Stillborn fetuses commonly demonstrate three mechanisms of death: hydrops, asphyxia, or shock. For each mechanism, the autopsy can discover any of multiple etiologies. This paper reviews the etiologies and pathogeneses of fetal death from that perspective.
KeelingJ, GoughD, IliffP.The pathology of non-Rhesus hydrops. Diagn Histopathol1983;6:89–111.
2.
Mostoufi-ZadehM, WeissLM, DriscollSG. Nonimmune hydrops fetalis: a challenge in perinatal pathology. Hum Pathol1985;16:785–789.
3.
Ruiz VillaespesaA, Suarez MierMP, LopezFerrer P, AlvarezBaleriola I, RodriguezGonzalez JI. Nonimmunologic hydrops fetalis: an etiopathogenetic approach through the postmortem study of 59 patients. Am J Med Genet1990;35:274–279.
IliffPJ, NichollsJM, KeelingJW, GoughJD. Non-immunologic hydrops fetalis: a review of 27 cases. Arch Dis Child1983;58:979–982.
6.
HutchisonAA, DrewJH, YuVY, WilliamsML, FortuneDW, BeischerNA. Nonimmunologic hydrops fetalis: a review of 61 cases. Obstet Gynecol1982;59:347–352.
7.
WafelmanLS, PollockBH, KreutzerJ, RichardsDS, HutchisonAA. Nonimmune hydrops fetalis: fetal and neonatal outcome during 1983–1992. Biol Neonate1999; 75:73–81.
8.
MachinG.Hydrops revisited: literature review of 1414 cases published in the 1980s. Am J Med Genet1989;34:366–390.
9.
JohnsonP, SharlandG, AllanLD, TynanMJ, MaxwellDJ. Umbilical venous pressure in nonimmune hydrops fetalis: correlation with cardiac size. Am J Obstet Gynecol1992;167:1309–1313.
10.
WeinerCP. Umbilical pressure measurement in the evaluation of nonimmune hydrops fetalis. Am J Obstet Gynecol1993;168:817–823.
11.
MendezHMM, OpitzJM. Noonan syndrome: a review. Am J Med Genet1985;21:493–506.
12.
SmytheJ, CopelJ, KleinmanC.Outcome of prenatally detected cardiac malformations. Am J Cardiol1992;69:1471–1474.
13.
BendonRW, SiddiqiT, de Courten-MyersG, DignanP.Recurrent developmental anomalies: 1. Syndrome of hydranencephaly with renal aplastic dysplasia; 2. Polyvalvular developmental heart defect. Am J Med Genet Suppl1987;3:357–365.
14.
TsakraklidesV, BurkeB, MastriA, RungeW, RoeE, AndersonR.Rhabdomyomas of heart: a report of four cases. Am J Dis Child1974;128:639–646.
15.
DeVoreGR, HakimS, KleinmanCS, HobbinsJC. The in utero diagnosis of an interventricular septal cardiac rhabdomyoma by means of real-time-directed, M-mode echocardiography. Am J Obstet Gynecol1982;143:967–969.
16.
PlattLD, GeiermanCA, TurkelSB, YoungG, KeeganKA. Atrial hemangioma and hydrops fetalis. Am J Obstet Gynecol1981;141:107–109.
17.
Perez-AytesA, SanchisN, BarbalA, Non-immunological hydrops fetalis and intrapericardial teratoma: case report and review. Prenat Diagn1995;15:859–863.
18.
McFaddenDE, TaylorGP. Cardiac abnormalities and nonimmune hydrops fetalis: a coincidental, not causal, relationship. Pediatr Pathol1989;9:11–17.
19.
WallenbergH.Chorangioma of the placenta thirteen new cases and a review of the literature from 1939 to 1970 with special reference to the clinical complications. Obstet Gynecol Surv1971;26:411–425.
20.
ZalevAH. Placental chorioangioma, an unusual cause of polyhydramnios: antenatal diagnosis. Can Assoc Radiol J1986;37:60–61.
21.
NuutinenEM, PuistolaU, HervaR, KoivistoM.Two cases of large placental chorioangioma with fetal and neonatal complications. Eur J Obstet Gynecol Reprod Biol1988;29:315–320.
22.
ImakitaM, YutaniC, Ishibashi-UedaH, MurakamiM, ChibaY.A case of hydrops fetalis due to placental chorioangioma. Acta Pathol Jpn1988;38:941–945.
23.
HadiHA, FinleyJ, StricklandD.Placental chorioangioma: prenatal diagnosis and clinical significance. Am J Perinatol1993;10:146–149.
24.
StillerAG, SkafishPR. Placental chorioangioma: a rare cause of fetomaternal transfusion with maternal hemolysis and fetal distress. Obstet Gynecol1986;67:296–298.
25.
HurwitzA, MilwidskyA, YarkoniS, PaltiZ.Severe fetal distress with hydramnios due to chorioangioma. Acta Obstet Gynecol Scand1983;62:633–635.
26.
BrandtCA, RyomC, GroveA.Chorioangioma placentae and feto-maternal transfusion; a report of two cases. Eur J Obstet Gynecol Reprod Biol1989;33:95–98.
27.
KohlerHG, IqbalN, JenkinsDM. Chorionic haemangiomata and abruptio placentae. Case report and review. Br J Obstet Gynaecol1976;83:667–670.
28.
WolfeR, WayG.Cardiomyopathies in infants of diabetic mothers. J Hopkins Med J1977;140:177–180.
29.
SteinmetzJC. Neonatal hypertension and cardiomegaly associated with a congenital neuroblastoma. Pediatr Pathol1989;9:577–582.
30.
NaeyeRL. Human intrauterine parabiotic syndrome and its complications. New Engl J Med1963;268:804–809.
CoxPM, BruetonLA, MurphyKW, Early-onset fetal hydrops and muscle degeneration in siblings due to a novel variant of type IV glycogenosis. Am J Med Genet1999;86:187–193.
KalousekD, SellerM.Differential diagnosis of posterior cervical hygroma in previable fetuses. Am J Med Genet1987;3(Suppl):83–92.
46.
PearceJ, GriffinD, CampbellS.Cystic hygromata in trisomy 18 and 21. Prenat Diagn1984;4:371–375.
47.
RedfordD, McNayM, Ferguson-SmithM, JamiesonM.Aneuploidy and cystic hygroma detectable by ultrasound. Prenat Diagn1984;4:377–382.
48.
AbramowiczJ, WarsofS, DoyleD, SmithD, LevyD.Congenital cystic hygroma of the neck diagnosed prenatally: outcome with normal and abnormal karyotype. Prenat Diagn1989;9:321–327.
49.
CarrR, OchsR, RitterD, KennyJ, FrideyJ, MingP.Fetal cystic hygroma and Turner's syndrome. Am J Dis Child1986;140:580–583.
50.
LangerJ, FitxgeraldP, DesaD, Cervical cystic hygroma in the fetus: clinical spectrum and outcome. J Pediatr Surg1990;25:58–62.
51.
ChervenakF, IsaacsonG, BlakemoreK, Fetal cystic hygroma: cause and natural history. N Engl J Med1983; 309:822–825.
52.
van der PutteSCJ. Lymphatic malformation in human fetuses. Virchows Arch A Pathol Anat Histopathol1977; 376:233.
53.
BraceR.Effects of outflow pressure on fetal lymph flow. Am J Obstet Gynecol1989;160:494–497.
54.
ShepardT, WenerM, MyhreS, HickokD.Lowered plasma albumin concentration in fetal Turner syndrome. J Pediatr1986;108:114–116.
55.
AndresR, BraceR.The development of hydrops fetalis in the ovine fetus after lymphatic ligation or lymphatic excision. Am J Obstet Gynecol1990;162:1331–1334.
56.
CowchockF, WapnerR, KurtzA, ChatzkelS, BarnhartJJ, LesnickD.Brief clinical report: not all cystic hygromas occur in the Ullrich-Turner syndrome. Am J Med Genet1982;12:327–331.
57.
CarsonH, TaxyJ.Role of the autopsy in congenital cystic hygroma. Pediatr Pathol1994;14:183–189.
MengertWF, GoodsonJH, CampbellRG, HaynesDM. Observations on the pathogenesis of premature separation of the normally implanted placenta. Am J Obstet Gynecol1953;66:1104–1112.
69.
PritchardJA, CunninghamFG, PritchardSA, MasonRA. On reducing the frequency of severe abruptio placentae. Am J Obstet Gynecol1991;165:1345–1351.
70.
ClausenI.Umbilical cord anomalies and antenatal fetal deaths. Obstet Gynecol Surv1989;44:841–845.
71.
BrowneFJ. On the abnormalities of the umbilical cord which may cause antenatal death. J Obstet Gynæcol Br Empir1925;32:17–48.
72.
GhoshA, WooJSK, MacHenryC, WanCW, O'HoyKM, MaHK. Fetal loss from umbilical cord abnormalities—a difficult case for prevention. Eur J Obstet Gynecol Re-prod Biol1984;18:183–198.
73.
JavertCT, BartonB.Congenital and acquired lesions of the umbilical cord and spontaneous abortion. Am J Obstet Gynecol1952;63:1065–1077.
74.
CorkillTF. The infant's vulnerable life-line. Aust N Z J Obstet Gynæcol1961;1:154–160.
75.
CollinsJH. Two cases of multiple umbilical cord abnormalities resulting in stillbirth: prenatal observation with ultrasonography and fetal heart rates. Am J Obstet Gynecol1993;168:125–128.
76.
PhelanJP, PlattLD, YehSY, BroussardP, PaulRH. The role of ultrasound assessment of amniotic fluid volume in the management of the postdate pregnancy. Am J Obstet Gynecol1985;151:304–308.
77.
LevenoKJ, QuirkJGJr., CunninghamFG, Prolonged pregnancy. I. Observations concerning the causes of fetal distress. Am J Obstet Gynecol1984;150(5 Pt 1):465–473.
78.
DavignonJ, LorenzRR, ShepherdJT. Response of human umbilical artery to changes in transmural pressure. Am J Physiol1965;209:51–59.
WangG, BoveKE, StanekJ.Pathological evidence of prolonged umbilical cord encirclement as a cause of fetal death. Am J Perinatol1998;15:585–588.
81.
LarsonJD, RayburnWF, CrosbyS, ThurnauGR. Multiple nuchal cord entanglements and intrapartum complications. Am J Obstet Gynecol1995;173:1228–1231.
82.
NaeyeRL. Disorders of the Placenta, Fetus and Neonate: Diagnosis and Clinical Significance. St Louis: Mosby Year Book, 1992.
83.
SpellacyWN, GravenH, FischRO. The umbilical cord complications of true knots, nuchal coils and cords around the body. Am J Obstet Gynecol1966;94:1136–1142.
84.
LundgrenAT, BoiceWA. True knotting of the umbilical cord. Illinois Med J1939;76:451–458.
85.
GoldsteinI, Timor-TrischIE, ZaidiseI.Sinusoidal pattern together with signs of moderate fetal hypoxia associated with a true knot of cord. Eur J Obstet Gynecol Reprod Biol1981;11:221–225.
86.
BlicksteinI, Shoham-SchwartzZ, LancetM.Predisposing factors in the formation of true knots of the umbilical cord—analysis of morphometric and perinatal data. Int J Gynecol Obstet1987;25:1288–1290.
87.
HartgeR.Uber das Vorkommen von Nabelschnurknoten. Geburstshilfe Frauenheilkd1979;32:976–980.
88.
CollinsJC, MullerRJ, CollinsCL. Prenatal observation of umbilical cord abnormalities: a triple knot and torsion of the umbilical cord. Am J Obstet Gynecol1993;169:102–104.
89.
DippelAL. Hematomas of the umbilical cord. Surg Gynecol Obstet1940;70:51–57.
90.
RuvinskyED, WileyTL, MorrisonJC, BlakePG. In utero diagnosis of umbilical cord hematoma by ultrasonography. Am J Obstet Gynecol1981;140:833–834.
91.
DillonWP, O'LearyJA. Detection of fetal cord compromise secondary to umbilical cord hematoma with the nonstress test. Am J Obstet Gynecol1981;141:102–103.
92.
GardnerR, TrussellR.Ruptured hematoma of the umbilical cord. Obstet Gynecol1964;24:791–793.
93.
SummervilleJW, PowerJS, UelandK.Umbilical cord hematoma resulting in intrauterine fetal demise. A case report. J Reprod Med1987;32:213–216.
HeifetzSA. Thrombosis of the umbilical cord: analysis of 52 cases and literature review. Pediatr Pathol1988;8:37–54.
96.
GoodwinT, GazitG, GordonE.Heterozygotes protein C deficiency presenting as severe protein C deficiency and peripartum thrombosis: successful treatment with protein C concentrate. Obstet Gynecol1995;86:662–664.
97.
BrewsterJA, QuenbySM, AlfirevicZ.Intra-uterine death due to umbilical cord thrombosis secondary to antiphos-pholipid syndrome. Lupus1999;8:558–559.
98.
KupfermincMJ, EldorA, SteinmanN, Increased frequency of genetic thrombophilia in women with complications of pregnancy [see comments]. N Engl J Med1999;340:9–13.
FortuneD, ÖstörA.Umbilical artery aneurysm. Am J Obstet Gynecol1978;131:339–340.
102.
ShererDM, AbramowiczJS, BabkowskiR, MetlayLA, RonM, WoodsJRJr.Extensive fetal intrathoracic injuries sustained in a motor vehicle accident. Am J Perinatol1993;10:414–416.
103.
KawabataI, ImaiA, TamayaT.Antenatal subdural hemorrhage causing fetal death before labor. Int J Gynaecol Obstet1993;43:57–60.
104.
RotmenschS, GrannumPA, NoresJA, In utero diagnosis and management of fetal subdural hematoma. Am J Obstet Gynecol1991;164(5 Pt 1):1246–1248.
105.
EvrardJR, SturnerWQ, MurrayEJ. Fetal skull fracture from an automobile accident. Am J Forensic Med Pathol1989;10:232–234.
106.
FriesMH, HankinsGD. Motor vehicle accident associated with minimal maternal trauma but subsequent fetal demise. Ann Emerg Med1989;18:301–304.
107.
FordRM, PickerRH. Fetal head injury following motor vehicle accident; an unusual case of intrauterine death. Aust N Z J Obstet Gynaecol1989;29:72–73.
108.
BecroftDM, GunnTR. Prenatal cranial haemorrhages in 47 Pacific Islander infants: is traditional massage the cause?N Z Med J1989;102(867):207–210.
109.
BurrowsRF, KeltonJG. Fetal thrombocytopenia and its relation to maternal thrombocytopenia. N Engl J Med1993;329:1463–1466.
110.
GiovangrandiY, DaffosF, KaplanC, ForestierF, MacAleese J, MoirotM.Very early intracranial haemorrhage in alloimmune fetal thrombocytopenia. Lancet1990; 336(8710):310.
111.
SingerDB, NeaveC, OyerCE, PinarH.Hepatic subcapsular hematomas in fetuses and neonatal infants. Pediatr Dev Pathol1999;2:215–220.
GolanA, AmitA, Baram, DavidM.Unusual cord intertwining in monoamniotic twins. Aust N Z J Obstet Gynaecol1982;22:165–167.
114.
CarpHJ, MashiachS, SerrDM. Vasa previa: a major complication and its management. Obstet Gynecol1979; 53:273–275.
115.
KouyoumdjianA.Velamentous insertion of the umbilical cord. Obstet Gynecol1980;56:737–742.
116.
TamWH, FungHY, HainesCJ. Intrapartum haemorrhage due to idiopathic rupture of the fetal placental artery. Aust N Z J Obstet Gynaecol1994;34:490–491.
117.
GadC.A case of haemorrhage in labour from a placental vessel causing foetal death. Acta Obstet Gynecol Scand1968;47:342–344.
118.
LeffM.Hemorrhage from a ruptured varicosity in the placenta causing the death of a fetus. Am J Obstet Gynecol1931;22:117–118.
119.
GhidiniA, SepulvedaW, LockwoodCJ, RomeroR.Complications of fetal blood sampling. Am J Obstet Gynecol1993;168:1339–1344.
120.
YoungPE, MatsonMR, JonesOW. Fetal exsanguination and other vascular injuries from midtrimester genetic amniocentesis. Am J Obstet Gynecol1977;129:21–24.
121.
KirshenEJ, BenirschkeK.Fetal exsanguination after amniocentesis. Obstet Gynecol1973;42:615–616.
122.
BendonRW, TysonRW, BaldwinVJ, CashnerKA, MimouniF, MiodovnikM.Umbilical cord ulceration and intestinal atresia: a new association?Am J Obstet Gynecol1991;164:582–586.
123.
LaubeD, SchaubergerC.Fetomaternal bleeding as a cause for “unexplained” fetal death. Obstet Gynecol1982; 60:649–651.
124.
OwenJ, StedmanCM, TuckerTL. Comparison of predelivery versus postdelivery Kleihauer-Betke stains in cases of fetal death. Am J Obstet Gynecol1989;161:663–666.
125.
KaplanC, BlancW, EliasJ.Identification of erythrocytes in intervillous thrombi: a study using immunoperoxidase identification of hemoglobins. Hum Pathol1982;13:554–557.
126.
DeviB, JennisonR, LangleyF.Significance of placental pathology in transplacental haemorrhage. J Clin Pathol1968;21:322–331.
127.
CatalanoP, CapelessE.Fetomaternal bleeding as a cause of recurrent fetal morbidity and mortality. Obstet Gynecol1990;76:972–973.
128.
EmbletonN, WariyarU, HeyE.Mortality from early onset group B streptococcal infection in the United Kingdom. Arch Dis Child1999;80(2):F139–F141.
129.
MoyoSR, TswanaSA, NystromL, BergstromS, BlombergJ, LjunghA.Intrauterine death and infections during pregnancy. Int J Gynaecol Obstet1995;51:211–218.
130.
OppenheimerEH, WinnKJ. Fetal gonorrhea with deep tissue infection occurring in utero. Pediatrics1982;69:74–76.
131.
BiderD, Ben-RafaelZ, BarkaiG, MashiachS.Intrauterine fetal death apparently due to candida chorioamnionitis. Arch Gynecol Obstet1989;244:175–177.
132.
TurkelSB, PettrossCW, ApplemanMD, SalminenCA, YonekuraML. Perinatal mortality associated with intrauterine infection due to pseudomonads. Pediatr Pathol1986;6:131–137.
133.
DehnerLP. Parvovirus-B19; hydrops-fetalis, and fetal wastage—an etiologic sequence. Am J Clin Pathol1991; 96:4–5.
134.
JordanJA. Identification of human parvovirus B19 infection in idiopathic nonimmune hydrops fetalis. Am J Obstet Gynecol1996;174:37–42.
SchwartzDA, LarsenSA, Beck-SagueC, FearsM, RiceRJ. Pathology of the umbilical cord in congenital syphilis: analysis of 25 specimens using histochemistry and immunofluorescent antibody to Treponema pallidum. Hum Pathol1995;26:784–791.
138.
GenestDR, Choi-HongSR, TateJE, QureshiF, JacquesSM, CrumC.Diagnosis of congenital syphilis from placental examination: comparison of histopathology, Steiner stain, and polymerase chain reaction for Treponema pallidum DNA. Hum Pathol1996;27:366–372.
139.
MalanAF, WoodsDL, van der ElstCW, MeyerMP. Relative placental weight in congenital syphilis. Placenta1990;11:3–6.
GarciaAGP, BassoNGDS, FonsecaMEFF, ZuardiJAT, OutanniHN. Enterovirus associated placental morphology: a light; viroogical; electron microscopic and immunologic study. Placenta1991;12:533–547.
145.
LabarrereC, MullenE.Fibrinoid and trophoblastic necrosis with massive chronic intervillositis: an extreme variant of villitis of unknown etiology. Am J Reprod Immunol Microbiol1987;15:85–91.
146.
JacquesSM, QureshiF.Chronic intervillositis of the placenta. Arch Pathol Lab Med1993;117:1032–1035.
147.
OrdiJ, IsmailMR, VenturaPJ, Massive chronic intervillositis of the placenta associated with malaria infection. Am J Surg Pathol1998;22:1006–1011.
148.
AxemoP, LiljestrandJ, BergstromS, Gebre-MedhinM.Aetiology of late fetal death in Maputo. Gynecol Obstet Invest1995;39:103–109.
149.
RhyanJC, StackhouseLL, QuinnWJ. Fetal and placental lesions in bovine abortion due to Tritrichomonas foetus. Vet Pathol1988;25:350–355.
150.
BendonRW, BornsteinS, Faye-PetersenOM. Two fetal deaths associated with maternal sepsis and with thrombosis of the intervillous space of the placenta. Placenta1998;19:385–389.
151.
WigglesworthJ.Morphological variations in the insufficient placenta. J Obstet Gynecol Br Comwlth1964;71:871–884.
152.
MayhewTM, JacksonMR, HaasJD. Microscopical morphology of the human placenta and its effect on oxygen diffusion: a morphometric model. Placenta1986;7:121–131.
153.
RamseyEM, DonnerMW. Placental Vasculature and Circulation. Philadelphia: WB Saunders, 1980.
154.
BartholomewRA, ColvinED, GrimesWHJr., FishJS, LesterWM, GallowayWH. Criteria by which toxemia of pregnancy may be diagnosed from unlabeled formalin-fixed placentas. Am J Obstet Gynecol1961;82:277–290.
155.
BendonRW, WilsonJ, GetahunB, van der Bel-KahnJ.A maternal death due to thrombotic disease associated with anticardiolipin antibody. Arch Pathol Lab Med1987;111:370–372.
156.
RedmanC.Pre-eclampsia and the placenta. Placenta1991;12:301–308.
157.
SilverM, LaxerR, LaskinC, SmallhornJ, GareD.Association of fetal heart block and massive placental infarction due to maternal autoantibodies. Pediatri Pathol1992;12:131–139.
158.
AndresRL, KuyperW, ResnikR, PiacquadioKM, BenirschkeK.The association of maternal floor infarction of the placenta with adverse perinatal outcome. Am J Obstet Gynecol1990;163:935–938.
159.
MandsagerNT, BendonR, MostelloD, RosennB, MiodovnikM, SiddiqiTA. Maternal floor infarction of the placenta: prenatal diagnosis and clinical significance. Obstet Gynecol1994;83(5 Pt 1):750–754.
160.
BenirschkeK, KaufmannP.Pathology of the Human Placenta, 3rd ed. New York: Springer-Verlag, 1995;246.
161.
BendonRW, HommelAB. Maternal floor infarction in autoimmune disease: two cases. Pediatr Pathol Lab Med1996;16:293–297.
162.
LabarrereCA, McIntyreJA, FaulkWP. Immunohistologic evidence that villitis in human normal term placentas is an immunologic lesion. Am J Obstet Gynecol1990;162:515–522.
163.
AlthalbeO, LabarrereC.Chronic villitis of unknown aetiology and intrauterine growth-retarded infants of normal and low ponderal index. Placenta1985;6:369–373.
164.
XuC, MaoD, HolersVM, PalancaB, ChengAM, MolinaH.A critical role for murine complement regulator crry in fetomaternal tolerance [see comments]. Science2000; 287(5452):498–501.
165.
SanderCM. Angiomatous malformation of placental chorionic stem vessels and pseudo-partial molar placentas: report of five cases. Pediatr Pathol1993;13:621–633.
166.
JaffeR, SiegalA, RatL, BernheimJ, GruberA, FejginM.Placental chorioangiomatosis—a high risk pregnancy. Postgrad Med J1985;61(715):453–465.
167.
LageJM. Placentomegaly with massive hydrops of placental stem villi, diploid DNA content, and fetal omphaloceles: possible association with Beckwith-Wiedemann syndrome. Hum Pathol1991;22:591–597.
168.
RayburnW, SanderC, BarrMJr, RygielR.The stillborn fetus: placental histologic examination in determining a cause. Obstet Gynecol1985;65:637–641.
169.
SilverMM, YegerH, LinesLD. Hemorrhagic endovasculitis-like lesion induced in placental organ culture. Hum Pathol1988;19:251–256.
170.
HartD.The nature of the tuberose fleshy mole. J Obstet Gynecol Br Emp1902;1:479–487.
WatsonWJ, FiegenMM. Fetal thyrotoxicosis associated with nonimmune hydrops. Am J Obstet Gynecol1995; 172:1039–1040.
174.
KohlerHG. Premature closure of the ductus arteriosus (P.C.D.A.): a possible cause of intrauterine circulatory failure. Early Hum Dev1978;2:15–23.
175.
HofstadlerG, TulzerG, AltmannR, SchmidtK, DanfordD, HuhtaJ.Spontaneous closure of the human fetal ductus arteriosus—a cause of fetal congestive heart failure. Am J Obstet Gynecol1996;174:879–883.
176.
WoodsKA, Camacho-HübnerC, SavageMO, ClarkAJL. Intrauterine growth retardation and postnatal growth failure associated with deletion of the insulin-like growth factor gene. N Engl J Med1996;335:1363–1367.