CME/CE

MARCH 2008

Recurrence of Fetal Growth Restriction

Wendy L. Kinzler, MD

As opposed to low birth weight, fetal growth restriction is a pathologic condition that may have implications for subsequent pregnancies. Identifying the causal pathology can direct preventive strategies to minimize such a risk.

Continuing Medical Education

GOAL To explore the possible causes of fetal growth restriction (FGR) in women and discuss preventive strategies. OBJECTIVES To examine potential fetal, maternal, and placental causes of fetal growth restriction (FGR). To consider the likelihood of recurrence in subsequent pregnancies. To recommend measures for preventing such recurrence. ACCREDITATION This activity has been planned and implemented in accordance with the Essential Areas and Policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint sponsorship of Albert Einstein College of Medicine and Quadrant HealthCom Inc. Albert Einstein College of Medicine is accredited by the ACCME to provide continuing medical education for physicians. This activity has been peer reviewed and approved by Brian Cohen, MD, professor of clinical ObGyn, Albert Einstein College of Medicine. Review date: February 2008. It is designed for ObGyns, primary care physicians, and nurse practitioners Albert Einstein College of Medicine designates this educational activity for a maximum of 1 AMA PRA Category 1 Credit™. Physicians should only claim credit commensurate with the extent of their participation in the activity. Participants who answer 70% or more of the questions correctly will obtain credit. To earn credit, see the instructions on page 45 and mail your answers according to the instructions on page 46. CONFLICT OF INTEREST STATEMENT The “Conflict of Interest Disclosure Policy” of Albert Einstein College of Medicine requires that authors participating in any CME activity disclose to the audience any relationship(s) with a pharmaceutical or equipment company. Any author whose disclosed relationships prove to create a conflict of interest, with regard to their contribution to the activity, will not be permitted to present. The Albert Einstein College of Medicine also requires that faculty participating in any CME activity disclose to the audience when discussing any unlabeled or investigational use of any commercial product, or device, not yet approved for use in the United States. Dr Kinzler reports no conflict of interest. Dr Cohen reports no conflict of interest.

Normal fetal growth depends on complex interactions between the fetal, placental, and maternal units. Small-for-gestational-age (SGA) infants are defined as those born with a weight less than the tenth percentile for gestational age. By contrast, fetal growth restriction (FGR) is defined as an abnormal growth trend, or growth less than the genetic potential of the individual fetus, and is always the result of a pathologic process. Once the diagnosis is established, an assessment of risk to subsequent pregnancies can be performed based on the etiology of the initial case. Factors that can adversely influence fetal growth can be intrinsic to the fetus, specific to the uteroplacental unit, or the result of underlying maternal conditions (Table).

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TABLE. Recurrence Risks of Fetal Growth Restriction

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INTRINSIC FETAL CAUSES

Chromosomal aberrations are a well established cause of FGR, and are estimated to be responsible for up to 20% of cases.1 Early onset of FGR, polyhydramnios, and structural malformations all increase the likelihood of a chromosomal etiology. When the cytogenetics of the placental mass differ from the cytogenetics of the fetus, it is termed confined placental mosaicism. This condition has been found in 15% of FGR cases, compared with fewer than 2% of appropriately grown fetuses. The recurrence risk of aneuploidy is approximately 1%, but a recurrence risk has not been established for confined placental mosaicism. The risk for FGR recurrence from nonaneuploid genetic syndromes depends on the specific condition.

Congenital infections (eg, rubella, cytomegalovirus, toxoplasmosis, herpes simplex, varicella) can also cause FGR. However, the proportion of FGR attributable to congenital infection is low (5%),2 and is not expected to recur.

For a variety of reasons, fetuses in multiple gestations have an increased incidence of FGR. The incidence in twins is 15% to 25%,3 making multiple gestations responsible for approximately 5% of all cases of FGR. This may be related to a relative reduction in nutrient supply, an increased incidence of placental and umbilical cord abnormalities, a greater likelihood of structural malformations and vascular anastomoses in monozygotic multiples, and/or an increased incidence of maternal complications linked with poor fetal growth. There are no specific data to assess recurrence risks for FGR when the index case is a multiple gestation.

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PLACENTAL FACTORS

Umbilical cord and placental abnormalities are frequently identified in pregnancies complicated by poor fetal growth. Fetal growth restriction may be up to twice as common in pregnancies with an isolated single umbilical artery compared with pregnancies with 3-vessel cords. Velamentous cord insertions, which enter the fetal membranes instead of the placental parenchyma, have been associated with higher rates of SGA infants (odds ratio [OR] 1.5)4 compared with normal insertions. These factors are generally considered to have low recurrence rates.

Placental bleeding at any gestational age in a pregnancy complicated by FGR may be a clinical manifestation of a chronic placental disorder that can recur. It is now recognized that women with a history of FGR are at risk for multiple adverse pregnancy outcomes, including recurrent FGR, preeclampsia, and abruption. It is also estimated that up to 3.7% of FGR is attributable to placenta previa.5

Microscopic placental examination from term pregnancies complicated by FGR has found a high incidence of infarction (24%).6 If there is a history of FGR and placental infarction, the risk of recurrent FGR is high—61% with 2 or more prior affected pregnancies.7 Massive perivillous fibrin deposition (maternal floor infarct), which is characterized by a heavy deposition of fibrin in the decidua basalis and intervillous space, prevents appropriate maternal-fetal exchange of nutrients. It is believed to be the result of an immune-mediated maternal response, and has been associated with high rates of poor fetal outcomes, including a 50% to 100% rate of FGR.8 Chronic villitis of unknown etiology—another potential immune-mediated lesion—is found in approximately 30% of pregnancies complicated by FGR, with a recurrence rate of 17%.6

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MATERNAL FACTORS

Careful review of the maternal history may identify nutritional disorders, anemia, maternal hypoxia-related conditions, environmental exposures, and maternal vascular disease, all of which have been implicated in FGR. Maternal substance abuse—particularly tobacco—is an important, preventable cause of poor fetal growth. The mechanism may involve direct toxic damage, as well as associated comorbidities such as inadequate nutrition. Approximately 20% of low-birth–weight and SGA births may be attributable to maternal smoking.9

Maternal vascular disease (eg, chronic hypertension, renal disease, diabetes mellitus, collagen vascular disease) is the most common cause of impaired fetal growth, especially when complicated by preeclampsia. These conditions account for nearly 33% of FGR cases, and will persist in subsequent pregnancies.10

Inherited thrombophilias may also be associated with FGR, including factor V Leiden mutation (FVL), prothrombin G20210A mutation, protein C deficiency, protein S deficiency, and antithrombin III deficiency, as well as other such familial conditions. Theoretically, placental thrombosis in patients with inherited thrombophilias may lead to an increased risk for FGR, although the published data are conflicting.11,12 Inherited thrombophilia in isolation does not seem to be a major risk factor for most cases of FGR. However, the contributing role of thrombophilias in combination with other risk factors—including previous FGR—may be important.13 Antiphospholipid antibody syndrome, an acquired thrombophilia, has been linked to several recurrent adverse pregnancy outcomes, including FGR.14

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PREVENTION

A comprehensive assessment of fetal, placental, and maternal factors is necessary for appropriate counseling. In many cases, this will also allow for the implementation of targeted, risk-specific strategies to reduce the risk of recurrence.

If there is an opportunity for preconception care, it should focus on the eliminating known maternal exposures (cocaine, smoking, alcohol), using folic acid supplementation to reduce the risk of congenital malformations, and optimizing maternal medical conditions. Although prospective trials of weight gain are lacking, patients with a suboptimal body mass index should be counseled about this potentially modifiable risk factor.

Any pregnancy at risk for a fetal growth abnormality should be screened during the first trimester to establish early, accurate gestational dating. Subsequent assessments of fetal growth trends will depend heavily on this accurate initial dating. When possible, obtaining a crown-rump length in the first trimester is best. If second-trimester ultrasonography (US) alone is available, the transcerebellar diameter should be measured, as it provides the most accurate dating in the second and even third trimester trimesters. For women at highest risk for FGR, serial fetal-growth US should be considered at approximately 4-to-6-week intervals to assess fetal growth trends.

In couples at risk for an aneuploid conceptus, several options are available for screening and prenatal diagnosis. In couples at high risk of recurrent autosomal trisomies or balanced translocation, in vitro fertilization with preimplantation genetic diagnosis can be offered. Others may opt for assisted reproduction with the use of a gamete donor. Once pregnancy is achieved, early prenatal diagnosis with either chorionic villous sampling or amniocentesis is available. For women undecided about invasive testing, prenatal screening should be offered—ie, first-trimester combined US nuchal translucency scanning and biochemical screening, with a subsequent detailed US fetal anatomy survey. It is important to involve a genetics specialist to coordinate testing for nonaneuploid genetic syndromes and aid in targeting the fetal US. Detailed US should also assess for umbilical cord abnormalities, placental cord insertion, and the presence of a placenta previa or circumvallate placentation. Uterine artery Doppler velocimetry can also be utilized as a screening tool for pregnancies at high risk of complications from ischemic placental disease.

There may be a modest benefit from low-dose acetylsalicylic acid use in pregnancies at high risk for poor fetal growth. Although such benefit has not been demonstrated by all studies,15 some have demonstrated a significant reduction in the risk of FGR among high-risk women treated with low-dose acetylsalicylic acid.16 Given the excellent safety profile of low-dose aspirin use in pregnancy, it seems reasonable to offer this to women at significant risk of recurrent FGR, starting preconception or as early in the pregnancy as possible. This is especially beneficial in those with a history of recurrent FGR and placental infarction, reducing the incidence of FGR from 61% in untreated to 13% in treated pregnancies.7

In the setting of antiphospholipid antibody syndrome, women should receive low-dose aspirin and prophylactic heparin during pregnancy. Several randomized, controlled trials have demonstrated improved outcomes compared with placebo or with aspirin alone.17 The optimal management of pregnancies complicated by recurrent chronic villitis or massive fibrin deposition has not been definitively determined. Although low-dose aspirin and/or heparin have been utilized with some benefit,18 these lesions are not the result of a coagulation abnormality, and may be best treated with intravenous immunoglobulin due to the suspected immune etiology.

Heparin has also been used to improve obstetric outcomes in high-risk women with inherited thrombophilias and adverse pregnancy events. Compared with acetylsalicyclic acid, heparin prophylaxis has been shown to improve live birth rates (86% versus 29%) and reduce the incidence of FGR (10% versus 30%) in women heterozygous for FVL or prothrombin G20210A mutation or with protein S deficiency.19

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CONCLUSION

Poor fetal growth can result from a myriad of fetal, placental, and maternal conditions. Because many of these factors can persist throughout subsequent pregnancies, women should be counseled and managed appropriately to minimize the risk of future adverse outcomes (Figure). It is also important to recognize that risk factors for FGR overlap those for many other obstetric concerns—eg, recurrent miscarriage, preeclampsia, placental abruption, fetal death. Therefore, the potential for these events should be duly considered in all subsequent pregnancies.

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FIGURE. Management algorithm for recurrent intrauterine growth restriction. CRL = crown-rump length; US = ultrasonography; BMI = body mass index; CVS = chorionic villus sampling; ASA = acetylsalicylic acid; IVIG = intravenous immunoglobulin. Reprinted from Seminars in Perinatology, vol 31, Wendy L. Kinzler, MD and Lillian Kaminsky, MD, “Fetal Growth Restriction and Subsequent Pregnancy Risks,” 126-134, Copyright 2007, with permission from Elsevier.

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Wendy L. Kinzler, MD, is Associate Professor, Division of Maternal-Fetal Medicine, Department of Obstetrics, Gynecology, and Reproductive Sciences, University of Medicine and Dentistry of New Jersey-Robert Wood Johnson Medical School, New Brunswick, NJ.

References

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DISCLAIMER

The opinions expressed herein are those of the author and do not necessarily represent the views of the sponsor or the publisher. Please review complete prescribing information of specific drugs or combination of drugs, including indications, contraindications, warnings and adverse effects before administering pharmacologic therapy to patients.

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