thematernal or the fetal circulation or both. In the majorityof these cases, there is diminished maternal uteroplacental blood flow caused by insufficient or incomplete trophoblastic invasion of the spiral arteries in the placentalbed. Under normal conditions, trophoblastic cells firstinfiltrate the decidua and then the myometrial portion ofthe spiral arteries, destroying the elastic and muscularlayers and replacing them with fibrinoid material.Another feature of abnormal placentation is the deposition of lipoprotein and the infiltration by foamymacrophages of the vascular wall, giving the appearanceof accelerated atherosclerosis. The rigid vessel walls aretransformed into flaccid sac-like structures that canaccommodate the increased uteroplacental blood flowthat occurs during pregnancy. These transformed spiralarteries are not affected by maternal vasoregulatorymechanisms. The initial phase of the trophoblastic invasion of the spiral arteries usually ends by the 16th weekof gestation, but in many cases completion of the adaptative changes does not occur until 20–22 weeks. Whenplacentation is abnormal, trophoblastic invasion islargely confined to the decidual layer with absent orincomplete changes in the myometrial portion of the spiral and radial arteries. The presence of spiral and radialarteries with intact muscular and elastic layers causesincreased vascular resistance and decreased blood flowto the intervillous space, restricting the maternal capacity to provide oxygen and nutrients to the fetus. Also, the vessels with absent or incomplete transformation remainreactive to vasoactive substances produced or ingestedby the mother. This placentation defect is not exclusiveof FGR and is also found in placentas of women withpreeclampsia, preterm labor, and preterm prematurerupture of the fetal membranes. Placentalinfarcts are present in up to 10% of normal pregnancies andthey probably result from the hypercoagulability of pregnancy combined with the slow blood flow through the intervillous space. The presence of multiple infarcts is stronglysuggestive of the possibility of congenital or acquired maternal thrombophilia. Antiphospholipid antibodies are themost common cause of acquired thrombophilia and factorV Leiden mutation, prothrombin promoter mutation,homozygosity for the methylene-tetra-hydro-folate reductase C677T mutation, and decreased protein S activity arethe most common congenitally acquired thrombophilicstates.A lesion in the maternal side associated with PFGR ismassive perivillous fibrin deposition. In these cases theintervillous space is occupied by fibrin and the villi embedded within the fibrinous mass are nonfunctional. In onestudy the incidence of PFGR in cases of massive perivillousfibrin deposition was 62.9% (Fuke et al., 1994). This lesionis also present in some cases of fetal demise and is stronglysuggestive of the possibility of maternal thrombophilia.Maternal floor infarction is another placental lesionassociated with PFGR and fetal demise. Pathologically,this condition is characterized by massive deposition offibrin in the maternal floor of the placenta encasing thecontiguous villi that become necrotic or atrophic. Thislesion is apparent macroscopically and can be identifiedeasily by looking at the maternal side of the placentawhich will be covered by pale, glassy, smooth tissue withan appearance that vaguely resembles the surface of abrain. Maternal floor infarct is found in 5 per 1000 to 9per 10,000 births. It is associated with PFGR in morethan 50% of cases and is a common finding in cases offetal death (Mandsager et al., 1994). Unfortunately, thiscondition frequently reoccurs in successive pregnancies.The pathophysiological basis for maternal floor infarct isunknown but maternal thrombophilia is a good possibility and should be researched systematically. Some investigators consider that maternal floor infarction and massiveperivillous fibrin deposition are related conditions(Katzman et al., 2002).Other placental lesions associated with PFGR arechronic villitis, hemorrhagic endovasculitis, and confinedplacental mosaicism. Lymphocytic and histiocytic infiltration of the villi are the markers of chronic villitis (Althabeand Labarrere, 1985), a nonspecific lesion that may occurin isolation but frequently is associated with vascularlesions in the maternal or fetal side of the placenta. Chronicvillitis may be immunological or viral in origin. When cellinfiltration by plasma cells occurs, the possibility of infection by cytomegalic virus is high. Chronic villitis occurs inapproximately 8% of normal pregnancies but the incidenceincreases three- to fourfold in cases of PFGR. Pathologicalfetal growth restriction is present in approximately 30%of patients with chronic villitis.Hemorrhagic endovasculitis is another lesion associatedwith poor pregnancy outcome and is histologically characterized by the presence of numerous extravascular erythrocytes infiltrating the villi. It is generally believed that hemorrhagic endovasculitis is another histological manifestation of maternal/fetal thrombophilia. Both chronic villitisand hemorrhagic endovasculitis are frequently present inplacentas from women with preeclampsia.In cases of confined placental mosaicism, the chromosomal composition of the placenta is not the same as that ofthe fetus. In these cases the placenta is usually trisomic andthe fetus has a normal karyotype but inherits both homologous chromosomes from one of the parents. Most commonly the placenta is trisomic for chromosome 16 but upto 12 other chromosomes could be involved. Most likelythe zygote is originally trisomic with subsequent expulsionof one of the trisomic chromosomes from the embryonicbut not from the trophoblastic tissue (Robinson et al.,1997). Confined placental mosaicism and fetal uniparentaldisomy is a condition associated with severe PFGR but mayalso occur in newborns with normal weight and in somethat are large for gestational age.Clotting and thrombosis may also be present in thefetal side of the placental circulation. In these cases theintravascular clotting affects the chorionic stem vessels,causing an infarct with avascular fibrous villi in the distribution territory of the affected vessel. This lesion hasbeen named fetal thrombotic vasculopathy (Redline andPappin, 1995). In many cases the lesions in the fetal circulation occur simultaneously with infarcts or decidualCHAPTER 4 FETAL GROWTH RESTRICTION 109vasculopathy in the maternal side of the placenta but inother cases they may occur without apparent maternalside lesions. In any case, the presence of fetal thromboticvasculopathy has a strong association with poor pregnancy outcome (Arias et al., 1998). Of particular importanceis the possibility of an association between this placentallesion and thromboembolic lesions in the fetal brain(Rayne and Kraus, 1993).Placental vascular insufficiency and impaired fetalgrowth of one or more fetuses are a relatively commonfinding in multifetal pregnancies. When the restriction ingrowth affects only one of the fetuses is named “selectiveFGR” condition that may occur in up to 21% of multifetal pregnancy. The problem occurs more frequently intwins with monochorionic placentation. Abnormal insertion of the umbilical cord, torsion of the cord, hemangiomas of the placenta, and placenta previa are situationsalso frequently associated with selective FGR. The overallprevalence of these abnormalities is low. 
• #10 The frequency of congenitally abnormal newborns among severely affected PFGR fetuses is approximately 10%. The majority of these genetically affected babies have asymmetric measurements in prenatal ultrasound examination with the head being larger than the abdomen. PFGR is common in chromosomal disorders, especially in somatic trisomies. It also occurs in patients with familial dysautonomy, osteogenesis imperfecta, and other multifactorial disorders.Single gene mutations do not affect fetal growth as much as do chromosomal defects. The possibility of a fetal congenital disorder should always be considered in patients with “idiopathic” or “unexplained” FGR. In a study of more than 13,000 malformed infants bornin Atlanta (Khoury et al., 1988) the overall frequency of PFGR was 22.3%. The most common abnormalities associated with PFGR were chromosomal, particularly trisomy 18. The mechanism of fetal growth impairment secondary to genetic syndromes is unknown but it is possiblethat chromosomal defects cause alterations in placental function, resulting in fetal malnutrition. A large number of fetuses affected by genetic conditions can be detected by a comprehensive or genetic ultrasound examination.Fetal infections are not a common cause of PFGR.Bacterial infections usually have acute courses and cause preterm labor, preterm rupture of membranes, or fetal death. Viral infections on the other hand may be chronic and affect fetal growth. The viral infections associated with impaired fetal growth are congenital rubella, cytomegalic virus, congenital varicella, human immunodeficiency virus, and acute herpes simplex virus infection 
• #25 The problems in diagnosing and managing pregnancieswith impaired fetal growth are substantial. This is due tothe confusion between fetuses that are small and healthyand those who have a pathological restriction in theirgrowth, to our inability to know what is the growthpotential of a given fetus, to the occurrence of FGR inpatients without recognizable high-risk factors, to theproliferation of measurements to assess fetal growth, tothe difficulties in estimating gestational age, and to different opinions about the ideal time to deliver these smallfetuses. 
• #28 Fig. 2. Fetal deterioration and monitoring in early-severe FGR. Placental disease affects a large proportion of the placenta, and this isreflected in changes in the UA Doppler in a high proportion ofcases. The figure depicts in a schematic and simplified fashion thepathophysiologic progression with the main adaptation/consequence in placental-fetal physiology, and the accompanying cascade of changes in Doppler parameters. The sequence illustrates theaverage temporal relation among changes in parameters, but theactual duration of deterioration is influenced by severity. Regardless of the velocity of progression, in the absence of accompanyingPE this sequence is relatively constant, particularly as regards endstage signs and the likelihood of serious injury/death. However,severe PE may distort the natural history and fetal deteriorationmay occur unexpectedly at any time (see text for abbreviations). 
• #29 Fig. 3. Fetal deterioration and monitoring in late-mild FGR. Placental disease is mild and UA Doppler values are not elevatedabove the 95th centile. The effects of fetal adaptation are best detected by the CPR, which can pick up mild changes in the AU andMCA Doppler. An important fraction of cases do not progress tobaseline hypoxia so that they remain only with abnormal CPR.Once baseline hypoxia is established, placental reserve is minimaland progression to fetal deterioration may occur quickly, as suggested by the high risk of severe deterioration or intrauterine fetaldeath after 37 weeks in these cases, possibly due to a combinationof a higher susceptibility to hypoxia of the term-mature fetus andthe more common presence of contractions at term (see text forabbreviations). 
• #39 Stage I Fetal Growth Restriction (Severe Smallness orMild Placental Insufficiency). Either UtA, UA or MCADoppler, or the CPR are abnormal. In the absence of other abnormalities, evidence suggests a low risk of fetal deterioration before term. Labor induction beyond 37 weeksis acceptable, but the risk of intrapartum fetal distress isincreased [44]. Cervical induction with Foley catheter isalso recommended. Weekly monitoring seems reasonable.Stage II Fetal Growth Restriction (Severe Placental Insufficiency). This stage is defined by UA absent-end diastolic velocity (AEDV) or reverse AoI. Although evidencefor UA AEDV is stronger than that for AoI, observational evidence suggests an association between the latter toabnormal neurodevelopment, so that both criteria become a single category. Delivery should be recommendedafter 34 weeks. The risk of emergent cesarean section atlabor induction exceeds 50%, and, therefore, elective cesarean section is a reasonable option. Monitoring twice aweek is recommended.Stage III Fetal Growth Restriction (Advanced Fetal Deterioration, Low-Suspicion Signs of Fetal Acidosis). Thestage is defined by reverse absent-end diastolic velocity(REDV) or DV PI >95th centile. There is an associationwith a higher risk of stillbirth and poorer neurologicaloutcome. However, since signs suggesting a very high riskof stillbirth within days are not present yet, it seems reasonable to delay elective delivery to reduce as possible theeffects of severe prematurity. We suggest delivery shouldbe recommended by cesarean section after 30 weeks.Monitoring every 24–48 h is recommended.Stage IV Fetal Growth Restriction (High Suspicion ofFetal Acidosis and High Risk of Fetal Death). There arespontaneous FHR decelerations, reduced STV (<3 ms) inthe cCTG, or reverse atrial flow in the DV Doppler. Spontaneous FHR deceleration is an ominous sign, normallypreceded by the other two signs, and thus it is rarely observed, but if persistent it may justify emergency cesareansection. cCTG and DV are associated with very high risksof stillbirth within the next 3–7 days and disability. Deliver after 26 weeks by cesarean section at a tertiary carecenter under steroid treatment for lung maturation. Intact survival exceeds 50% only after 26–28 weeks, and before this threshold parents should be counseled by multidisciplinary teams. Monitoring every 12–24 h until delivery is recommended.Particularly at early gestational ages, and at whateverstage, coexistence of severe PE may distort the naturalhistory and strict fetal monitoring is warranted since fetaldeterioration may occur unexpectedly at any time.