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been restricted because the former is lower, but this is

incorrect. Second, the finding of a 1-6% excess (95% CI03-3%) of infants with a birthweight below the 3rd centileof weight for gestation (4-2% vs 2-6%) and a 3-4% excess(95% CI 1’0-5.7%) of infants below the 10th centile did notresult from a prior hypothesis. These chance findings mayneed to be balanced against data from other trials. Three ofthe controlled trials on routine ultrasonography applied as ascreening technique in early pregnancy provide data on thenumber of babies with low birthweight.4 In all three5-7 theincidence of low birthweight was less among singletoninfants born to mothers who underwent routine ultrasoundthan among infants born to mothers in the control groups;in two of the trials this difference reached statistical

significance.5,6 Admittedly, low birthweight is not the sameas low weight for gestation; the interventions tested in thesetrials and in that of Newnham and colleagues are definitelynot the same; and there is no valid reason to attach more

weight to one unanticipated statistical difference than toanother. Therefore we should be careful not to put toomuch emphasis on what, at most, is an interestinghypothesis for further study. Third, if, as the data ofNewnham et al suggest, frequent exposure to ultrasoundhas adverse effects on fetal weight or growth, one mightexpect this to be either an all-or-nothing or a dose-

dependent effect. An all-or-nothing effect would probablyhave escaped detection since all participating women had ascan at entry into the trial; and unfortunately there are nodata to relate the quantity of exposure to the quantity of thealleged effect.The greatest drawback with an outcome measure such as

low weight for gestational age is that it is not a singlemeasure. Weight for gestation is influenced by variations inboth weight and gestational age, and the way in which thesetwo variables interact is still poorly understood.8,9 Mostpeople assume that weight depends on gestational age, butthis is only an assumption; in some instances, the relation isalmost exactly inverse. The simplest example is inductionof labour for alleged fetal growth retardation, in which fetalsize and estimated weight prompt the intervention thatdetermines the length of gestation. There are several otherwell-documented examples of the lack of straightforwardrelations between birthweight and gestational age.8-10Nevertheless, birthweight for gestational age standards stillenjoy an assurance of fact and scientific respect that shouldbe reserved for knowledge rather than assumption orhypothesis. Thus, even if the higher incidence of lowweight for gestational age infants born after frequentprenatal ultrasound examinations is a real and causal effe4,this tells us nothing about how the relation between

gestational age and birthweight was effected. The effectmay depend on variations in both weight and gestationalage, especially since neither variable differed significantlybetween the intervention and control groups and since ashift in the gestational age distribution (preterm birthweight) was a prior hypothesis whereas birthweight was not.There are several well-documented benefits of doppler

flow measurements in high-risk pregnancies.ll This factdoes not necessarily mean that prenatal ultrasound is aharmless intervention. Clearly it is prudent to limit suchexaminations to circumstances in which the information is

likely to be useful.

Marc J N C KeirseDepartment of Obstetrics, Gynaecology and Reproduction, Leiden University Hospital,Leiden, Netherlands

1 Robinson D, Shettles LB. The use of diethylstilbestrol in threatenedabortion. Am J Obstet Gynecol 1952; 63: 1330-33.

2 Salvesen KA, Vatten LJ, Eik-Nes SH, Hughdahl K, Bakketeig LS.Routine ultrasonography in utero and subsequent handedness andneurological development. BMJ 1993; 307: 159-64.

3 Salvesen KA, Bakketeig LS, Eik-Nes SH, Undheim JO, Okland O.Routine ultrasonography in utero and school performance at age 8-9years. Lancet 1992; 339: 85-89.

4 Neilson JP. Routine ultrasonography in early pregnancy. In: EnkinMW, Keirse MJNC, Renfrew MJ, Neilson JP. Pregnancy andchildbirth module. Cochrane Database of Systematic Reviews. Reviewno 3872. Oxford: Update Software, spring, 1993.

5 Waldenstrom U, Axelsson O, Nilsson S, et al. Effects of routineone-stage ultrasound screening in pregnancy: a randomised controlledtrial. Lancet 1988; ii: 585-88.

6 Ewigman B, LeFevre M, Hesser J. A randomised trial of routineprenatal ultrasound. Obstet Gynecol 1990; 76: 189-94.

7 Bakketeig LS, Jacobsen G, Brodtkorb CJ, et al. Randomised controlledtrial of ultrasonographic screening in pregnancy. Lancet 1984; ii:207-10.

8 Keirse MJNC. Aetiology of intrauterine growth retardation. In: VanAssche FA, Robertson WB, eds. Fetal growth retardation. Edinburgh:Churchill Livingstone, 1981: 37-56.

9 Wilcox AJ. Birth weight, gestation and the growth curve. Am J ObstetGynecol 1981; 139: 863-67.

10 Keirse MJNC. Epidemiology and aetiology of the growth retardedbaby. Clin Obstet Gynaecol 1984; 11: 415-36.

11 Neilson JP. Doppler ultrasound in high risk pregnancies. In: EnkinMW, Keirse MJNC, Renfrew MJ, Neilson JP. Pregnancy andchildbirth module. Cochrane Database of Systematic Reviews. Reviewno 3889. Oxford: Update Software, spring, 1993.

Xenografting: probability, possibility, orpipe dream?

The advent of cyclosporin immunosuppression’ ushered ina new era of organ transplantation. Not only did results forkidney grafts improve but also the transplantation of otherorgans expanded beyond all reasonable expectation. Heart,lung, pancreas, liver, and various combination organtransplants are now carried out regularly. Whilst rejectioncontinues to be a challenge in the clinical management ofrecipients, the main limitation in organ transplantation isthe supply of cadaveric organs. This shortage of organs hasled to the exploitation of donor sources which wouldotherwise be judged inappropriate or ethicallyunacceptable. Purchase of kidneys from living unrelateddonors is now outlawed in many countries although thetrade still flourishes. Transplants from living relateddonors of pancreas, liver, and even lung have been carriedout successfully, and it must only be a matter of time beforetrade in these organs is also established. Governments have

instigated various legal and public relations manoeuvres toincrease cadaveric donation. Nevertheless, all availabledata2 suggest that, however efficient these manoeuvresprove to be, demand will continue to outstrip supply.A possible solution is the use of animals (xenografting)

rather than human beings (allografting) as a source oforgans. Reemtsma3 showed more than twenty-five yearsago that transplants from chimpanzee to man could providelong-term life-supporting function. Use of organs frombaboons has met with less success, although recent

developments in immunosuppressive strategies have

encouraged the belief that long-term graft survival couldsoon be achieved in concordant xenograft combinations.4However, use of non-human primates as an organ source isof limited value. Many primate species are scarce andprotected, and those that are more plentiful, such as the

880

baboon, grow to a maximum size (30 kg) that limits the useof their organs in adults. In some cultures use of primates asa source of organs is ethically unacceptable.Some of these difficulties could be resolved by use of

porcine organs. Pigs are domesticated, easy to breed, havelarge litters, and grow rapidly to the size of the very largesthuman being. In addition, pig and man have manyanatomical and physiological similarities. However,transplantation of a pig organ to a human being results inimmediate hyperacute rejection of the graft. This responseis generally attributed to naturally occurring anti-pigantibodies in the recipient; such antibodies activate thecomplement cascade which, in turn, causes a rapid loss ofvascular integrity within the xenograft. Hyperacuterejection can be prevented by complement depletion of therecipient with cobra venom factor,S but such an approachhas never been considered clinically feasible. An excitingapproach lately advocated by Cooper et al6 is to knock outthe targets to which naturally occurring anti-pig antibodiesbind. Such an approach, diligently pursued, offers the

- possibility of avoiding delay as well as hyperacute rej ection.Loss of the appropriate enzymes, however, may beincompatible with life. There is also a possibility thatantispecies antibodies can protect xenografts from

rejection. As yet, homologous recombination has not beenachieved in pigs. Nevertheless, new techniques inmolecular biology have led to the possibility of geneticallyengineering pig organs that can inhibit the activity ofhuman complement within the xenograft. There are

proteins on all cells that block the action of endogenouscomplement and thereby protect against autolysis. Theseregulators of complement activation (RCAs) are largelyspecies restricted, so pig RCA molecules do not protect pigtissue from human complement. Transfer of human RCAproducts to animal tissues either biochemically7 or bytransfection8 confers protection against human

complement on the animal tissue to a degree that should besufficient to inhibit hyperacute rejection. Work has nowprogressed from tissue culture studies to the whole animal.Mice have been made transgenic for human RCA

products.9 These products are expressed and functionappropriately without any ill effects on the mice, whichgrow and breed normally. More recently, the first pigstransgenic for human RCA have been produced.loEven with the successful production of these pigs many

questions remain unanswered. Since there are several RCAproteins, will it be necessary to incorporate all of them in asingle animal, and will the genetic engineers have to providea greater degree of protection for a xenograft than occursnaturally with an allograft? Moreover, will this geneticmanipulation by itself prevent hyperacute rejection or willtherapies have to be devised to remove the antibodies, as isthe case for ABO incompatibility. If hyperacute rejectioncan be avoided, the likelihood of a subsequent immuneattack on the xenograft is unknown and our ability tosuppress it is unsure. Even if all the immunologicaldifficulties can be overcome, there may well be

physiological barriers to pig organs supporting life in ahuman being. Although xenotransplantation still has a longway to go before becoming a clinical reality, the increasingshortage of organs for transplantation increases the

pressure to devise such techniques.

David White, John WallworkImutran Laboratories, University of Cambridge, Cambridge, UK

1 Calne RY, White DJG, Rolles K, et al. Cyclosporin A initially as theonly immunosuppressant in 34 recipients of cadaveric organs: 32kidneys, 2 pancreases, and 2 livers. Lancet 1979; ii: 1033-36.

2 Gore S, Hinds C, Rutherford A. Organ donation from intensive careunits in England. BMJ 1989; 299: 1193-97.

3 Reemtsma K, McCraken BH, Schlegel JV. Renal heterotransplation inman. Ann Surg 1964; 160: 384-410.

4 Hasan RI, Sriwatanawongsa V, Wallwork J, White DJ. Consistentprolonged "concordant" survival of hamster-to-rat cardiac xenograftsby inhibition of anti-species antibodies with methotrexate. TransplantProc 1993; 25: 421-22.

5 Kemp E, Kemp G, Starklint H, Larsen S. Immunosuppression withcobra venom factor, anti-platelet aggregator and cyclosporin A in renalxenotransplantation. Transplant Proc 1982; 14: 116.

6 Cooper DKC, Koren E, Oriol R. Genetically engineered pigs. Lancet1993; 342: 682-83.

7 Dalmasso AP, Vercelloti GM, Platt JL, Bach FH. Inhibition ofcomplement mediated cytotoxicity by decay accelerating factor.Potential for prevention of xenograft hyperacute rejection.Transplantation 1991; 52: 530-33.

8 Oglesby TJ, Allen CJ, Liszewski MK, White DJ, Atkinson JP.Membrane cofactor protein (CD46) protects cells from complement-mediated attack by an intrinsic mechanism. J Exp Med 1992; 175:1547-51.

9 Cary N, Moody J, Yannoutsos N, Wallwork J, White D. Tissueexpression of human decay accelerating factor, a regulator ofcomplement activation expressed in mice: a potential approach toinhibition of hyperacute xenograft rejection. Transplant Proc 1993; 25:400-401.

10 James A. Transplants with transgenic pig organs? Lancet 1993; 342: 45.

Microalbuminuria and insulin resistance indiabetes mellitus

See page 883

Reaven was the first to suggest that the concurrence ofseveral cardiovascular risk factors, including glucoseintolerance, dyslipidaemia, and hypertension, might beattributable to resistance to insulin-stimulated glucoseuptake (insulin resistance). Insulin resistance, so the theorywent, could either arise as an inherited defect or be acquiredas the result of ageing, lack of exercise, obesity, or drugs.Although this syndrome X hypothesis remains

controversial, it might go some way towards explaining theincreased cardiovascular risk seen in diabetics, especiallythe rate of attrition in diabetic nephropathy.2Two reports, one from Guy’s Hospital in London

published in this issue of The Lancet and the other fromHelsinki,3 may shed some light on this difficult area. Bothgroups studied diabetic patients with microalbuminuria,defined as an albumin excretion rate above the normal rangebut below the level of dipstick detection (in practice 20-200ag/min). Microalbuminuria is predictive for developmentof renal failure and cardiovascular disease in diabetic

patients. Yip et al assessed insulin sensitivity in relation toother cardiac and renal risk factors in non-obesenormotensive type 1 diabetics with microalbuminuria

compared with normoalbuminuric duration-matched

patients. Microalbuminuric diabetics had significantlylower insulin sensitivity (ie, increased insulin resistance)and higher 24 hour ambulatory blood pressure, plasma totalcholesterol, and very-low-density lipoprotein than didnormoalbuminuric patients. The difference in insulin

sensitivity persisted after adjustment for blood pressureand body mass index.The Finnish researchers studied type 2 diabetics, about

half of whom had hypertension and one third

microalbuminuria, by comparison with matched, healthy,non-diabetic controls. Hypertension per se and a