Recurring complications of pregnancy

SEMINARS IN PERINATOLOGY TOPICS FOR 2006

OPTIMIZING CARE AND OUTCOMES FOR

INFANTS:PART1

Tonse N. K. Raju, MD

OPTIMIZING CARE AND OUTCOMES FOR

INFANTS:PART2

Tonse N. K. Raju, MD

ADVANCES IN NEONATOLOGY: SELECTED PROCEEDINGS OF THE INTERNATIONAL PERINATAL

COLLEGIUM

William Oh, MD, and Harry Bard, MD BPD:STATE

OF THE

ART

Vineet Bhandari, MD, DM

CESAREAN DELIVERY ON MATERNAL REQUEST

Catherine Y. Spong, MD, and Uma M. Reddy, MD, MPH

INHERITED RESPIRATORY DISORDERS OF THE NEONATE

Lawrence M. Nogee, MD, and Aaron Hamvas, MD

TOPICS FOR 2007

NEONATAL INFECTIONS

Robert S. Baltimore, MD, and Hal B. Jensen, MD

NUTRITIONAL PRACTICES FOR

THE EVIDENCE BASE

SUPPORTING

VERY

LOW BIRTH WEIGHT INFANTS

Richard A. Ehrenkranz, MD, and Brenda B. Poindexter, MD, MS

RECURRING COMPLICATIONS

OF

PREGNANCY

John C. Smulian, MD, MPH

COAGULATION DISORDERS IN THE PERINATAL

PERIOD

Michael J. Paidas, MD

PAIN

K. J. S. Anand, MD, and Richard W. Hall, MD

ORGAN TRANSPLANTATION AND REPRODUCTION

Lloyd Ratner, MD, and Mary D’Alton, MD

Volume 31, Number 3 June 2007

Introduction

. . .Whoever wishes to foresee the future must consult the past; for voted to some of the most significant pregnancy complica- human results ever resemble those of preceding times.

tions encountered by clinicians. (There clearly are many Niccoló Machiavelli (The Discourses, 1517)

more pregnancy complications with a tendency to recur, regnancy is associated with many unique health prob-

which deserve the same careful scrutiny as those reviewed lems that occur at no other time in life and in no specialty

here.) Because recurrence research is complicated and re-

other than Obstetrics. Complications can be medical or sur- quires different thinking about epidemiologic and statistical gical and may affect the mother, the baby, or both. What is

methodologies, there is included an important eighth article even more unique is that we have the opportunity to follow

that addresses challenges specific to the study of recurrent women through successive pregnancies, each of which is at

pregnancy complications.

risk for either occurrence or recurrence of these complica- The selected topics covered in this issue illustrate how tions. Whereas prediction of complications for nulliparous

important the concept of recurrence is to Obstetrics. These women with no pregnancy track record is notoriously diffi-

articles review what is known about the epidemiology of cult, it is becoming clear that a history of a pregnancy com-

recurrence for each specific complication, proposed etiologic plication is the greatest predictor of a future pregnancy com-

pathways, prevention options, and management recommen- plication. It is the role of research in complication recurrence

dations for successive pregnancies. Each article also is meant to grow our understanding of the heterogeneity of pregnan-

to highlight knowledge gaps and areas with a pressing need cy-associated diseases and give insight into etiologies and

for research. Unfortunately, our knowledge gaps about re- risk. This will ultimately lead to better clinical prediction,

currence are wide for many of these conditions. counseling, and management. As clinicians, we should not

It is my hope that this issue of Seminars in Perinatology will manage these at-risk women the same as women who have

provide information to directly help with the clinical care of never had a pregnancy or who have had previous normal

our highest risk women. I also hope that these articles will pregnancy outcomes. We also should avoid the practice of

stimulate further research on the recurrence of complications “anecdotal medicine,” where wide variations in clinical care

in successive pregnancies and promote collaborations be- can be driven by either insufficient experience or the trauma

tween epidemiologists and clinicians to advance our under- of a previous adverse event.

standing of this very important area of medicine. This issue of Seminars in Perinatology is organized around the theme of recurrent pregnancy complications. There are

John C. Smulian, MD, MPH eight articles by recognized experts, of which seven are de-

Guest Editor

0146-0005/07/$-see front matter © 2007 Elsevier Inc. All rights reserved.

doi:10.1053/j.semperi.2007.03.007

Fetal Growth Restriction and Subsequent Pregnancy Risks

Wendy L. Kinzler, MD, and Lillian Kaminsky, MD

Fetal growth restriction can result from a variety of intrinsic or extrinsic insults, resulting from maternal, fetal, and placental factors. Determining the underlying cause of poor fetal growth can be difficult but is essential for assessing potential risks for future pregnancies. Importantly, recurrence risks greatly depend on these underlying conditions. Understand- ing these risks can allow more appropriate patient counseling and may influence manage- ment strategies to optimize future pregnancies. Semin Perinatol 31:126-134 © 2007 Elsevier Inc. All rights reserved.

KEYWORDS fetal growth restriction, recurrence risks

N Etiology-Specific Risks for FGR

ormal fetal growth is dependent on complex interac-

tions between the fetal, placental, and maternal units. Poor fetal growth can result from a variety of intrinsic or

There are multiple factors which can adversely influence fetal extrinsic insults. Determining the underlying cause can be

growth. In broad terms, contributing factors can be intrinsic difficult but is essential for assessing potential risks for future

to the fetus, they can be specific to the uteroplacental unit, or pregnancies.

they may be the result of underlying maternal conditions. Small for gestational age (SGA) infants are defined as those

Determining which of these was responsible for FGR can be the most difficult but the most useful part of the evaluation

born with a weight ⬍10th percentile for gestational age. Fetal during a woman’s subsequent pregnancy. Prior medical growth restriction (FGR) can be defined as an abnormal records, including prenatal labs and notes, previous ultra-

growth trend, which is less than the genetic growth potential sound reports, maternal and infant hospital records, and pla- of the individual fetus and which is always pathological. This

cental pathology, should be requested and carefully re- pathological FGR may affect only 3% to 5% of births. Impor-

viewed, with particular attention being made to the following tantly, not all SGA babies have FGR since some may be con-

etiologic pathways.

stitutionally small. Conversely, a fetus still may be growth restricted if it is above the 10th percentile in weight if it is substantially smaller than its growth potential would predict.

Fetal Causes

It is important to accurately determine as best as possible Chromosomal aberrations are a well-established cause of fe- whether a previous pregnancy was complicated by patho-

tal growth restriction and are estimated to be responsible for logic FGR or merely a constitutionally SGA infant. Informa-

up to 20% of cases. 1 Early onset of growth restriction, the tion that might be helpful for establishing a diagnosis of fetal

presence of polyhydramnios, and the presence of structural growth restriction in a previous pregnancy is listed in Table

malformations all increase the likelihood of a chromosomal

1 . Once the diagnosis of FGR is established, an assessment of abnormality. Triploidy is most common in severe cases of subsequent pregnancy risk can be performed based on the

FGR when ⬍26 weeks gestation, and Trisomy 18 is the most etiology of the initial case.

common aneuploidy noted with severe FGR after 26 weeks gestation. 1 However, other trisomies, deletions/additions, and ring chromosomes have all been associated with various

Division of Maternal Fetal Medicine, Department of Obstetrics, Gynecology

degrees of fetal growth abnormalities. Fetal aneuploidy is not

and Reproductive Sciences, UMDNJ-Robert Wood Johnson Medical

the only chromosomal abnormality to be associated with

School, New Brunswick, NJ. Address reprint requests to Wendy L. Kinzler, MD, Department of Obstet-

poor fetal growth. Confined placental mosaicism is present

rics, Gynecology and Reproductive Sciences, Clinical Academic Build-

when the cytogenetics of the placental mass are different than

ing, 2nd Floor, 125 Paterson Street, New Brunswick, NJ 08901. E-mail:

the cytogenetics of the fetus. It occurs either as the result of a

kinzlewe@umdnj.edu

meiotic rescue of a trisomic embryo or due to a mitotic

126 0146-0005/07/$-see front matter © 2007 Elsevier Inc. All rights reserved.

doi:10.1053/j.semperi.2007.03.004

Fetal growth restriction 127

Table 1 Information Useful for Establishing a Diagnosis of ternal complications linked with poor fetal growth. There are FGR in a Previous Pregnancy

no data to assess recurrence risks for FGR when the index ● Previous birth weight and gestational age to determine

case is a multiple gestation. However, the risks in a subse- birth weight centile

quent singleton pregnancy are likely to be increased mini- ● Antepartum complications (bleeding, multiple gestation,

mally, if at all.

congenital abnormalities, preeclampsia) ● Maternal pre-pregnancy BMI and weight gain during

Placental Factors

pregnancy

● Social history (tobacco, alcohol, or illicit drug use) Umbilical cord and placental abnormalities are frequently ● Medication exposure

identified in pregnancies complicated by poor fetal growth. A ● Prenatal fetal growth trends and ultrasound reports

● Medical complications (chronic hypertension, IDDM, single umbilical artery is present in approximately 0.4% of

SLE, anemia, asthma, etc.) pregnancies 15 and has been associated with fetal structural ● Birth weights of other pregnancies

malformations, particularly cardiac. In cases of an isolated ● Maternal birth weight

two-vessel cord, FGR is estimated to be up to twice as com- ● Neonatal complications (respiratory, metabolic, 16 mon as in pregnancies with three-vessel cords. Velamen-

congenital abnormalities, NICU admission, and length tous cord insertions, which enter the fetal membranes instead of stay)

of the placental parenchyma, have a reported incidence of 1% to 2%. 15 They have been associated with higher rates of low birth weight (OR 2.3), small-for-gestational age infants (OR postzygotic error. 2 It has been found in approximately 15%

1.5), and preterm delivery (OR 2.1) 17 compared with umbil- of intrauterine growth restriction cases, compared with ⬍2%

ical cords normally inserted into the placenta. This suggests of appropriately grown fetuses. The recurrence risk of aneu-

that at least some of these low-birth-weight and SGA births ploidy is approximately 1%, but a recurrence risk for con-

have FGR. Circumvallate placentation is defined as an ele- fined placental mosaicism has not been established.

vated edge of the placenta ⬎50% of the circumference, and Nonaneuploid genetic syndromes have also been associ-

has been associated with poor fetal growth and prematuri- ated with fetal growth restriction but may be more difficult to

ty. 18 These factors are generally considered to have low re- identify without a known family history and/or detailed ge-

currence rates.

netic evaluation. Lower birth weights are also often identified Placental bleeding at any trimester places a pregnancy at in infants born with structural malformations, especially

increased risk for adverse outcomes. The incidence of first when cardiac, even in the presence of a normal fetal karyo-

trimester intrauterine hematoma is reported to be 3% in the type. 3 Uniparental disomy (UPD) is the inheritance of two

general population with increased risks of hypertensive dis- homologous chromosomes from only one parent. There are

orders of pregnancy (2- to 4-fold), abruption (5-fold), pre- clinical syndromes which are known to be the result of UPD

term delivery (2-fold), and FGR (2.4-fold). 19 Abruption at (Silver Russell Syndrome, for example) and have significant

term is also significantly associated with FGR (2-fold in-

creased risk), stillbirth, preterm delivery, and pregnancy-in- association with poor fetal growth has been established, UPD

growth restriction as part of their phenotype. 4 Although an

duced hypertension. 20,21 Placental bleeding at any gestational

age in a pregnancy complicated by FGR may be a clinical recurrence from these causes is dependent on the specific

is an uncommon finding in most cases. 5 The risk for FGR

manifestation of a chronic placental disorder that can recur. associated condition.

Although the majority of low-birth-weight neonates deliv- Congenital infections, namely rubella, cytomegalovirus,

ered from pregnancies complicated by placenta previa are toxoplasmosis, herpes simplex, and varicella, have been as-

small due to preterm gestational age at birth, at least one sociated with FGR. 6-9 Despite this clear association, the pro-

report estimated that as much as 3.7% of FGR is attributable portion of growth restriction attributed to congenital infec-

to placenta previa. 22

tion is low (5%), 10 and they are not expected to recur. Microscopically, many placental lesions have been identi- For a variety of reasons, fetuses within multiple gestations

fied in cases of abnormal fetal growth. Placental infarctions have an increased incidence of growth restriction. The inci-

have been associated with FGR and abnormal fetal blood dence of growth restriction in twins is 15% to 25%, 11-13 mak-

flow. 23 Placental examination from term pregnancies compli- ing multiple gestations responsible for approximately 5% of

cated by idiopathic FGR also found a high incidence of in- all cases of FGR. There is a significant increase in the rate of

farction (24%). 24 The placenta can also be the target of im- fetal growth abnormalities in direct relationship to the num-

mune-mediated injury, such as occurs with massive fibrin ber of fetuses present. 14 This may be related to a reduction in

deposition and chronic villitis.

cell size or a relative reduction in nutrient supply as the Massive perivillous fibrin deposition, previously referred nutritional demands of the fetuses increase. This form of FGR

to as maternal floor infarct, is a significant placental lesion is usually mild. Nevertheless, other contributing factors may

characterized by a heavy deposition of fibrin in the decidua include an increased incidence of placental and umbilical

basalis and extending into the intervillous space, preventing cord abnormalities (velamentous insertions), a greater likeli-

appropriate maternal–fetal exchange of nutrients. It is be- hood of structural malformations and vascular anastomoses

lieved to be the result of an immune-mediated maternal re- in monozygotic multiples, and an increased incidence of ma-

sponse and has been associated with high rates of poor fetal

128 W.L. Kinzler and L. Kaminsky

outcomes, including a 15% to 40% fetal death rate, a 30% to anticonvulsants, can also be associated with FGR. The risk for 60% preterm birth rate, and a 50% to 100% rate of FGR. 25,26

recurrence of FGR for these exposures is likely linked to their Another potential immune-mediated lesion is chronic vil-

continued presence or their discontinuation. litis of unknown etiology (VUE). Chronic villitis has been

Clinical maternal vascular disease secondary to chronic found in approximately 30% of pregnancies complicated by

hypertension, renal disease, diabetes mellitus, and collagen FGR. 24,27 Other, rare placental abnormalities include placen-

vascular disease, especially when complicated by preeclamp- tal mesenchymal dysplasia, which is a placenta vascular mal-

sia, is the most common cause of impaired fetal growth, formation that is often confused clinically with a partial hy-

accounting for nearly a third of FGR cases. 2 Both preeclamp- datiform mole. This abnormality can predispose to placental

sia and FGR may share a similar pathophysiology involving thrombosis. In one series, 50% of the cases were associated

abnormal placentation leading to placental insufficiency. 44 with FGR and 43% of the pregnancies were complicated by a

Chronic hypertension is associated with a two- to threefold fetal death. 28

increase in the rate of FGR, an association mostly due to the presence of superimposed preeclampsia. 45 In fact, when

Maternal Factors

growth restriction cases due to preeclampsia, smoking, and malnutrition are excluded, diabetes and hypertension may

Multiple maternal factors have been implicated in poor fetal no longer be independent risk factors. 46 The association of growth. Careful review of the maternal history for potential

chronic hypertension and poor fetal growth may also be par- contributing factors can sometimes identify nutritional dis-

tially mediated by the effect of antihypertensive medications, orders, anemia and maternal hypoxia-related conditions, en-

such as beta-blockers. 47 The risk of FGR in pregnancies af- vironmental exposures (particularly tobacco or cocaine use),

fected by pregestational diabetes is dependent on the severity and conditions with maternal vascular disease. Any review

and duration of the disease. 45 The incidence of FGR in should include a family history, as it has been shown that

chronic renal disease has been reported to be as high as familial factors influence the risk of SGA births. 29 23%. 48 Patients with systemic lupus have an eightfold in- Malnutrition is an uncommon, but nonetheless important,

creased risk for developing FGR, 45,49-51 with the highest risks risk factor for poor fetal growth, especially in developing

noted in women diagnosed before pregnancy and those with countries. The effect of starvation was best studied in a Dutch

active renal and central nervous system involvement. 49-51 cohort during the famine of 1944 to 1945. Pregnant women

These risk factors will persist in subsequent pregnancies. under such severe nutritional deprivation experienced

Inherited thrombophilias are a group of genetic conditions weight loss and a drop in birth weight by 250 to 300 g. 30 that increase the risk of thromboembolic disease. They in- Women with eating disorders have also been shown to have

clude Factor V Leiden (FVL), prothrombin G20210A muta-

tion, protein C deficiency, protein S deficiency, antithrombin deficiency is likely to reduce recurrence risk.

higher rates of SGA births. 31 Correction of such nutritional

III deficiency, and MTHFR mutation, as well as other, less Maternal conditions leading to hypoxemia can lead to a

studied, familial conditions. Theoretically, placental throm- reduction in fetal growth potential. Studies have inconsis-

bosis in patients with inherited thrombophilias may lead to tently linked maternal anemia, including sickle cell anemia,

an increased risk for FGR, although the published data are and low birth weight. 32-34 Chronic respiratory disease, such

conflicting. A number of studies have demonstrated an asso- as asthma, can also lead to decreased fetal growth through

ciation between maternal inherited thrombophilias and fetal hypoxia. 35 Likewise, women with congenital cyanotic

FGR. 52-55 However, other studies were unable to show an heart disease and those living at high altitude are at higher

association. 56-59 Based on the conflicting current data, inher- risk for lower birth weight babies. 36,37

ited thrombophilia in isolation does not seem to be a major Maternal substance abuse, including tobacco, alcohol, and

risk factor for most cases of FGR. However, the contributing cocaine, is an important preventable cause of poor fetal

role of thrombophilias in combination with other risk factors, growth. The mechanism may involve direct toxic damages of

including previous FGR, may be important. Antiphospho- these substances as well as associated comorbidities, such as

lipid antibody syndrome (with or without underlying sys- inadequate nutrition, maternal infections, etc. Smoking is

temic lupus) is an acquired thrombophilia, which has been associated with an increased risk of delivering a low-birth-

linked to several recurrent adverse pregnancy outcomes, in- weight or SGA infant in a dose-dependent fashion.

cluding FGR, fetal death, and recurrent miscarriages. 60,61 been estimated that approximately 20% of low-birth-weight

It has

and SGA births are attributable to maternal smoking. 40 Bada

Evaluation Options to

and coworkers estimated that, if smoking could be com-

pletely prevented during pregnancy, 13.8% of FGR cases

Assess FGR Etiologies and Risks

would be eliminated. 41 FGR is one of the major features of Once the diagnosis of FGR has been confirmed and the above fetal alcohol syndrome, which is also associated with facial

etiologies have been evaluated by history and examination,

dysmorphia and central nervous system disorders. 42 The ad-

there may continue to be gaps in knowledge that may have a

significant impact on further management. Some of these well as on placental abruption, preterm birth, and intrauter-

verse effects of prenatal cocaine exposure on fetal growth 43 as

gaps, however, can be filled with the addition of a few simple ine fetal demise have been well established. Various thera-

steps. If not already done, consider having the previous pla- peutic drugs, such as warfarin, folic acid antagonists, and

cental slides reviewed for histologic abnormalities by a peri-

Fetal growth restriction 129

natal pathologist. If there is evidence of a prior abruption, or women with untreated inherited or acquired thrombophilia placental thromboses and/or infarctions are noted, it is im-

A cohort study of 491 portant to assess for maternal risk factors that may contribute

is approximately 66% to 83%. 63,69

patients with a history of adverse pregnancy outcomes has to coagulation abnormalities. Testing for acquired and inher-

demonstrated that the presence of a maternal thrombophilia itable thrombophilias is recommended in these cases, partic-

is associated with fetal loss after 14 weeks (OR 3.4, 95% CI ularly when the growth restriction is severe, associated with

1.9-6.1), abruption (OR 3.6, 95% CI 1.4-9.1), and pre- preterm delivery, or noted in the presence of a family history

eclampsia (OR 3.2, 95% CI 1.2-8.6). 70 Women who deliv- of thromboembolic disease. Specific evaluations would in-

ered infants ⬍3rd percentile may be three times more likely clude maternal testing for lupus anticoagulant, anticardio-

to have initial or recurrent preeclampsia in the next preg- lipin antibodies (IgG and IgM), and ␤2-glycoprotein-1 anti-

nancy compared with those who deliver infants ⬎10th per- bodies. It is important to remember that 10% to 15% of

centile. 71 They may also be at increased risk of fetal demise, women with systemic lupus erythematosus will have second-

especially when the previous fetal growth abnormalities were ary antiphospholipid antibody syndrome and should be

identified at early gestational ages. 72 Interestingly, of the 23% tested if their antiphospholipid status is not already known. 62 of women experiencing recurrent SGA in one study, the poor Genetic thrombophilia testing should include an evaluation

fetal growth was not more severe the second time. 73 for deficiencies in protein C, protein S, and antithrombin III

Previous abruption is a risk factor for FGR, as well as other and the presence of the Factor V Leiden and prothrombin

adverse obstetrical outcomes. Recurrent placental abruption gene mutations. If immune-mediated placental dysfunction

has been observed in 22% of subsequent pregnancies. 74 After is suspected, testing for the antiphospholipid antibody syn-

an abruption, the risk of a SGA infant is 18.5%, the risk of a drome and screening for other autoimmune disorders are

spontaneous preterm birth is 36%, and the risk of pregnancy- warranted. There is insufficient information to support test-

induced hypertension is 6%. 75 A previous SGA birth in- ing the affected offspring for the presence of thrombophilias

creases the risk of abruption by 1.6-fold and by 2.5- to 6.0- at this time.

fold if there is preexisting chronic hypertension or diabetes. 76 If the prior child was found to have structural malforma-

If a first delivery has been complicated by a preterm birth, tions (prenatally or postnatally diagnosed), and/or there have

SGA infant, or perinatal death, the risk of an abruption in the been concerns about development delay, genetic counseling

second pregnancy is 7/1000 if no abruption was present in and possible evaluation by a pediatric geneticist is recom-

the initial pregnancy and 33/1000 if there was a prior abrup- mended. Review of prior records, including autopsy reports

tion. 77

or infant discharge summaries, can be very helpful, as parents If there has been a history of FGR and placental infarction, may not be fully aware of known or suspected diagnoses. If

the risk of recurrent growth restriction is high. It has been there has been a documented or suspected case of aneu-

estimated to be 61% when two or more prior pregnancies ploidy, parental karyotypes should be considered. This is

have been similarly affected. 78 Recurrent villitis has been particularly important for cases of aneuploidy other than the

noted in 17% of gestations, and has been associated with autosomal trisomies thought to be the result of meiotic non-

FGR, pregnancy loss, preterm delivery, and postnatal death. disjunction, such as unbalanced translocations and ring

There is an even higher rate of recurrence of massive inter- chromosomes. A formal genetics evaluation is also essential

villous fibrin deposition and poor fetal growth (67%). 79 Pla- in detecting and counseling about nonaneuploid genetic syn-

cental mesenchymal dysplasia is a rare finding with an un- dromes.

likely risk of recurrence.

In women with an underlying medical condition, assessing the severity of the disorder can also provide insight into the

Prevention of Recurrent FGR

ongoing obstetrical risks. This would include determining the presence of renal dysfunction in women with systemic

The importance of a thorough evaluation for potential etiol- lupus or other autoimmune processes and evaluating the

ogies in evaluating a woman’s risk of adverse obstetrical out- degree of vascular and/or end-organ disease in women with

comes as the result of a prior FGR birth cannot be overem- long-standing diabetes or chronic hypertension.

phasized. A comprehensive assessment will lead to appropriate counseling and, in many cases, will allow the implementation of targeted risk-specific strategies to reduce

Assess Risks for a Subsequent Pregnancy

recurrence ( Fig. 1 ).

The diagnosis and/or risk factors that have been identified in If there is an opportunity for preconceptional care, it the above steps will allow appropriate counseling regarding

should focus on the elimination of known maternal expo- the risk(s) to subsequent pregnancies ( Table 2 ). It is clear that

sures (cocaine, smoking, alcohol), folic acid supplementation the data on etiology-specific FGR recurrence risks are sparse.

to reduce the risk of congenital malformations, and the opti- Recently, it has been recognized that women with a history of

mization of maternal medical conditions. Low prepregnancy FGR are at risk for multiple adverse pregnancy outcomes in

body mass index (BMI) is a risk factor for FGR. If a woman subsequent pregnancies that include recurrent FGR, pre-

continues to have a suboptimal BMI in the next pregnancy,

this risk persists. However, an increase in maternal BMI be- vant in the setting of an acquired or inherited thrombophil-

eclampsia, and abruption. 63 These risks are particularly rele-

tween pregnancies has been associated with a decreased SGA ia. 64-68 The recurrence rate of adverse pregnancy outcomes in

risk. 80 Although prospective trials of weight gain are lacking,

130 W.L. Kinzler and L. Kaminsky

Table 2 Recurrence Risks of Etiologies and FGR Based on Etiology of the Poor Fetal Growth in the Previous Pregnancy 1,3,10-13,16-18,20,21,24,25,27,28,45,48,52-55

Risk of SGA with Previous Pregnancy Condition

Risk of Recurrence of Etiologic

Factor in Subsequent Pregnancy

Recurrent Risk Factor

Fetal Autosomal trisomy

Abnormality-specific risk Sex chromosome abnormality

1% or maternal age-related risk

Abnormality-specific risk Triploidy

Unbalanced translocation, de novo

Abnormality-specific risk Unbalanced translocation, inherited

Abnormality-specific risk Autosomal recessive conditions

Variable

Abnormality-specific risk Structural malformations, isolated

Abnormality-specific risk Congenital infection

Variable, 3-5% for multifactorial inheritance

Infection-specific risk Multifetal gestation

Up to 25% Maternal Malnutrition

Variable, 3% of live births

Minimal risk if treated Maternal conditions leading to hypoxemia

Situation dependent

Largely unknown, but likely higher than background risk Substance abuse

Variable depending on condition

Substance-specific risk Maternal vascular disease (chronic

Situation dependent

Largely unknown, but consider hypertension, renal disease, diabetes

Generally persistent

very high risk (at least 50%) mellitus, collagen vascular disease) Inherited or acquired thrombophilia

Up to 30-83% if untreated Placental abruption

Generally persistent

At least 18%, even without recurrent abruption Placental Single umbilical artery

Up to 7% Velamentous cord insertion

15-20% Circumvallate placentation

1-2%

Largely unknown Placental infarction

61% untreated Villitis

Massive perivillous fibrin deposition

50-100%

patients should be counseled about this potentially modifi- several options for screening and prenatal diagnosis are avail- able risk factor. Other nutritional supplements, such as fish

able. In couples at high risk of recurrent autosomal trisomies oil, are unproven. 81 In cases of underlying medical condi-

or in those in which a balanced translocation has been iden- tions (diabetes, systemic lupus, hypertension, asthma), the

tified, in vitro fertilization with preimplantation genetic di- woman’s health should be optimized before subsequent

agnosis can be offered. Others may opt for assisted reproduc- pregnancies and actively managed during the pregnancy in a

tion with the use of a gamete donor. Once a pregnancy is multidisciplinary fashion.

achieved, early prenatal diagnosis with either chorionic vil- If assisted reproduction is required, there should be cau-

lous sampling or amniocentesis is available. For women un- tious use of ovulation induction agents and attention paid to

decided about invasive testing, prenatal screening should be the number of embryos transferred as it relates not only to the

offered. First trimester combined nuchal translucency and chance of successful implantation, but also to the risks of

biochemical screening is an excellent start, with a subsequent multifetal gestations.

detailed sonographic fetal anatomy survey. For some non- Any pregnancy at risk for a fetal growth abnormality

aneuploid genetic syndromes, genetic testing is available. It is should be screened in the first trimester to establish early and

important to involve a provider specialized in genetics to accurate gestational dating. Subsequent assessments of fetal

assist in coordinating this testing and also to aid in targeting growth trends will depend heavily on accurate dating. When

the fetal ultrasound.

possible, a crown–rump length in the first trimester is best. If Detailed sonography should also assess umbilical cord ab-

a second trimester ultrasound alone is available due to a delay normalities, such as single umbilical artery. Placental cord in presenting for prenatal care, the transcerebellar diameter

insertion should be visualized to rule out a velamentous cord should be measured, as it provides the most accurate dating

insertion. The placental cord insertion can be identified in

99% of cases with gray scale and color Doppler ultrasound, 83 highest risk for FGR, serial fetal growth ultrasounds should

in the 2nd and even 3rd trimesters. 82 For women at the

with identification of a velamentous insertion having a sen-

be considered at approximately 4- to 6-week intervals to sitivity of 100%, specificity of 99.8%, a positive predictive assess fetal growth trends.

value of 83%, and a negative predictive value of 100%. 84 In those couples at risk for having an aneuploid conceptus,

Other placental anomalies, such as placenta previa and cir-

Fetal growth restriction 131

Fetal Growth

1 st trimester CRL

Restriction

Serial growth ultrasounds

Identify probable etiology

Increase BMI Nutrition consult

Chromosomal Abnormalities

Umbilical Cord Ultrasound Maternal Hypoxia-

evaluation related conditions

Optimize

Abnormalities

underlying disease

Non-chromosomal Abnormalities

Immune-mediated IVIG Substance Abuse

Counseling/Detox

Injury (fibrin

Smoking cessation

deposition, chronic villitis)

Low-dose Disease

Maternal Vascular

Optimize

Genetic counseling

underlying disease

Prenatal diagnosis (CVS,

Placental infarction ASA ±

amniocentesis)

heparin

Prenatal screening

Thrombophilias

Heparin

Targeted ultrasound

Placental

Low-dose ASA

Abruption

Uterine artery Dopplers

Preeclampsia

Figure 1 Management of subsequent pregnancy based on presumed etiology of FGR.

cumvallate placentation, should be noted. The sonographic of low-dose aspirin use in pregnancy, it seems reasonable to diagnosis of placental abruption relies on the identification of

offer this to women at significant risk of recurrent FGR, start-

a thickened placenta, a hematoma (retroplacental, subchori- ing as early in the pregnancy as possible. It has been found to

be especially beneficial in those with a history of recurrent blood.

onic, or preplacental), 85 or the presence of intraamniotic

FGR and placental infarction, reducing the incidence of FGR Uterine artery Doppler velocimetry has been utilized as a

from 61% in the untreated to 13% in the treated pregnan- screening tool for pregnancies at high risk of complications

cies. 78

from ischemic placental disease. At 20 weeks’ gestation, bi- In the setting of antiphospholipid antibody syndrome (ei- lateral diastolic notching and mean resistance index of

ther primary or secondary), women should receive low-dose ⬎90 th %ile had a positive predictive value of 57% for severe

aspirin and prophylactic heparin during pregnancy. Several preeclampsia ⫾ FGR and a 93% positive predictive value for

randomized control trials have investigated this issue and

have demonstrated improved outcomes compared with pla- verse pregnancy outcomes on low-dose aspirin therapy, the

mild or severe disease. 86 Even in women with previous ad-

cebo or with aspirin alone. 91-94 The optimal management of presence of a diastolic notch at 23 weeks gestation was asso-

pregnancies complicated by recurrent chronic villitis or mas- ciated with a higher rate of vascular complications such as

sive fibrin deposition has not been definitively determined. preeclampsia and FGR (31% versus 5%). 87 Although low-dose aspirin and/or heparin have been utilized

There may be a modest benefit of low-dose aspirin use in with some benefit, 79 these lesions are not the result of a co- pregnancies at high risk for poor fetal growth from specific

agulation abnormality and may be best treated with intrave- maternal or placental conditions. Although a benefit has not

nous immunoglobulin 95 due to the suspected immune etiol-

been demonstrated by all studies, 88 many have demonstrated

ogy.

a significant reduction in the risk of FGR among high-risk In high-risk women with inherited thrombophilias and women treated with low-dose aspirin. 89,90

adverse pregnancy events, heparin has been used to improve low-dose aspirin use suggested an 18% reduction in FGR, but

A meta-analysis of

obstetrical outcomes. Heparin prophylaxis (compared with

a much greater effect (OR 0.35) when therapy was instituted aspirin) has been shown to improve live birth rates (86% before 17 weeks gestation. Given the excellent safety profile

versus 29%) and reduce the incidence of FGR (10% versus

132 W.L. Kinzler and L. Kaminsky

30%) in women heterozygous for either FVL or prothrombin

nancies at risk for congenital cytomegalovirus infection. Obstet

G20210A mutation or with protein S deficiency. 96 Other tri-

Gynecol 82:481-486, 1993

als examining the use of heparin and/or low-dose aspirin for 9. Daffos F, Forestier F, Capella-Pavlovsky M, et al: Prenatal management prevention of recurrent adverse pregnancy outcomes in of 746 pregnancies at risk for congenital toxoplasmosis. N Engl J Med

318:271-275, 1988

women with genetic thrombophilias had relatively small

10. Khan NA, Kazzi SN: Yield and costs of screening growth-retarded in-

numbers of subjects, were observational, included heteroge-

fants for torch infections. Am J Perinatol 17:131-135, 2000

neous groups of patients, had various dosages of heparin, and

11. Arbuckle TE, Wilkins R, Sherman GJ: Birth weight percentiles by ges-

often used historical controls. 63,69,97-99 Nevertheless, these

tational age in Canada. Obstet Gynecol 81:39-48, 1993

studies suggest that there may be some benefit to using hep- 12. Houlton MC, Marivate M, Philpott RH: The prediction of fetal growth

retardation in twin pregnancy. Br J Obstet Gynaecol 88:264-273, 1981

arin in selected circumstances.

13. Secher NJ, Kaern J, Hansen PK: Intrauterine growth in twin pregnan- cies: prediction of fetal growth retardation. Obstet Gynecol 66:63-68,

Targeted Areas for Future Research

Despite the vast amount of research that has been done on 14. Sherer DM, Divon MY: Fetal growth in multifetal gestation. Clin Obstet

Gynecol 40:764-770, 1997

FGR, there are many knowledge gaps that persist, particu-

15. Bjoro K Jr: Vascular anomalies of the umbilical cord. I. Obstetric im-

larly in the areas of defining etiology-specific risks and inter-

plications. Early Hum Dev 8:119-127, 1983

ventions for preventing recurrence. The heterogeneity of the

16. Predanic M, Perni SC, Friedman A, et al: Fetal growth assessment and

condition has hindered our ability to determine optimal

neonatal birth weight in fetuses with an isolated single umbilical artery.

treatments for individual cases. In addition, our understand-

Obstet Gynecol 105:1093-1097, 2005

ing of the complex biologic– environmental interactions and 17. Heinonen S, Ryynanen M, Kirkinen P, et al: Perinatal diagnostic eval-

uation of velamentous umbilical cord insertion: clinical, Doppler, and

genetic susceptibilities that exist is limited. Future research

ultrasonic findings. Obstet Gynecol 87:112-117, 1996

should attempt to use risk-specific inclusion criteria and

18. Rolschau J: Circumvallate placenta and intrauterine growth retarda-

should take into consideration the array of adverse outcomes

tion. Acta Obstet Gynecol Scand Suppl 72:11-14, 1978

that can result from similar underlying conditions (ie, isch-

19. Nagy S, Bush M, Stone J, et al: Clinical significance of subchorionic and

emic placental disease).

retroplacental hematomas detected in the first trimester of pregnancy. Obstet Gynecol 102:94-100, 2003

20. Ananth CV, Berkowitz GS, Savitz DA, et al: Placental abruption and

Conclusions

adverse perinatal outcomes. J Am Med Assoc 282:1646-1651, 1999 21. Sheiner E, Shoham-Vardi I, Hallak M, et al: Placental abruption in term

In summary, poor fetal growth can result from a myriad of

pregnancies: clinical significance and obstetric risk factors. J Matern

fetal, placental, and maternal conditions. Since many of these

Fetal Neonatal Med 13:45-49, 2003

factors can persist throughout subsequent pregnancies, 22. Ananth CV, Demissie K, Smulian JC, et al: Relationship among placenta

previa, fetal growth restriction, and preterm delivery: a population-

women should be counseled and managed appropriately to

based study. Obstet Gynecol 98:299-306, 2001

minimize future adverse outcomes. It is also important to

23. Laurini R, Laurin J, Marsal K: Placental histology and fetal blood flow in

recognize that risk factors for FGR overlap the risk factors for

intrauterine growth retardation. Acta Obstet Gynecol Scand 73:529-

many other obstetrical concerns, such as recurrent miscar-

riage, preeclampsia, abruption, and fetal death. Therefore, 24. Salafia CM, Vintzileos AM, Silberman L, et al: Placental pathology of

idiopathic intrauterine growth retardation at term. Am J Perinatol

future pregnancies should be given close attention to the

9:179-184, 1992

development of these possible events.

25. Bane AL, Gillan JE: Massive perivillous fibrinoid causing recurrent placental failure. Br J Obstet Gynaecol 110:292-295, 2003

References

26. Mandsager NT, Bendon R, Mostello D, et al: Maternal floor infarction of 1. Snijders RJ, Sherrod C, Gosden CM, et al: Fetal growth retardation:

the placenta: prenatal diagnosis and clinical significance. Obstet Gy- associated malformations and chromosomal abnormalities. Am J Ob-

necol 83:750-754, 1994

stet Gynecol 168:547-555, 1993 27. Bjoro K Jr, Myhre E: The role of chronic non-specific inflammatory 2. Creasy RLR: Maternal–Fetal Medicine. Philadelphia, PA, Saunders,

lesions of the placenta in intra-uterine growth retardation. Acta Pathol 2005

Microbiol Immunol Scand [A] 92:133-137, 1984 3. Khoury MJ, Erickson JD, Cordero JF, et al: Congenital malformations

28. Pham T, Steele J, Stayboldt C, et al: Placental mesenchymal dysplasia is and intrauterine growth retardation: a population study. Pediatrics 82:

associated with high rates of intrauterine growth restriction and fetal 83-90, 1988

demise: a report of 11 new cases and a review of the literature. Am J Clin 4. Hannula K, Lipsanen-Nyman M, Kristo P, et al: Genetic screening for

Pathol 126:67-78, 2006

maternal uniparental disomy of chromosome 7 in prenatal and postna- 29. Svensson AC, Pawitan Y, Cnattingius S, et al: Familial aggregation of tal growth retardation of unknown cause. Pediatrics 109:441-448,

small-for-gestational-age births: the importance of fetal genetic effects. 2002

Am J Obstet Gynecol 194:475-479, 2006 5. Kotzot D, Lurie IW, Mehes K, et al: No evidence of uniparental disomy

30. Stein AD, Ravelli AC, Lumey LH: Famine, third-trimester pregnancy 2, 6, 14, 16, 20, and 22 as a major cause of intrauterine growth retar-

weight gain, and intrauterine growth: the Dutch Famine Birth Cohort dation. Clin Genet 58:177-180, 2000

Study. Hum Biol 67:135-150, 1995

6. Brown ZA, Vontver LA, Benedetti J, et al: Effects on infants of a first 31. Kouba S, Hallstrom T, Lindholm C, et al: Pregnancy and neonatal episode of genital herpes during pregnancy. N Engl J Med 317:1246-

outcomes in women with eating disorders. Obstet Gynecol 105:255- 1251, 1987

7. Meyberg-Solomayer GC, Fehm T, Muller-Hansen I, et al: Prenatal ul- 32. Murphy JF, O’Riordan J, Newcombe RG, et al: Relation of haemoglobin trasound diagnosis, follow-up, and outcome of congenital varicella syn-

levels in first and second trimesters to outcome of pregnancy. Lancet drome. Fetal Diagn Ther 21:296-301, 2006

1:992-995, 1986

8. Donner C, Liesnard C, Content J, et al: Prenatal diagnosis of 52 preg- 33. Steer P, Alam MA, Wadsworth J, et al: Relation between maternal

Fetal growth restriction 133

haemoglobin concentration and birth weight in different ethnic groups. botic factors in nulliparous women do not compromise blood flow in Br Med J 310:489-491, 1995

the feto-maternal circulation and are not associated with preeclampsia 34. Lu ZM, Goldenberg RL, Cliver SP, et al: The relationship between

or intrauterine growth restriction. Am J Obstet Gynecol 191: maternal hematocrit and pregnancy outcome. Obstet Gynecol 77:190-

2002-2009, 2004

194, 1991 58. Franchi F, Cetin I, Todros T, et al: Intrauterine growth restriction and 35. Sheiner E, Mazor M, Levy A, et al: Pregnancy outcome of asthmatic

genetic predisposition to thrombophilia. Haematologica 89:444-449, patients: a population-based study. J Matern Fetal Neonatal Med 18:

237-240, 2005 59. Infante-Rivard C, Rivard GE, Guiguet M, et al: Thrombophilic poly- 36. Jensen GM, Moore LG: The effect of high altitude and other risk factors

morphisms and intrauterine growth restriction. Epidemiology 16:281- on birthweight: independent or interactive effects? Am J Public Health

87:1003-1007, 1997 60. Yasuda M, Takakuwa K, Tokunaga A, et al: Prospective studies of the 37. Galan HL, Rigano S, Radaelli T, et al: Reduction of subcutaneous mass,

association between anticardiolipin antibody and outcome of preg- but not lean mass, in normal fetuses in Denver, Colorado. Am J Obstet

nancy. Obstet Gynecol 86:555-559, 1995 Gynecol 185:839-844, 2001

61. Levine JS, Branch DW, Rauch J: The antiphospholipid syndrome. 38. Hammoud AO, Bujold E, Sorokin Y, et al: Smoking in pregnancy re-

N Engl J Med 346:752-763, 2002

visited: findings from a large population-based study. Am J Obstet 62. Alarcon-Segovia D: Clinical manifestations of the antiphospholipid Gynecol 192:1856-1862, discussion 1862-1863, 2005

syndrome. J Rheumatol 19:1778-1781, 1992 39. Spinillo A, Capuzzo E, Nicola SE, et al: Factors potentiating the smok-

63. Paidas MJ, Ku DH, Arkel YS: Screening and management of inherited ing-related risk of fetal growth retardation. Br J Obstet Gynaecol 101:

thrombophilias in the setting of adverse pregnancy outcome. Clin Peri- 954-958, 1994

natol 31:783-805, 2004

40. U.S. Department of Health and Human Services. Women and Smoking: 64. Alfirevic Z, Roberts D, Martlew V: How strong is the association be- A Report of the Surgeon General. Public Health Service, Office of the

tween maternal thrombophilia and adverse pregnancy outcome? A sys- Surgeon General, 2001

tematic review. Eur J Obstet Gynecol Reprod Biol 101:6-14, 2002 41. Bada HS, Das A, Bauer CR, et al: Low birth weight and preterm births:

65. Robertson L, Wu O, Langhorne P, et al: Thrombophilia in pregnancy: a etiologic fraction attributable to prenatal drug exposure. J Perinatol

systematic review. Br J Haematol 132:171-196, 2006 25:631-637, 2005

66. Kupferminc MJ, Eldor A, Steinman N, et al: Increased frequency of 42. Floyd RL, O’Connor MJ, Sokol RJ, et al: Recognition and prevention of

genetic thrombophilia in women with complications of pregnancy. fetal alcohol syndrome. Obstet Gynecol 106:1059-1064, 2005

N Engl J Med 340:9-13, 1999

43. Bada HS, Das A, Bauer CR, et al: Gestational cocaine exposure and intrauterine growth: maternal lifestyle study. Obstet Gynecol 100:916-

67. Lim W, Crowther MA, Eikelboom JW: Management of antiphospho- 924, 2002

lipid antibody syndrome: a systematic review. J Am Med Assoc 295: 44. Ness RB, Sibai BM: Shared and disparate components of the pathophys-

1050-1057, 2006

68. ACOG Practice Bulletin #68: Antiphospholipid syndrome. Obstet Gy- iologies of fetal growth restriction and preeclampsia. Am J Obstet Gy-

necol 106:1113-1121, 2005

necol 195:40-49, 2006 45. Bernstein PS, Divon MY: Etiologies of fetal growth restriction. Clin

69. Stella CL, Sibai BM: Thrombophilia and adverse maternal-perinatal Obstet Gynecol 40:723-729, 1997

outcome. Clin Obstet Gynecol 49:850-860, 2006 46. Villar J, Carroli G, Wojdyla D, et al: Preeclampsia, gestational hyper-

70. Roque H, Paidas MJ, Funai EF, et al: Maternal thrombophilias are not tension and intrauterine growth restriction, related or independent

associated with early pregnancy loss. Thromb Haemost 91:290-295, conditions? Am J Obstet Gynecol 194:921-931, 2006

47. Abalos E, Duley L, Steyn DW, et al: Antihypertensive drug therapy for 71. Rasmussen S, Irgens LM, Albrechtsen S, et al: Predicting preeclampsia mild to moderate hypertension during pregnancy. Cochrane Database

in the second pregnancy from low birth weight in the first pregnancy. of Systematic Reviews 2001:CD002252

Obstet Gynecol 96:696-700, 2000

48. Stettler RW, Cunningham FG: Natural history of chronic proteinuria 72. Salihu HM, Sharma PP, Aliyu MH, et al: Is small for gestational age a complicating pregnancy. Am J Obstet Gynecol 167:1219-1224, 1992

marker of future fetal survival in utero? Obstet Gynecol 107:851-856, 49. Yasmeen S, Wilkins EE, Field NT, et al: Pregnancy outcomes in women

with systemic lupus erythematosus. J Matern Fetal Med 10:91-96, 73. Kuno N, Itakura A, Kurauchi O, et al: Decrease in severity of intrauter- 2001

ine growth retardation in subsequent pregnancies. Int J Gynaecol Ob- 50. Rahman P, Gladman DD, Urowitz MB: Clinical predictors of fetal out-

stet 51:219-224, 1995

come in systemic lupus erythematosus. J Rheumatol 25:1526-1530, 74. Furuhashi M, Kurauchi O, Suganuma N: Pregnancy following placental 1998

abruption. Arch Gynecol Obstet 267:11-13, 2002 51. Julkunen H, Jouhikainen T, Kaaja R, et al: Fetal outcome in lupus

75. Rasmussen S, Albrechtsen S, Dalaker K: Obstetric history and the risk pregnancy: a retrospective case-control study of 242 pregnancies in

of placenta previa. Acta Obstet Gynecol Scand 79:502-507, 2000 112 patients. Lupus 2:125-131, 1993

76. Rasmussen S, Irgens LM, Dalaker K: A history of placental dysfunction 52. Kupferminc MJ, Rimon E, Ascher-Landsberg J, et al: Perinatal outcome

and risk of placental abruption. Paediatr Perinat Epidemiol 13:9-21, in women with severe pregnancy complications and multiple throm-

bophilias. J Perinat Med 32:225-227, 2004 77. Rasmussen S, Irgens LM, Albrechtsen S, et al: Women with a history of 53. Kupferminc MJ, Many A, Bar-Am A, et al: Mid-trimester severe intra-

placental abruption: when in a subsequent pregnancy should special uterine growth restriction is associated with a high prevalence of

surveillance for a recurrent placental abruption be initiated? Acta Ob- thrombophilia. Br J Obstet Gynaecol 109:1373-1376, 2002

stet Gynecol Scand 80:708-712, 2001