Small-for-Gestational-Age Infants and Risk of Fetal Death

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					PERSPECTIVE                                                                              Bone Loss after Cardiac Transplantation

                creases osteoclast apoptosis and reduces the over-           Shane et al. report a nonsignificant trend toward
                all number of active osteoclasts, thereby reducing       fewer fractures in the treatment groups; the study,
                bone resorption. Alendronate may also reduce the         however, was limited both by its small size and by
                frequency with which new units are activated. These      the lack of randomized controls, so this observa-
                effects have been well documented in postmeno-           tion is of unclear import. Although one may spec-
                pausal women with osteoporosis. In addition, alen-       ulate that combination treatment with calcitriol and
                dronate may prolong the survival of osteoblasts.         a bisphosphonate might confer an additive skele-
                    Calcitriol therapy, which has also been investi-     tal benefit, it is important to conduct further stud-
                gated in postmenopausal women with osteopo-              ies in order to assess this possibility. Ultimately,
                rosis, reduces bone resorption at low doses but          post-transplantation immunosuppressive proto-
                increases bone resorption at higher doses. The de-       cols that minimize the use of glucocorticoids, cal-
                crease in resorption occurs through an indirect          cineurin inhibitors, and other medications that have
                mechanism: the reduction of the circulating para-        adverse effects on the skeleton will go a long way
                thyroid hormone level, as was seen in the study by       toward reducing the prevalence of fractures after
                Shane et al. The primary effect of calcitriol is the     cardiac transplantation.
                stimulation of intestinal calcium absorption —
                hence the requirement to control and monitor cal-        From the Regional Bone Center, Helen Hayes Hospital, West Hav-
                cium excretion.                                          erstraw, N.Y.

Small-for-Gestational-Age Infants and Risk of Fetal Death
in Subsequent Pregnancies
Jun Zhang, Ph.D., M.D., and Mark A. Klebanoff, M.D., M.P.H.

                One of the triumphs of modern obstetrics has been        Register to demonstrate that women whose first
                the dramatic reduction in late fetal mortality (de-      infant was severely small for its gestational age had
                fined as the rate of antepartum or intrapartum fetal     a significantly higher risk of late fetal death at 28 or
                death at 20 weeks of gestation or later) in the devel-   more weeks of gestation in the subsequent preg-
                oped world during the second half of the 20th cen-       nancy than women whose first infant was not small
                tury. The reduction can be attributed to better access   for gestational age. The increased risk was further
                to vastly improved antepartum and intrapartum            amplified if the first delivery was also preterm. For
                care; improved antepartum fetal surveillance; the        example, as compared with women with a first de-
                virtual elimination of Rh isoimmunization; and the       livery at term of an infant that was not small for
                revolution in neonatal care that enabled obstetri-       gestational age, women who had a first delivery
                cians to deliver a fetus, particularly one remote from   at term of an infant that was small for gestational
                term, when its health was in jeopardy. The fetal         age had twice the risk of subsequent fetal death.
                mortality rate in the United States decreased from       The odds ratio increased to 3.4 if the first delivery
                18.4 per 1000 total births in 1950 to 6.7 per 1000       was also moderately preterm (occurring at 32 to 36
                births in 2000. However, the pace of the decrease        weeks of gestation) and to 5.0 if the first delivery
                has slowed substantially during the past 20 years.       occurred before 32 weeks of gestation. Surkan et al.
                The number of fetal deaths is now equal to the num-      defined an infant that was “small for gestational
                ber of infant deaths in the United States. The psy-      age” as one with a birth weight that was more than
                chological effects of a late fetal loss on a woman and   2 SD below the mean at a given week of gestation
                her family can be as profound as those of the loss of    (i.e., below the 2.5th percentile) — a cutoff that is
                a child.                                                 considered to indicate a severely small-for-gesta-
                    In this issue of the Journal, Surkan et al. (pages   tional-age infant by U.S. standards.
                777–785) use data from the Swedish Medical Birth             Women who have a small-for-gestational-age in-

754                                                                       n engl j med 350;8       february 19, 2004

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PERSPECTIVE                                         Small-for-Gestational-Age Infants and Risk of Fetal Death in Subsequent Pregnancies

                                                       Abruption                                     15

                                                       Anomalies                           10

                                                        Infection                      9

                                                        Diabetes              4

                                                    Hypertension          3

                                                            Labor     2

                                   Intrauterine growth restriction                                   15

                                                            Other                                          17

                                                     Unexplained                                                              25

                                                                                     Percent of Fetal Deaths

                      Figure. Causes of Fetal Death.
                      Data, for 61,957 pregnancies between 1978 and 1995, are from Fretts RC, Usher RH. Causes of fetal death in women of ad-
                      vanced maternal age. Obstet Gynecol 1997;89:40-5. Fetal death was considered to have been caused by abruption if there
                      was antepartum bleeding or a retroplacental blood clot; by an anomaly if there was a potentially lethal anomaly; by infec-
                      tion if there was pathological evidence of infection in the fetus or the placenta; by diabetes if the mother was diabetic and
                      the fetal death was otherwise unexplained; by hypertension if the mother was hypertensive and the fetal death was oth-
                      erwise unexplained; by labor if there was unexplained intrapartum asphyxia; and by intrauterine growth restriction (“fetal
                      malnutrition”) if the death was asphyxial or unexplained and the weight of the fetus was below the third percentile; a fetal
                      death was attributed to intrauterine growth restriction only if there was no other identified cause, except in the case of
                      hypertension (if there was both intrauterine growth restriction and maternal hypertension, the death was attributed to
                      the former condition). The “other” category included the following causes: a prolapsed cord, knots, placenta previa,
                      hydrops, twin–twin transfusion, maternal disease, trauma, and Rh disease.

                     fant, a preterm delivery, or a fetal death tend to have          plained even after careful pathological examination
                     these outcomes repeated in subsequent pregnan-                   of the fetus and the placenta. When one considers
                     cies. Surkan et al. further demonstrate that a histo-            that conditions such as placental abruption, hyper-
                     ry of delivering a small-for-gestational-age infant,             tensive disorders, and idiopathic growth restriction
                     particularly one delivered remote from term, is also             themselves often have unknown causes, our lack of
                     associated with an increased risk of late fetal death            understanding of the underlying causes of late fe-
                     in the succeeding pregnancy. This association pre-               tal death becomes even more apparent. In order
                     sumably occurs because reduced fetal growth and                  to focus on this long-neglected area, the National
                     fetal death often share underlying causes, such as               Institute of Child Health and Human Development
                     congenital anomalies, placental defects, and ma-                 recently launched the Stillbirth Collaborative Re-
                     ternal vascular disease. Abnormalities in placental              search Network, a cooperative network of five sites
                     implantation, vascularization, and function play a               in the United States that are using standardized pro-
                     particularly important role. As the fetus grows larg-            tocols to investigate the scope and causes of still-
                     er with advancing gestation, the demands on the                  birth in a given population.
                     placenta increase. Poor growth in a fetus at less than               Unfortunately, many of the underlying causes of
                     32 weeks’ gestation suggests that, even remote from              fetal death can neither be predicted accurately nor
                     term, the maternal–placental unit has already ex-                be prevented. Although recent literature suggests
                     hausted its reserve. The data presented by Surkan                that Doppler velocimetry may help to prevent fetal
                     et al. demonstrate that the conditions that cause this           death through the earlier detection and confirma-
                     exhaustion tend to recur and can have manifold                   tion of fetal compromise in high-risk pregnancies,
                     effects.                                                         its low predictive value implies that many high-risk
                         The broad categories of obstetrical conditions               women would need to be monitored in order to pre-
                     that are associated with fetal death are shown in the            vent one fetal death. In addition, because abnormal
                     Figure. Fully one quarter of fetal deaths are unex-              findings on Doppler velocimetry are not specific for

n engl j med 350;8      february 19, 2004                                                                                        755

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PERSPECTIVE                              Small-for-Gestational-Age Infants and Risk of Fetal Death in Subsequent Pregnancies

               immediate fetal jeopardy, its use may lead to unnec-    restriction for another. This variability may partial-
               essary early delivery, with its attendant risks. Once   ly explain why, in the Swedish study, most of the
               a compromised fetus is discovered and the compro-       women who had a fetal death (84 percent) had giv-
               mise is deemed to be severe enough to place the         en birth at term to an infant that was not small for
               fetus at high risk of imminent death, there are few     gestational age in the previous pregnancy. At the
               specific therapeutic options other than delivery,       same time, pregnant women and their physicians
               which is undertaken after the administration of cor-    should be reassured by the fact that even when the
               ticosteroids to the mother to promote fetal lung        previous delivery occurred at less than 32 weeks of
               maturity if the fetus is remote from term.              gestation and the infant was severely small for ges-
                   Although being severely small for gestational age   tational age, the probability of a late fetal death in
               is generally considered to be pathologic, a weight      the current pregnancy was still less than 2 percent.
               above the cutoff point may not necessarily mean that
                                                                       From the Division of Epidemiology, Statistics, and Prevention Re-
               the fetal growth is normal. Since fetuses have vary-
                                                                       search, National Institute of Child Health and Human Develop-
               ing potential for growth, a given birth weight may      ment, National Institutes of Health, Department of Health and Hu-
               be appropriate for one fetus but indicative of growth   man Services, Bethesda, Md.

756                                                                     n engl j med 350;8        february 19, 2004

      Downloaded from on August 25, 2007 . Copyright © 2004 Massachusetts Medical Society. All rights reserved.

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