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on-Placental Causes ofntrauterine Growth Restrictionancy Hendrix, MD, and Vincenzo Berghella, MD

Placental insufficiency, in some form or fashion, is associated with the majority of cases ofintrauterine growth restriction (IUGR). There are numerous causes of IUGR which are notcaused primarily by placental insufficiency, but indirectly lead to it. The causes of IUGR canbe subdivided into fetal and maternal etiologies. The fetal etiologies consist of geneticdiseases, congenital malformations, infections, multiple gestations, and placental/cordabnormalities. The maternal etiologies are categorized as follows: (1) decreased uteropla-cental blood flow, (2) reduced blood volume, (3) decreased oxygen carrying capacity, (4)nutrition status, (5) teratogens, and (6) miscellaneous causes such as short interpregnancyintervals, race, maternal age, and low socioeconomic status. Knowledge of the etiologiesof fetal growth restriction is essential, so that future care can be targeted at prevention.There are several primary and secondary prevention strategies that can be adopted.Semin Perinatol 32:161-165 © 2008 Elsevier Inc. All rights reserved.

KEYWORDS intrauterine growth restriction, fetal growth restriction, fetal development

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he regulation of fetal growth is multifactorial and com-plex. Many factors, including intrinsic fetal conditions as

ell as maternal and environmental issues, can lead to intra-terine growth restriction (IUGR), or an estimation of fetaleight �10th percentile for gestational age. The terms IUGRr FGR (fetal growth restriction) are used mostly inter-hangeably in the literature. The term small for gestationalge (SGA) is reserved for the definition of a neonate with airth weight �10th percentile for gestational age. AlthoughUGR is probably a physiologic adaptation to various stimuli,t is associated with distinct short- and long-term morbidi-ies.1 Understanding and identifying the cause(s) of IUGR arehe keys to proper screening, work-up, testing, management,nd other aspects covered in the subsequent chapters.

auses of IUGRlacental insufficiency, in some form or fashion, is associatedith the majority of cases of IUGR. There are numerous

auses of IUGR which are not caused primarily by placental

epartment of Obstetrics & Gynecology, Thomas Jefferson University, Phil-adelphia, PA.

ddress reprint requests to Vincenzo Berghella, Department of Obstetricsand Gynecology, Thomas Jefferson University, 834 Chestnut Street,Suite 400, Philadelphia, PA 19107. E-mail: vincenzo.berghella@

ljefferson.edu

146-0005/08/$-see front matter © 2008 Elsevier Inc. All rights reserved.oi:10.1053/j.semperi.2008.02.004

nsufficiency, but indirectly lead to it. The causes of IUGR cane subdivided into fetal and maternal etiologies (Table 1).

etal Causesetal causes are varied and range from genetic and structuralalformations to infections. Mention is also made of placen-

al abnormalities, although a later chapter will cover them inreater detail.

Genetic diseases of the fetus constitute 5% to 20% ofauses of IUGR.2 Chromosomal abnormalities, such as tri-omy 21 (Down syndrome), trisomy 18 (Edwards syn-rome), trisomy 13 (Patau syndrome), and many others, canause growth restriction presumably through the reducedumber of small muscular arteries in the tertiary stem villi.3

rowth restriction is more severe with trisomy 184,5 thanith trisomy 13 and 21.6 Trisomy 16, which is usually lethal

n the nonmosaic state, can cause growth restriction whenccurring as confined placental mosaicism.7,8 Up to 16% ofases of IUGR have been associated with confined placentalosaicism. Trisomy 9q mosaic is another example. Partialeletions of chromosomes such as 4q, known as Wolf-Hir-chhorn syndrome, and 5q or Cri du chat syndrome, as wells complete deletion of a sex chromosome in Turner syn-rome (45X), have all been linked to FGR. Triploidy or anxtra set of chromosomes is also strongly associated withGR.Single-gene disorders associated with FGR include Corne-

ia de Lange syndrome, Brachmann–de Lange syndrome,

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162 N. Hendrix and V. Berghella

ulibrey Nanism syndrome, Rubenstein–Taybi syndrome,ussell–Silver syndrome, Dubowitz syndrome, Seckel syn-rome, Bloom syndrome, Johanson–Blizzard syndrome,anconi syndrome, Roberts syndrome, De Sanctis–Cac-hione syndrome, and many others, including some skeletalysplasias.9

Uniparental disomy for chromosomes 6,10 14, and 16 haseen found to be associated with FGR. Gene polymorphismsf the matrix metalloproteinase 2 C-1306T gene in the fetuss well as in the maternal LRP8 gene,11 and maternal detox-fication enzyme CYPP1A112 gene have also been associatedith IUGR. Given this high incidence of genetic abnormali-

ies, an amniocentesis, as well as a placental biopsy (alsoalled “late” chorionic villus sampling), should be consideredn cases of otherwise unexplained IUGR.

Congenital malformations, in the absence of identifiableenetic defects, are responsible for another 1% to 2% of FGR.hese include congenital heart disease, diaphragmatic her-ia, abdominal wall defects such as omphalocele and gastros-hisis, anencephaly, and many others. Khoury and cowork-rs13 found that the frequency of FGR increased withncreasing number of defects in the infant. The authors pos-ulated three mechanisms: (1) IUGR can be as a result of or a

able 1 Possible Causes or Risk Factors Associated withUGR

etal● Genetic diseases (5% to 20%) (eg, aneuploidy,

uniparental disomy, growth factor mutations, etc.)● Infection (5% to 10%) (eg, CMV, toxoplasmosis,

malaria, rubella)● Malformations (1% to 2%)● Multiple gestation (3%)● Placental/cord abnormalities (3%) (abruption,

mosaicism, chorioangiomas, 2 vessel cord,velamentous insertion, etc.)

aternal● Hypertensive disorders (20% to 30%)● Pregestational diabetes● Autoimmune disease (eg, APS, SLE)● Cardiac disease (eg, complex cyanotic congenital

heart diseases)● Other maternal diseases (especially if poorly

controlled)● Toxic exposure (smoking, alcohol, cocaine, drugs)● Malnutrition● Living at high altitudes● Living in developing country● Low socio-economic status● Race (eg, Afro-American)● Family or prior history of IUGR● Extremes of maternal age● Infertility/ART?● Short interpregnancy interval

bbreviations: IUGR, intrauterine growth restriction; CMV, cyto-megalovirus; APS, antiphospholipid syndrome; SLE, systemiclupus erythematosus; ART, assisted reproductive technologies.

odified from Sabogal and Weiner.2

eaction to the presence of malformations, (2) IUGR predis- r

oses the fetus to malformations, and (3) IUGR coexists withalformations because of common etiologic factors. They

lso argue that these mechanisms are not mutually exclusive.detailed ultrasound of the fetus should be done to exclude

nomalies in all cases of IUGR. In cases of death, an autopsys the test most revealing in terms of etiology of IUGR.

Fetal infections are responsible for up to 10% of growthestriction cases in the US. The TORCH [Toxoplasmosis,ther (Syphilis), Rubella, Cytomegalovirus and Herpes] or-

anisms have been historically considered as the group tovaluate, although some authors express concern for the lowield associated with the cost.14 Presently, the most commonauses are toxoplasmosis and cytomegalovirus in developedountries, and they should be the ones tested for most fre-uently. Rubella is less of a threat due to vaccination. Syphilis

s still being encountered in pregnancy both in developednd developing countries. Malaria is the predominant infec-ious cause in Africa, South-East Asia, and other countrieshere malaria is endemic, accounting for 40% of cases.15

ytomegalovirus is associated with direct cytolysis and lossf functional cells.16 Rubella causes vascular insufficiency byamaging the endothelium of small vessels and also reducesell division.16 Syphilis creates marked vasculitis, mildhrombosis, and villous edema of the placenta. Nucleated redlood cells suggest fetal anemia and chronic fetal hypoxia asn important mechanism of FGR.17 The pathogenesis of ma-aria activates immune-mediated inflammatory processes, asell as platelets which become deposited in the vascular

ystem and lead to vessel obstruction.18

Multiple gestations are associated with about 3% of casesf IUGR. To estimate growth in multiple gestations, appro-riate growth charts should be used.19 A fetus that is part of awin gestation, for example, physiologically decreases his/herrowth rate after about 28 weeks of gestation. Discordantrowth of multiples can also be assessed, and is usually de-ned as a 20% reduction in EFW of the smaller comparedith the larger fetus (difference of larger minus smaller EFW,ivided by larger EFW). It is not the discordance per se, even

f �30%, but evidence of IUGR of one (or more) fetus(es) thats associated with adverse neonatal outcome. The risk of mor-ality or neonatal morbidity is higher among neonates inGA-discordant twins than in AGA (appropriate for gesta-ional age)-discordant twins (20% versus 6%).20 Growth re-triction is a determinant of outcome in preterm discordantwins.20 IUGR in a twin fetus may be a marker for structuralr genetic anomalies, infection, but also for twin-to-twinransfusion syndrome, or placental issues. Placental and cordbnormalities, such as placental tumor (chorioangiomas,tc.), accreta, infarction, partial abruption, previa, and vela-entous cord insertion, are well known factors because of

he end effect of decreased uteroplacental blood flow, whichestricts the fetus’s growth.

Confined placental mosaicism21 (as discussed above) andingle umbilical artery22,23 are also features associated withrowth restriction in utero. Most studies, but not all,24 foundn increased risk of SGA in fetuses with an isolated singlembilical artery. Raio and coworkers25 found an inverse cor-

elation between worsening of the resistance to blood flow in

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Non-placental causes of IUGR 163

he umbilical artery and umbilical vein area, which may beue to remodeling as a result of persistent reduction in um-ilical blood flow velocity with increasing fetoplacental im-edance. Placenta and cord should not only be carefully ex-mined prenatally by ultrasound, but also examined carefullyacroscopically at birth, and sent to pathology for carefulacro- and microscopic investigation.

aternal Causesaternal causes of IUGR are usually related to reduced utero-

lacental blood flow, reduced maternal blood volume, re-uced oxygen-carrying capacity, or decreased nutrition tohe fetus. Often the etiology is associated with more than onef these mechanisms.

ecreased Uteroplacental Blood Flowaternal etiologies of IUGR are listed in Table 1. Maternal

iseases that affect blood circulation will result in decreasedteroplacental blood flow and are to blame for the majority ofUGR cases. These diseases include hypertensive disordersgestational and nongestational),26 diabetes, chronic renalisease such as renal insufficiency,27 systemic lupus erythem-tosus, antiphospholipid syndrome, and others. Acquiredhrombophilias, such as anticardiolipin antibodies and lupusnticoagulant, can cause poor pregnancy outcomes such asarly-onset preeclampsia and fetal demise in addition toUGR. Inherited thrombophilia polymorphisms (eg, anti-hrombin III deficiency, factor V Leiden, protein C and Seficiencies, and prothrombin G20210A) were not found toe associated with IUGR.28

educed Blood Volumeomen who live at high altitudes29 or have genetic condi-

ions such as angiotensinogen gene mutations30 will haveompromised placental blood flow because of reduced bloodolume from poor pregnancy-associated volume expansion.

educed Oxygen-Carrying Capacityomen who smoke,31 live at high altitudes,29 or have cya-

otic heart disease,32 parenchymal lung disease, hemoglobi-opathies, and anemias will have decreased oxygen carryingapacity which can result in IUGR. Smoking causes symmet-ic IUGR not only because of a reduction in oxygen-carryingapacity, but also because of impaired uterine blood flow.ouhours-Nouet and coworkers33 found that, whereas to-acco use causes decreased mitochondrial respiratory func-ion in cardiomyocytes and lung tissue, it also causes placentalitochondrial dysfunction which limits energy availability in

ells, contributing to restricted fetal growth. Okah and cowork-rs34 found that smoking in combination with alcohol useaused the most pronounced effect on birth weight.

ecreased Nutritionecause glucose drives and is essential for fetal growth,repregnancy maternal weight and maternal weight gain inregnancy are important variables contributing to birtheight. Thus, poor weight gain or low prepregnancy weight

associated with decreased nutrition to the fetus) can be as-

ociated with IUGR. It has been shown that protein restric- c

ion rather than caloric restriction before 26 weeks can causeymmetric IUGR.35,36 On the contrary, high protein supple-entation is associated with an increase in the incidence ofGR as well as neonatal death.37

Gastrointestinal diseases, such as Crohn’s disease, ulcer-tive colitis, and gastrointestinal bypass surgery, can causeower birth weight because of decreased nutrition to the fe-us, although IUGR is not necessarily increased with theseonditions.38

eratogensrescription medications such as coumadin and hydantoinerivatives as well as alcohol abuse are definitely associatedith certain dysmorphic features as well as impaired fetalrowth. One study demonstrated IUGR with the consump-ion of one to two drinks daily in the absence of fetal alcoholyndrome.39

Maternal illicit drug use will cause IUGR by its associationith poor diet as well as a probable direct effect. Use oferoin40 or cocaine41 is associated with IUGR in 50% and0%, respectively, of cases.

iscellaneoushe use of artificial reproductive technologies is a risk factor

or IUGR mostly because of the resulting multiple gestationregnancies. However, ART/infertility has been shown to ben independent risk factor for IUGR even in singleton gesta-ions.42,43 Twin gestations were first observed to have a dif-erent growth curve than that of singletons in 1966 by Gru-nwald.19 A progressive fall in growth after 28 to 32 weeksmplies placental insufficiency to sustain the growth of morehan one fetus in the third trimester. IUGR becomes moreronounced with higher order multiple gestations,44 andhere is a higher likelihood of IUGR after multifetal reduc-ion,45,46 although this is not a consistent etiology.47

A short interpregnancy interval48 is associated with IUGRven when controlled for confounding variables such as ex-remes of reproductive age, marriage status, tobacco use, andocioeconomic status. Race and extremes of maternal age,specially young mothers, have been found to be risk factorsor IUGR.49-51 A low socioeconomic status52 and living in aeveloping country have also been found to be risk factors.ow socioeconomic status is possibly related to the mother’sutrition as well as substance abuse, whereas living in a de-eloping country is associated with maternal anemia or mal-utrition as the most frequent causes of IUGR.53

After having an infant that is small-for-gestational-age, theother has a 25% risk for having another IUGR infant. Herersonal history,54,55 as well as her weight at birth, prepreg-ancy weight, and weight gain in pregnancy account for ap-roximately 10% of the variance.Maternal periodontal disease has been associated with low

irth weight as well as preterm birth probably through theame mechanism of systemic bacteremia infecting the amni-tic cavity that is associated with fetal infections.56

onclusionnowledge of the etiologies of FGR is essential, so that future

are can be targeted at prevention. The term “idiopathic”

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164 N. Hendrix and V. Berghella

UGR should be used only in uncommon cases in which nonef the possible etiologies listed in Table 1 have been identifiedfter a careful work-up for them. As detailed in a recent articlen prevention of recurrent fetal growth restriction,57 there areeveral primary and secondary prevention strategies that cane adopted. A preconception visit is the optimal time to re-iew the patient’s history, as well as any of the risk factorsisted in Table 1, and form a plan to minimize the patient’sisks of occurrence or recurrence.

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