There is little doubt that certain congenital heart diseases progress adversely in utero generating abnormal flow patterns that compromise cardiac function by impairing normal chamber growth and maturation. What has been elusive so far is the consistent means to intervene early enough to reverse, if possible, or halt the progression of such lesions so as to provide a near normal heart or at least the opportunity for a postnatal two-ventricle repair. While a minimalistic approach is certainly preferable as has been attempted for the Hypoplastic Left Heart Syndrome (HLHS) with fetal balloon valvuloplasties1, a case for open fetal cardiac surgery does exist for lesions like the Ebstein’s anomaly or pulmonary atresia or for removal of endocardial fibroelastosis (EFE) in the setting of HLHS. And it is here that new paradigms have to be set and old ones readjusted to suit the needs of the myriad components of the fetal-maternal unit.

 

Historical Perspective

Standing on the proverbial shoulders of giants, much of the progress in fetal surgery has been offshoots of very elegant studies done by Dr.Rudolph and other investigators on fetal lambs. We now better understand the fundamental hemodynamics and physiology of the fetal-maternal unit and its response to various factors that it is likely to be exposed to during surgical manipulations. These studies paved the way for the eventual launch of fetal surgery as a specialty2. With fetal echocardiography providing an excellent picture of the structural and functional abnormalities in early gestation3, the natural next step was to explore the safest ways and means to tackle the problem at the earliest possible time point. We will cover the early years in the journey from 1978 through ’95 in this historical section.


Animal models of congenital heart disease 


An intrauterine lamb model of LV inflow and outflow obstruction was created by Rudolph et al with characterization of the consequences on flow and chamber dimensions that resembled HLHS and severe congenital aortic stenosis respectively4. This was followed by fetal lamb models of simulated creation and repair of pulmonary and aortic stenosis by Turley et al in 1982 and another group in ’875,6. More invasive cardiac procedures entailed the need for successful fetal extracorporeal circulation and methods of myocardial preservation, stimulating a flurry of research in the field.



Fetal Cardiopulmonary Bypass

  The earliest attempts to address the twin problems was in 1991 by Hawkins et al who placed fetal lambs on cardiopulmonary bypass at hypothermia and normothermia, and administered cold crystalloid cardioplegia.7 These studies revealed the emergence of placental insufficiency as an added problem, which remains a formidable barrier till date. The placental dysfunction arising from increased vascular resistance manifested as reduced oxygenation and impaired ventilation leading to fetal acidosis, myocardial depression and death minutes after bypass. The early 1990s witnessed studies designed to better comprehend the nature of the placental hemodynamics and studies attempting to circumvent the placental dysfunction with the fetus on cardiopulmonary bypass. Verrier and Vlahakes provide a succinct review of the developments in fetal cardiac bypass of those times in an interesting 1992 article8.

Understanding the Placental Hemodynamics

Assad, Lee and Hanley placed the isolated in situ lamb placenta on bypass (Fig.1)

Fig.1: Schematic representation of extracorporeal circuit of isolated placental preparation. (NTP = Nitroprusside). From Assad, et al. J Appl Physiol 1992;72(6):2176-80.

and studied the placental vascular resistance and compliance to varying flow rates, quantified the large capacitance of the placental vessels and calculated the precise perfusion rates and pressures required to create and hence avoid increased placental vascular resistance9,10. It was apparent that a high flow rate was required during bypass to sustain placental function and as a corollary, low umbilical flow rates induced placental dysfunction. These inferences were independently validated by Bradley, Hanley and associates who documented redistribution of blood away from the placenta during fetal bypass causing dysfunction11, and by Hawkins and co-workers who demonstrated improved placental function with higher bypass flow rates12. Since higher flows were limited by cannula sizes used on the fetal heart, Fenton, Heinemann and Hanley inquired the possibility of excluding the placenta from the bypass circuit and hence provide adequate systemic perfusion with lower flow rates and with an oxygenator in the circuit13.



The Humoral aspect of Placental Dysfunction

Apart from hemodynamic factors, studies also revealed a humoral component to placental insufficiency. Sabik, Assad and Hanley speculated on the role of vasoconstrictive prostaglandins and demonstrated the beneficial role of indomethacin and high-dose steroid administration in preserving placental blood flow during fetal bypass14,15. Fenton, Heinemann and Hanley also hypothesized the role of the fetal stress response with catecholamine release in response to anesthesia and surgical stress in causing decreased placental perfusion16. In this study, ketamine anesthesia was shown to be inferior in preserving placental blood flow when compared with total spinal anesthesia in lamb fetuses on bypass. Using the combination of indomethacin and spinal anesthesia, Fenton and colleagues placed fetal lambs (80% gestation) on bypass, returned them to the uterus after weaning from the pump and followed to term, achieving 80% survival among singleton fetuses17.
Certain caveats exist regarding the possible application of the two pharmacological strategies mentioned above to the human context. While Indomethacin is detrimental to certain vascular beds, notably of the kidneys, there is a legitimate concern regarding the fetal use of steroids in causing premature closure of the ductus arteriosus and venosus. While the fetal stress response study used spinal anesthesia, it was not compared to narcotics that are used in preterm and term neonates, due to the lack of opioid receptors in sheep.



The Current Era

As of 1996 unanswered questions prevailed on preventing placental dysfunction applicable to a primate model and on issues regarding myocardial preservation during cardiopulmonary bypass. This section encompasses the advances that have occurred in the past decade.

 

Understanding the Bypass Circuit

Maternal blood prime and exposure of fetal blood to the large extracorporeal surface area of the circuit were concerns addressed by early studies in this period. The conventional fetal bypass circuits had a volume of about 150 ml which were filled with crystalloids, maternal blood or a combination of both. Large crystalloid volumes caused fetal hemodilution and maternal blood in amounts sufficient to replace the fetal blood volume, especially in small fetuses, may impair fetal tissue and placental oxygenation18.
That the extracorporeal circuit triggered a systemic inflammatory reaction by the activation of complement and eicosanoids in adults and children was well established by that time19,20. This was also shown by Reddy et al in the fetal setting in a study that revealed significantly elevated IL-6 levels post bypass21. Our group also tested a novel In-Line axial flow pump (Fig.2),

Fig.2: Hemopump circuit. The Hemopump is housed as shown and the internal rotating axial pump is depicted in the inset. (Ao = Aorta; IVC = inferior vena cava; PA = main pulmonary artery; RA = right atrium; SVC = superior vena cava.) From: Reddy VM, et al. Ann Thorac Surg 1996;62(2):393-400..

the Hemopump, that minimized extracorporeal surface area and used no priming volume and demonstrated significantly higher placental flow and reduced placental resistance during and after bypass compared to a conventional circuit (Fig.3)22.

Fig.3: Conventional roller pump circuit used in the control group fetuses. Abbreviations are the same as for figure 1. From: Reddy VM, et al. Ann Thorac Surg 1996;62(2):393-400.

This pump was also used on long term studies of fetal survival to term post bypass and proved the technical feasibility of such an undertaking23.
In further studies comparing the Hemopump with the conventional roller pump, they found significantly increased neutrophil degranulation accompanying placental dysfunction in the fetuses on roller pumps further underscoring the necessity to minimize extracorporeal surface area during fetal bypass24. The pump however, suffered the drawback of being overly simplistic and lacking the mechanism to deal with inadvertent air embolism. Lombarti et al, in a recent study used a similar miniaturized circuit with a centrifugal pump for placing immature fetal sheep on bypass25. The same group had earlier published a study with vacuum assisted venous drainage for enhancing bypass flows to offset placental dysfunction26.
 

Focus on the Endothelium

Champsaur and co-workers evaluated the various beneficial effects of a pulsatile flow during fetal lamb bypass as opposed to the conventional continuous flow obtained with roller pumps. Their first study was published in 1994 with subsequent studies in ’97 and 2000. In their earliest study, they documented higher pump flows and placental flow with decreased systemic vascular resistance in the pulsatile pump group27.
A salutary role for shear stress in inducing the release of Nitric Oxide was postulated as the reason behind the beneficial effects of pulsatility in better preserving placental flow during bypass28. The group further demonstrated higher endothelin-1 levels and plasma renin concentration in fetuses on continuous flow bypass as opposed to the pulsatile flow fetuses suggesting a major role for endothelial dysfunction mediated by the renin-angiotensin system in placental insufficiency29.
Reddy et al provided further evidence for endothelial dysfunction as an etiological factor for placental insufficiency by documenting selective impairment of endothelial-dependent vasodilation post bypass in the lamb fetus, linking it to a combination of decreased nitric oxide levels and elevated circulating endothelin-1 levels acting via vasoconstrictive endothelin-A receptors30.

 

Fetal Myocardial Protection

The fetal myocardial ultrastructure differs substantially from that of the mature myocardium spawning significant differences in fetal cardiac function. A reduced concentration of sarcomeres per unit mass of myocardium results in the decreased ventricular compliance observed in fetal hearts8. The fetal cardiac myocyte also has a reduced sarcoplasmic reticular content, with depreciated calcium storage and transport capacity31. These factors necessitate tailoring the myocardial protection strategies to the fetal context.
To this end Malhotra et al compared the efficacy of cardioplegia solutions with varying calcium concentrations in preserving myocardial function on an isolated fetal sheep heart preparation32. They documented improved post-ischemia recovery and better preservation of myocardial function with solutions that had a reduced calcium concentration as opposed to normocalcemic or hypercalcemic cardioplegia preparations. In another study with a similar preparation, the group documented no difference in post-arrest cardiac function between normothermic fibrillation and hypothermic normocalcemic cardioplegia33. The latter study was performed to circumvent the theoretical difficulty of maintaining fetal hypothermia in utero.

 

Ongoing research and Future Directions

It is a truism that fetal cardiac surgery endured many teething troubles some of which still persist, and progress has been pretty incremental. As has been obvious so far, almost all the work has been on lamb fetuses, and it is common knowledge to any researcher in the field as to how resilient the sheep uterus is to any manipulation. All the principles gleaned in all these years of research have to be prudently applied to primate models before their ultimate translation to human benefit. The first such primate model was reported by Ikai et al where they demonstrated the technical feasibility of placing baboon fetuses that are less than 1000 grams on bypass, and discerned the beneficial effects of isoflurane anesthesia over fentanyl and midazolam in causing adequate uterine relaxation34.
Eghtesady and colleagues in a recent inventive study reported maternal hemodynamic response to fetal cardiac bypass in sheep35. They noted significant subsidence in uterine arterial flow independent of the overall maternal hemodynamic status but associated with specific events during fetal bypass correlating with worsening fetal blood gases. This study certainly adds a new dimension to the parameters that contribute to success in fetal cardiac surgery. This group has also recently published the role of vasopressin36 and perturbations in the Nitric Oxide pathway in placental dysfunction following ovine fetal bypass37.
Currently in our lab we are working on isolated fetal heart models to better address the cardioplegia issue, have placental perfusion studies planned to better comprehend the microvasculature and are actively working toward bettering the techniques of fetal bypass in lamb fetuses.
In as yet unpublished studies, we have attempted to include a membrane oxygenator in the circuit to maintain physiological levels of paO2 and paCO2 during bypass and have found some benefit in delaying hemodynamic deterioration in the post-bypass fetus. Our studies have also correlated post-bypass thromboxane B2 levels with reduced umbilical flows and are investigating the use of thromboxane antagonists to overcome this phenomenon.
Using the isolated rabbit fetal heart Langendorff model, we are currently investigating the effects of crystalloid and blood cardioplegia at varying temperatures and pressures on fetal myocardial protection. Preliminary studies have revealed warm crystalloid cardioplegia at low pressure as being more cardioprotective compared to cold temperatures and higher pressures
To summarize, there is yet a silver bullet to address the issues of placental dysfunction, myocardial preservation and uterine perfusion. Future studies leavened with a molecular perspective will catalyze a more fundamental understanding of the factors involved. Until then, complex questions in fetal cardiac surgery remain relevant.¨ © Gulf Heart Association 2008.

 

References:


1. Kohl T, Sharland G, Allan LD, et al. World experience of percutaneous ultrasound-guided balloon valvuloplasty in human fetuses with severe aortic valve obstruction. Am J Cardiol 2000;85(10):1230-1233.

2. Harrison MR. The University of California at San Francisco Fetal Treatment Center: a personal perspective. Fetal Diagn Ther 2004;19(6):513-524.

3. Silverman NH, Golbus MS. Echocardiographic techniques for assessing normal and abnormal fetal cardiac anatomy. J Am Coll Cardiol 1985;5(1 Suppl):20S-9S.

4. Fishman NH, Hof RB, Rudolph AM, Heymann MA. Models of congenital heart disease in fetal lambs. Circulation 1978;58(2):354-364.

5. Turley K, Vlahakes GJ, Harrison MR, et al. Intrauterine cardiothoracic surgery: the fetal lamb model. Ann Thorac Surg 1982;34(4):422-426.

6. Bical O, Gallix P, Toussaint M, et al. Intrauterine creation and repair of pulmonary artery stenosis in the fetal lamb. Weight and ultrastructural changes of the ventricles. J Thorac Cardiovasc Surg 1987;93(5):761-766.

7. Hawkins JA, Paape KL, Adkins TP, Shaddy RE, Gay WA, Jr. Extracorporeal circulation in the fetal lamb. Effects of hypothermia and perfusion rate. J Cardiovasc Surg (Torino) 1991;32(3):295-300.

8. Verrier ED, Vlahakes GJ. The foundations of fetal cardiac surgery. Tex Heart Inst J 1992;19(3):210-216.

9. Assad RS, Lee FY, Bergner K, Hanley FL. Extracorporeal circulation in the isolated in situ lamb placenta: hemodynamic characteristics. J Appl Physiol 1992;72(6):2176-2180.

10. Assad RS, Lee FY, Hanley FL. Placental compliance during fetal extracorporeal circulation. J Appl Physiol 2001;90(5):1882-1886.

11. Bradley SM, Hanley FL, Duncan BW, et al. Fetal cardiac bypass alters regional blood flows, arterial blood gases, and hemodynamics in sheep. Am J Physiol 1992;263(3 Pt 2):H919-H928.

12. Hawkins JA, Clark SM, Shaddy RE, Gay WA, Jr. Fetal cardiac bypass: improved placental function with moderately high flow rates. Ann Thorac Surg 1994;57(2):293-296; discussion 6-7.

13. Fenton KN, Heinemann MK, Hanley FL. Exclusion of the placenta during fetal cardiac bypass augments systemic flow and provides important information about the mechanism of placental injury. J Thorac Cardiovasc Surg 1993;105(3):502-510; discussion 10-2.

14. Sabik JF, Assad RS, Hanley FL. Prostaglandin synthesis inhibition prevents placental dysfunction after fetal cardiac bypass. J Thorac Cardiovasc Surg 1992;103(4):733-741; discussion 41-2.

15. Sabik JF, Heinemann MK, Assad RS, Hanley FL. High-dose steroids prevent placental dysfunction after fetal cardiac bypass. J Thorac Cardiovasc Surg 1994;107(1):116-124; discussion 24-5.

16. Fenton KN, Heinemann MK, Hickey PR, Klautz RJ, Liddicoat JR, Hanley FL. Inhibition of the fetal stress response improves cardiac output and gas exchange after fetal cardiac bypass. J Thorac Cardiovasc Surg 1994;107(6):1416-1422.

17. Fenton KN, Zinn HE, Heinemann MK, Liddicoat JR, Hanley FL. Long-term survivors of fetal cardiac bypass in lambs. J Thorac Cardiovasc Surg 1994;107(6):1423-1427.

18. Itskovitz J, Goetzman BW, Roman C, Rudolph AM. Effects of fetal-maternal exchange transfusion on fetal oxygenation and blood flow distribution. Am J Physiol 1984;247(4 Pt 2):H655-60.

19. Chenoweth DE, Cooper SW, Hugli TE, Stewart RW, Blackstone EH, Kirklin JW. Complement activation during cardiopulmonary bypass: evidence for generation of C3a and C5a anaphylatoxins. N Engl J Med 1981;304(9):497-503.

20. Greeley WJ, Bushman GA, Kong DL, Oldham HN, Peterson MB. Effects of cardiopulmonary bypass on eicosanoid metabolism during pediatric cardiovascular surgery. J Thorac Cardiovasc Surg 1988;95(5):842-849.

21. Reddy VM, McElhinney DB, Rajasinghe HA, Rodriguez JL, Hanley FL. Cytokine Response to Fetal Cardiac Bypass. Journal of Maternal-Fetal Investigation 1998;8(1):46-49.

22. Reddy VM, Liddicoat JR, Klein JR, McElhinney DB, Wampler RK, Hanley FL. Fetal cardiac bypass using an in-line axial flow pump to minimize extracorporeal surface and avoid priming volume. Ann Thorac Surg 1996;62(2):393-400.

23. Reddy VM, Liddicoat JR, Klein JR, Wampler RK, Hanley FL. Long-term outcome after fetal cardiac bypass: fetal survival to full term and organ abnormalities. J Thorac Cardiovasc Surg 1996;111(3):536-544.

24. Parry AJ, Petrossian E, McElhinney DB, Reddy VM, Hanley FL. Neutrophil degranulation and complement activation during fetal cardiac bypass. Ann Thorac Surg 2000;70(2):582-589.

25. Lombarti J, Sedgwick JA, Schenbeck J, et al. Cardiopulmonary bypass in the immature fetus through novel use of a mini-centrifugal pump. Perfusion 2006;21:185-191

26. Lubbers WC,Baker RS,Sedgwick JA, et al. Vacuum-assisted venous drainage during fetal cardiopulmonary bypass. ASAIO 2005;51(5):644-648

27. Champsaur G, Parisot P, Martinot S, et al. Pulsatility improves hemodynamics during fetal bypass. Experimental comparative study of pulsatile versus steady flow. Circulation 1994;90(5 Pt 2):II47-50.

28. Champsaur G, Vedrinne C, Martinot S, et al. Flow-induced release of endothelium-derived relaxing factor during pulsatile bypass: experimental study in the fetal lamb. J Thorac Cardiovasc Surg 1997;114(5):738-744; discussion 44-5.

29. Vedrinne C, Tronc F, Martinot S, et al. Better preservation of endothelial function and decreased activation of the fetal renin-angiotensin pathway with the use of pulsatile flow during experimental fetal bypass. J Thorac Cardiovasc Surg 2000;120(4):770-777.

30. Reddy VM, McElhinney DB, Rajasinghe HA, et al. Role of the endothelium in placental dysfunction after fetal cardiac bypass. J Thorac Cardiovasc Surg 1999;117(2):343-351.

31. Friedman WF, Pool PE, Jacobowitz D, Seagren SC, Braunwald E. Sympathetic innervation of the developing rabbit heart. Biochemical and histochemical comparisons of fetal, neonatal, and adult myocardium. Circ Res 1968;23(1):25-32.

32. Malhotra SP, Thelitz S, Riemer RK, Reddy VM, Suleman S, Hanley FL. Fetal myocardial protection is markedly improved by reduced cardioplegic calcium content. Ann Thorac Surg 2003;75(6):1937-1941.

33. Malhotra SP, Thelitz S, Riemer RK, Reddy VM, Suleman S, Hanley FL. Induced fibrillation is equally effective as crystalloid cardioplegia in the protection of fetal myocardial function. J Thorac Cardiovasc Surg 2003;125(6):1276-1282.

34. Ikai A, Riemer RK, Ramamoorthy C, et al. Preliminary results of fetal cardiac bypass in nonhuman primates. J Thorac Cardiovasc Surg 2005;129(1):175-181.

35. Eghtesady P, Sedgwick JA, Schenbeck JL, et al. Maternal-fetal interactions in fetal cardiac surgery. Ann Thorac Surg 2006;81(1):249-255; discussion 55-6.

36. Lam CT, Sharma S, Baker RS et al. Fetal stress response to fetal cardias curgery. Ann Thor Surg 2008; 85(5): 1719-1727.

37. Lam CT, Baker RS, McNamara J et al. Role of nitric oxide pathway in placental dysfunction following fetal bypass. Ann Thor Surg 2007; 84(3): 917-924.


 

THE FETAL CIRCULATION

The relatively less-well-oxygenated blood entering the right atrium from the superior vena cava preferentially flows across the tricuspid valve into the right ventricle. From there it is ejected into the pulmonary trunk. Only a small portion flows to the lungs via the pulmonary arteries; the bulk goes into the descending aorta via the ductus arteriosus. Blood flow in the descending aorta supplies the abdominal organs and lower extremeties and returns blood to the placenta via the umbilical arteries, thus completing the circuit.