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Ann Thorac Surg 2006;81:249-256
© 2006 The Society of Thoracic Surgeons

Original article: Cardiovascular

Maternal-Fetal Interactions in Fetal Cardiac Surgery

Pirooz Eghtesady, MD, PhD a , b , * , Joseph A. Sedgwick c , Jennifer L. Schenbeck, BS, RVT a , Christopher Lam c , John Lombardi, CCP a , b , Robert Ferguson, CCP, CCT a , b , Aimee Gardner, CCP a , b , Jerri McNamara, BA, BS a , b , Peter Manning, MD a , b

a Division of Cardiothoracic Surgery, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio
b Department of Surgery, University of Cincinnati, Cincinnati, Ohio
c Department of Biomedical Engineering, University of Cincinnati, Cincinnati, Ohio

Accepted for publication June 20, 2005.

* Address correspondence to Dr Eghtesady, Division of Cardiothoracic Surgery, Cincinnati Children's Hospital Medical Center, 3333 Burnet Ave, Cincinnati, OH 45229-3032 (Email: pirooz.eghtesady{at}cchmc.org).

Presented at the Forty-first Annual Meeting of The Society of Thoracic Surgeons, Tampa, FL, Jan 24–26, 2005.


   Abstract
Top
 Abstract
Introduction
 Material and Methods
 Results
 Comment
 Discussion
 Acknowledgments
 References
 
BACKGROUND: We examined potential maternal-fetal interactions during fetal cardiopulmonary bypass. these interactions, not previously described, may significantly influence attempts at fetal cardiac surgery.

METHODS: Eight fetal sheep underwent cardiopulmonary bypass (5 singletons, 3 twins; 100–109 days) for 60 minutes using a centrifugal microcircuit (20 mL prime), and the placenta as oxygenator. We measured maternal hemodynamics, arterial blood gases, and changes in blood flow to the gravid uterus using bilateral uterine artery flow probes. Maternal measurements were correlated to fetal hemodynamics, blood gases, and umbilical blood flows. After bypass, fetuses were followed for 60 minutes.

RESULTS: Decreases in uterine blood flow occurred without changes in maternal hemodynamics or arterial blood gases, but were associated with worsening fetal arterial blood gases (pH decreased from 7.2 ± 0.2 to 7.0 ± 0.1, partial pressure of carbon dioxide increased 45.6% and partial pressure of oxygen decreased 15.4%). Changes in maternal hemodynamics (decreased systolic blood pressure [17.5%, SD = 11] and decreased diastolic blood pressure [20.3%, SD = 15]) were only noted when uterine blood flows decreased by greater than 38.2% (SD = 26). Correction of maternal hypocalcemia (0.89g/dL, SD = 0.1) led to improved uterine artery flows (28.3% increase, SD = 30). Finally, fetal sternotomy, cannulation, and cardiopulmonary bypass each decreased uterine artery flows by 27.5% (SD = 18), 31.0% (SD = 26), and 39.7% (SD = 25), respectively. Similar changes were not observed in the nonbypass twin.

CONCLUSIONS: Significant changes in uterine blood flow can occur during fetal cardiopulmonary bypass support without apparent changes in maternal hemodynamics or arterial blood gases. These changes imply a unique transplacental maternal-fetal interaction. Limited data from the twin fetus suggest a localized mechanism involving only the segment of placenta exposed to extracorporeal circulation.


   Introduction
Top
 Abstract
 Introduction
Material and Methods
 Results
 Comment
 Discussion
 Acknowledgments
 References
 
Congenital heart disease is the most common of all birth defects (~1% of all births) [1]. Despite great advances, certain complex conditions continue with significant morbidity or mortality, either in utero or shortly after birth [2–4]. To alter these outcomes, a few centers are now attempting experimental catheter-based or endoscopic fetal cardiac intervention for select defects [5–7]. A few select defects may benefit from fetal open-heart surgery [8, 9], which in turn depends on cardiopulmonary bypass (CPB) support and understanding the physiologic changes induced by fetal surgery[10, 11]. Fetal CPB has been pursued since it was proven feasible in the early 1980s [12] and a single attempt has been made in a human fetus [13].

Early studies demonstrated that a fetus could be placed on bypass reproducibly, but fetal death invariably ensued [[14–17]. These studies showed that placental dysfunction after CPB, manifested as a progressive fetal acidosis and hypoxia develops secondary to an increase in placental vascular resistance 17–19]. Indeed the gradual but invariable rise in placental vascular resistance in response to bypass is currently the Achilles heel preventing progress in fetal cardiac surgery.

Maternal-fetal placental interactions have been extensively studied and proven to be important in the regulation of placental physiology. The majority of these studies have been in obstetrics and related to pregnancy-associated complications such as preeclampsia [20–22]. Most investigations of the effects of fetal CPB on placenta have focused only on the fetal aspect of the placenta [13–18]; the maternal side of the placental circulation had not been as extensively studied. To investigate further the potential maternal contribution to placental dysfunction, we evaluated changes in uteroplacental blood flow during CPB on both the fetal and maternal sides of the placenta.


   Material and Methods
Top
 Abstract
 Introduction
 Material and Methods
Results
 Comment
 Discussion
 Acknowledgments
 References
 
Surgical Preparation
Experimental subjects were eight mixed-breed pregnant ewes (five singletons, three twins) of 100 to 109 days gestation (term, 145 to 148 days). Fetuses were placed on bypass for a total of 60 minutes and then observed for another 60 minutes postbypass. All animals received humane care in compliance with the "Principles of Laboratory Animal Care" formulated by the National Society for Medical Research and the "Guide for the Care and Use of Laboratory Animals" prepared by the National Academy of Sciences and published by the National Institutes of Health (National Institutes of Health publication 85-23, revised 1985). The Committee for Animal Care at Cincinnati Children's Hospital Medical Center also approved the experimental protocol.

Pregnant ewes had food withheld for 24 hours prior to the day of surgery and received 2 million units of penicillin G and 100 mg gentamicin sulfate 60 minutes prior to surgery. The ewes were premedicated with diazepam (0.25 mg/kg) and ketamine (10 mg/kg), and placed under general anesthesia (2% isoflurane and 100% fractional inspired oxygen concentration). An additional infusion of ketamine (20 mg/kg) and fentanyl (3–5 mcg/kg) was then administered to the pregnant ewes over 60 minutes for further suppression of any pain or stress response.

Ventilator adjustments were made to keep maternal arterial carbon dioxide tension (PaCO 2) in the physiologic range for pregnancy (25 to 35 mm Hg). Enteric contents were removed through a rumen tube. A central venous catheter placed into the maternal jugular vein allowed delivery of intravenous fluids (Lactated Ringers solution at 75 mL/hour). Arterial access was gained through the femoral artery, from which the maternal heart rate and blood pressure were measured and arterial blood gas values were determined. After sterile preparation, a midline laparotomy was performed, and the horn of the uterus containing the fetus was exposed. The uterus was examined, checking both the size and number of the fetuses, as well as the health of the uterus, by gentle palpation. Bilateral uterine arteries were exposed and ultrasonic flow probes (4-6S, Transonic Systems Inc, Ithaca, NY) were placed on each. A 2 to 3 cm hysterotomy was made over a fetal hind limb to establish access to the fetal femoral artery and vein for measurement of fetal blood gas values and delivery of intravenous fluids (D10LR at 4mL/kg/hour). Supplemental intramuscular analgesia and anesthesia (valium 0.1 mcg/kg, ketamine 20 mcg/kg, and fentanyl 5 mcg/kg) were also administered to the fetus at this time. Dosing of drugs in the fetus was calculated based on established normograms of estimated fetal weights at specific gestational ages [23]. Finally, an ultrasonic flow probe (8S) was also placed around the umbilical artery for measurement of umbilical blood flows.

Fetal CPB Procedure
Midline sternotomy and pericardiotomy were performed, and the heart was exposed. Pericardial retention sutures were placed. After administration of 300 units/kg heparin to the fetus, purse string sutures were placed on the main pulmonary artery for arterial cannulation and on the superior vena cava adjacent to its junction with the right atrium for venous cannulation. Arterial and venous cannulae were connected with 0.25-inch and 0.375-inch polyvinyl tubing, respectively, to the bypass circuit, which incorporated a centrifugal pump (AMED, West Sacramento, CA) and an in-line flow probe. Approximately 21 mL of fetal blood was needed to prime the bypass circuitry. After initiation of bypass, pump flows were maintained at maximum achievable flow in each animal (generally about 250 to 300 mL/kg–1/min–1). In our experimental protocol the placenta functioned as oxygenator; flows were monitored continuously with the in-line flow probe. After 60 minutes of CPB support, the fetuses were weaned from bypass and decannulated. In the sheep, the twin fetuses have separate amniotic sacs (and in separate uterine horns) but share a placenta; we performed CPB on one twin, but measured flows to both uterine horns. The twin that was not placed on bypass will be referred to as the nonbypass twin.

After completion of the study the ewes and fetuses were euthanized by an overdose of intravenous pentobarbital and an autopsy was performed on both the fetuses and the placenta. Fetal weights were measured and compared with values estimated at the beginning of the protocol as noted above [23]. The average weight of fetuses (970 grams) and the standard deviation in our estimated and measured weights was ± 400 grams.

Hemodynamic and Blood Gas Monitoring
Maternal and fetal hemodynamics (central venous pressure, heart rate, systolic blood pressure, diastolic blood pressure, and mean arterial pressure), maternal PCO 2, maternal and fetal oxygen saturation, temperature, EKG, and temperature were all continuously monitored using Surgivet Vital Signs Monitor (Surgivet Inc, Waukesha, WI catalog V1886). Maternal arterial pressure was also confirmed noninvasively (cuffed forearm).

Fetal and maternal arterial blood gas (PaCO 2, PaO 2, bicarbonate [HCO3]), oxygen saturation, and pH values were measured on a pH/blood gas analyzer, Rapidlab 800 System (Bayer Diagnostics, Tarrytown, NY) or i-STAT (Abbot, East Windsor, NJ). Maternal blood gas values were measured every 30 minutes to ensure adequate ventilation and electrolyte levels. Fetal blood gas values were measured after placement of fetal catheters every 15 minutes until completion of the study.

Additional Data Recorded
In addition to the preceding measurements, both maternal and fetal electrolytes, ionized calcium, hemoglobin, and hematocrit values were checked and recorded using the Rapidlab 800 System or i-STAT machine, at same time intervals as for the above blood gas measurements.

Data Analysis
Statistical analysis was performed using Microsoft Excel XP (Microsoft, Redmond, WA). Differences between groups before and after each surgical event were assessed by paired two-tailed t tests, assuming unequal variance. A similar approach was used to assess the significance of changes in hemodynamic variables, before and after bypass. All values are expressed as the mean with standard deviations. A statistical significance is declared at a p value less than 0.05.


   Results
Top
 Abstract
 Introduction
 Material and Methods
 Results
Comment
 Discussion
 Acknowledgments
 References
 
Umbilical blood flows, reflecting placental blood flow from the fetal side, decreased with bypass (185 mL/kg/minute, SD = 56 before bypass; 100.8 mL/kg/minute, SD = 30, after bypass; p < 0.05) as previously reported [19, 24, 25]. Since the primary focus of our research was to determine changes on the maternal side, all subsequent references to uteroplacental blood flow refer to uterine artery flows unless stated otherwise.

In all animals, uteroplacental blood flow demonstrated moderate variability between 300 and 500 mL/minute throughout the experimental protocol (Fig 1). Certain discrete events could be related to fluctuations in these flows. For instance, we noted dosing of maternal analgesia-anesthesia at the beginning of the operation (ketamine-fentanyl infusion) had a significant effect on the flows as evidenced by a 35.3% decrease (391 ± 82 mL/minute before; 253 ± 108 mL/minute after; p < 0.01) in flows during their infusion. Similarly, we often noted some degree of hypocalcemia upon evaluation of the first maternal blood gas. Correction of this hypocalcemia was invariably associated with an increase (average 29%) in uterine artery flows (326 ± 108 ml/minute before; 419 ± 184 mL/minute after; p < 0.05). Although in some animals (as in Fig 1) performing a hysterotomy led to an increase in uteroplacental flows, in the majority of animals creating a hysterotomy led to a 12% decrease in flows (before hysterotomy 394 mL/minute, SD = 94; after hysterotomy 344 mL/minute, SD = 54; p < 0.26). This variable response in uterine artery flows to what would be considered a harmful insult (uterine incision) has previously been reported and is partly related to salutary effects of partial exteriorization of the fetus (during surgery) on the uteroplacental flows [26].



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  		Fig 1. Uterine artery flows vary with fetal cardiac surgery. A representative plot from one animal shows uterine artery flow of the operated horn throughout the study period. Surgical manipulations during the experimental period are indicated by arrows. The typical range of uterine artery flows was between 300 and 500 mL/minute throughout the entire surgical period, indicated by dashed horizontal lines. Open squares refer to time points of measurement.

 
All subsequent measurements used for analysis were recorded after the above interventions and when uterine artery flows had stabilized. Surprisingly, a reproducible variability in uterine artery flows occurred, correlating to specific events and fetal interventions during the study period (Fig 1). A comparison of the changes in uteroplacental flows with surgical events (Table 1) showed that the most significant (p < 0.05) decrease (40%) in flows occurred after initiation of bypass although decreases in flows were also noted with sternotomy (25%) and cannulation (27%) (Fig 2).


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  		Table 1. Alterations in Uterine Artery Flows Before and After Fetal Cardiac Surgical Procedures
 


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  		Fig 2. Uterine artery blood flows in the operated horn before and after fetal surgical events: sternotomy (A), cannulation (B), and initiation of bypass (C). ({square}----{square} = individual case; •—• = mean ± SD.)

 
The preceding changes in maternal uteroplacental flows were also associated with deterioration of fetal arterial gases as shown in Figure 3. As before, these changes in fetal gas exchange were most notable at these discrete surgical events. However, the greatest alterations in pH and PaCO 2occurred with initiation of CPB (Table 2). By comparison fluctuations in pH with other major surgical procedures such as sternotomy and cannulation were minimal. Similarly, with initiation of CPB, PaCO 2 increased by 45.6%, with minimal changes noted after sternotomy (12.3%) or cannulation (-3.8%). With all three surgical procedures, there was a decrease in PaO 2 (23.2%, 10.3%, and 15.4% decrease with sternotomy, cannulation, and CPB, respectively).



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  		Fig 3. Effects of sternotomy (A), cannulation (B), and initiation of bypass (C) on fetal arterial gases before and after these surgical events are shown. Values shown are the mean ± SD. Closed squares and diamonds refer to data points.

 

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  		Table 2. Changes in Fetal Blood Gases Before and After Major Surgical Procedures and Fetal Cardiopulmonary Bypass
 
In marked contrast to these measured changes, maternal arterial gases remained constant throughout the procedure without any alterations in ventilator parameters (Fig 4). These values remained on average as follows: maternal pH (7.4 ± 1), PaCO 2 (41 ± 12 mm Hg) and PaO 2(391 ± 86 mm Hg). Moreover, changes in the fetal blood gases or the maternal uteroplacental flows did not correlate to any significant changes in maternal hemodynamics (Fig 5).



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  		Fig 4. Effects of sternotomy (A), cannulation (B), and initiation of bypass (C) on maternal arterial gases before and after surgical manipulations of the fetus are shown. Values shown are the mean ± SD. Closed squares and diamonds refer to data points.

 


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  		Fig 5. Effects of sternotomy (A), cannulation (B), and initiation of bypass (C) on maternal mean arterial pressure and heart rate are shown. The values shown are the mean ± SD. Closed squares and diamonds refer to data points.

 
The preceding changes in maternal uteroplacental flows, however, were able to recover and return to baseline over time. For example, the depressed uterine artery flows noted immediately after initiation of bypass gradually returned to baseline during the 60 min bypass period. Indeed, they reached their highest value at the termination of bypass (Fig 6). Once the fetus was weaned off bypass the uterine artery flows began to decrease once again. Of note, although this trend was observed upon analysis of data, the average differences did not reach statistical significance. Finally, in the twin fetuses (nonbypass) uteroplacental flows were also variable during bypass (Fig 7). However, despite sharing the placenta with its twin, no significant changes or fluctuations in uteroplacental flows were noted in the nonoperated twin as noted for the fetus exposed to bypass.



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  		Fig 6. Uterine artery flows before, during, and after bypass (10 minute intervals). Points of bypass initiation and termination are indicated by arrows. Closed diamonds refer to data points.

 


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  		Fig 7. A representative pattern of uterine artery flows in a fetal twin nonoperated horn during surgical manipulations (indicated by arrows) of the twin fetus exposed to 60 minute bypass. Open squares refer to time points of measurement.

 

   Comment
Top
 Abstract
 Introduction
 Material and Methods
 Results
 Comment
Discussion
 Acknowledgments
 References
 
Previous studies of fetal CPB, mostly focusing on the fetal side of the placenta, have demonstrated an increase in placental vascular resistance, presumably secondary to vasoconstriction of the fetal component of the placenta. However, placental dysfunction and deterioration of fetal gas exchange may also occur in response to decreases in uteroplacental blood flows from the maternal side. Indeed, this study demonstrates significant changes in maternal uteroplacental flows in response to fetal CPB, implying a unique transplacental maternal-fetal interaction during fetal cardiac surgery. Specifically, we found significant decreases in uteroplacental flows in response to surgical events such as fetal sternotomy and cannulation as well as the initiation of fetal CPB. Simultaneously, there was a marked deterioration of fetal gases, suggesting a potentially significant role of these flows in maintaining homeostasis in the fetus. These changes in placental perfusion occurred without apparent changes in maternal hemodynamics or arterial blood gases, which would indicate that maternal hemodynamics alone are not necessarily reflective of the functioning of the placenta or the health of the fetus, as previously documented [27–29]. We also observed a simultaneous decrease in fetal umbilical blood flows, as reported previously. How these changes on the fetal and maternal side relate to each other remain to be further elucidated.

Regardless of the mechanism(s), our results emphasize a critical role for maternal blood flow to the placenta in mediating sufficient and necessary perfusion of the fetus during bypass. This observation has not previously been reported and should be considered in attempting to determine the optimum conditions for fetal bypass. Moreover, based on the occurrence of hypocalcemia in the mother with the experimental procedures, we now routinely increase the calcium supplementation for our ewes and no longer see the same severity of hypocalcemia. Our observation that correction of hypocalcemia was invariably associated with an increase in uterine artery flows demonstrates first, that (1) uterine artery flows are not necessarily maximized, (2) flows can be adjusted in either direction (not just down), and (3) maternal calcium levels can affect uterine artery flows in a beneficial way.

Our results suggest that a presumed "fetal factor" released in response to bypass, such as a prostaglandin or nitric oxide as suggested previously, could be mediating changes on the maternal side of placental circulation [17, 19, 30]. Alternatively, the decrease in uterine artery flows may be the maternal response to fetal stress. Fetal stress response has been shown to be an important contributor to placental dysfunction [18].

At first such a mechanism (decrease blood flow from mom to placenta in response to stress) would appear counterintuitive; it would imply an adverse maternal response to fetal stress. However, the response may be a manifestation of a mechanism designed to minimize perfusion mismatch, analogous to the hypoxic pulmonary vasoconstriction seen during a pulmonary insult. In the setting of local collapse or loss of airway (for example, because of pneumonia), this mechanism ensures diversion of blood to other alveoli that are better ventilated. Similarly, if a segment of the placenta were poorly perfused from the fetal side, it would make sense to have a mechanism to divert the maternal blood to another segment of the placenta that is better perfused. Such a hypothesis has been previously proposed as an explanation for observed paradoxical changes seen in the setting of another placental pathophysiology—preeclampsia [21, 31]. Indeed, it is conceivable that fetal CPB is an artificial model of induced preeclampsia.

The mechanism(s) underlying such a hypothetical process were not identified in our experiments. Further studies are warranted to determine the potential mechanisms involved. The processes may be multifactorial and affected by such simple parameters as fetal pH or PaO 2. Alternatively, other yet unidentified fetal factor(s) may be involved. If, in fact, the fetal stress response is responsible, further studies focused on mitigating the stress responses would be of importance. Although previous investigators have suggested a lack of response to opiates by the ovine model [13, 30], we and others have found that the mature sheep and the fetal sheep do indeed respond to opiates, including fentanyl [32, 33]. Further studies of the role of opiates in mitigating the observed changes may be of interest.

Data supportive of maternal-fetal interaction similar to what we have seen has also been reported in other experimental settings. In the goat placenta, changes in maternal uterine blood flow have been noted to occur in the same direction as the imposed changes in umbilical perfusion [34]. Similarly, ligation of a portion of the ovine umbilical vasculature in vivo leads to a 33% decrease in adjacent maternal uterine blood flow [35].These experiments show that maternal placental circulation is responsive to changes in adjacent fetal circulation. Similar changes in the reverse direction have also been shown [36], demonstrating the dynamic nature of maternal-fetal interactions. Of import, in these previous investigations, the noted changes occurred in the manipulated cotyledons (sheep placental units) and not in the remainder of the placenta, arguing against a systemic fetal or maternal response.

Similarly, preliminary data evaluating twin fetuses suggest that in this particular experimental set-up, CPB procedures have minimal effect on the portion of the placenta not exposed to extracorporeal circulation. This would suggest that the mechanisms leading to increased uterine vascular resistance occur at a local level and are not merely a reflection of global hemodynamic changes in the mother or uteroplacental blood flows.

Our results may have certain implications as further attempts are made toward clinical fetal cardiac surgery. However, there are significant differences between the ovine epitheliochorial and the primate hemochorial placenta and therefore caution must be exercised in extrapolating ovine data to the human. Nevertheless, our results do add to previous observations of fetal CPB in the experimental setting and indicate that it may be important also to monitor flows to the uterus intraoperatively. Perhaps in the future, near infrared spectroscopy technology can be applied to assess uteroplacental perfusion. Deterioration of uterine flows can alert the anesthesiologist to make appropriate interventions to improve delivery of blood to the placenta.

Finally, we would like to point out some significant limitations to our experiments. Our results are based on observations made on a limited number of animals. Further experiments are warranted to corroborate our findings. Although the maternal hemodynamics did not alter significantly, the changes observed in uterine artery flows may have been secondary to changes in maternal cardiac output. A decrease in maternal cardiac output would cause a decrease in uterine flows and a secondary deterioration of fetal gas exchange. However, while we did not measure maternal cardiac output in these experiments, in subsequent experiments using this model we have not found changes in maternal cardiac output with fetal CPB (data not shown). In addition, our studies were conducted in the relatively immature ovine fetus at midgestation (100 to 109 days). With one exception [13], all previous fetal CPB studies have utilized mature ovine fetuses (mean, ~127 days gestation). We elected to use a model that recapitulates the current practice of fetal therapy (21 to 29 weeks human gestation). Differences in uteroplacental flows with progression of gestation may account for why similar observations may not have been made in the past.

In summary, our results suggest important changes in uteroplacental flows occur on the maternal side of placental circulation in response to fetal cardiac surgery. It appears that this response is localized and mediated across the placenta by unknown fetal factor(s). These data are consistent with the concept of a local regulatory interaction between maternal and fetal placental vascular beds, suggesting a mutual dependence of adjacent placental circulations. Future investigations are warranted to explore potential mechanisms involved.


   Discussion
Top
 Abstract
 Introduction
 Material and Methods
 Results
 Comment
 Discussion
Acknowledgments
 References
 
DR JEFFREY P. JACOBS (St. Petersburg, FL): I'd like to just ask one question, more related to the overall clinical application of this important work. I think with the increasing incidence of transcatheter and interventional cardiology interventions on the fetus, I was wondering what you thought about the future role of fetal treatment of congenital heart disease with either surgery with bypass versus transcatheter interventions.

DR EGHTESADY: I think in the future there's room for both. Certainly our cardiology colleagues and their catheter intervention techniques are further ahead. Indeed, currently many centers are now pursuing fetal cardiac intervention using these approaches, partly as a byproduct of previous poor results using more invasive open-fetal surgical procedures that were used to treat some noncardiac defects such as congenital diaphragmatic hernia. I think in the future the more important question is not so much how we treat these babies, but who (or what lesions) we choose to treat in utero, what we use to measure outcomes, and most importantly, how we manage them. I bet many of the same techniques we have today are adequate.

Certainly, the "less-invasive" catheter-based interventions have not turned out to be as successful as had been hoped. For example, it had been hoped that one could prevent the development of hypoplastic left heart syndrome with intrauterine treatment of the aortic stenosis; thus far, really it's only about 10% to 15% of the fetuses treated that have an alteration in their course. From the standpoint of "intention to treat" the data become less convincing. Hypoplastic left heart syndrome is not a lethal lesion in utero and potentially you've increased the mortality of these fetuses by attempting to treat them in utero (versus waiting until after birth to provide a good Norwood operation or transplantation); some of the data would suggest perhaps that current attempts in fact increase the mortality of these babies by 30%. So perhaps in the beginning these techniques should be limited to the sickest (hydrops) or most at risk babies (hypoplasts with an intact atrial septum).

Finally, regarding fetal cardiac intervention, either catheter-based or fetal cardiac surgery, from my perspective a critical element has been absent from all previous approaches. I believe, for the outcomes to improve (regardless of approach), that in the future we need to have a different point of view or a paradigm shift in our thinking about fetal intervention, taking this critical element into consideration.

Today, when I talk to our perinatology or even fetal surgery colleagues and suggest to them the concept of an ICU (intensive care unit) where the fetus is monitored, where you take blood gases from the fetus, where you give bicarb or a blood transfusion, where you check the mixed venous gases, where you measure lactates, et cetera, and sort of have an assessment continuously with intravascular fetal catheters, their eyes open up and they look at me as if I'm crazy. But I actually think that's the way to go; that is I think for this venture to succeed we need to be more invasive and not less invasive! In fact, that is why I think previous attempts at open fetal surgery were not successful—the fetus was left to his or her own to recover from a stressful surgery. I think if today you took a neonate and did a major procedure or surgery and then dropped off the baby in the NICU (natal ICU) and said, "OK baby, you are on your own," you would be considered crazy, especially if you are dealing with a baby that has a heart that is compromised for a variety of reasons.

Similarly, and even for the less invasive procedures with cardiac catheterization, I think perhaps in the future we'll see the fetuses that have intervention done will have some catheters left in place so they can receive at least 24 to 48 hours of inotropic therapy to support them and that would result in better outcomes with some of these interventions that thus far have been less successful.

DR JACOBS: I think that's a very intriguing idea. Twenty-five years ago if we told cardiologists and pediatricians about having a pediatric cardiac ICU their eyes would have rolled, so that may be where we're headed.


   Acknowledgments
Top
 Abstract
 Introduction
 Material and Methods
 Results
 Comment
 Discussion
 Acknowledgments
References
 
This work was supported through the Cincinnati Children's Hospital TRI Initiative grant and generous contributions of the Cincinnati Children's Heart Association and the Investment in Excellence Trust of Cincinnati Children's Hospital Medical Center (CCHMC), Cincinnati, Ohio. The authors would like to acknowledge Dr Mekibib Altaye, Department of Biostatistics and Epidemiology at CCHMC, for his insightful comments and statistical guidance.


   References
Top
 Abstract
 Introduction
 Material and Methods
 Results
 Comment
 Discussion
 Acknowledgments
 References
 

  1. AHA Youth and Cardiovascular Diseases — Statistics. American Heart Association; 2004.
  2. Huhta JC. Guidelines for the evaluation of heart failure in the fetus with or without hydrops Pediatr Cardiol 2004;25:274-286.[Medline]
  3. Becker S, Hofbeck M, Kendziorra H, Wallwiener D, Mielke G. Double-chamber right ventricle associated with severe fetal cardiac failure Ultrasound Obstet Gynecol 2004;23:411-413.[Medline]
  4. Sklansky M. New dimensions and directions in fetal cardiology Curr Opin Pediatr 2003;15:463-471.[Medline]
  5. 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;85:1230-1233.[Medline]
  6. Tworetzky W, Marshall AC. Fetal interventions for cardiac defects Pediatr Clin North Am 2004;51:1503-1513vii.[Medline]
  7. Huhta J, Quintero RA, Suh E, Bader R. Advances in fetal cardiac intervention Curr Opin Pediatr 2004;16:487-493.[Medline]
  8. Allen BS. Fetal cardiac surgerysimplicity versus success in a new frontier. J Thorac Cardiovasc Surg 2003;126:1254-1256.[Free Full Text]
  9. Park HK, Park YH. Fetal surgery for congenital heart disease Yonsei Med J 2001;42:686-694.[Medline]
  10. Hedrick HL. Ex utero intrapartum therapy Semin Pediatr Surg 2003;12:190-195.[Medline]
  11. Rychik J, Tian Z, Cohen MS, et al. Acute cardiovascular effects of fetal surgery in the human Circulation 2004;110:1549-1556.[Abstract/Free Full Text]
  12. Turley K, Vlahakes GJ, Harrison MR, et al. Intrauterine cardiothoracic surgerythe fetal lamb model. Ann Thorac Surg 1982;34:422-426.[Abstract]
  13. Ikai A, Riemer RK, Ramamoorthy C, et al. Preliminary results of fetal cardiac bypass in nonhuman primates J Thorac Cardiovasc Surg 2005;129:175-181.[Abstract/Free Full Text]
  14. 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;263:919-928.
  15. 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;105:502-510discussion 510–512.[Abstract]
  16. Hawkins JA, Clark SM, Shaddy RE, Gay Jr WA. Fetal cardiac bypassimproved placental function with moderately high flow rates. Ann Thorac Surg 1994;57:293-296discussion 296-7.[Abstract]
  17. Sabik JF, Assad RS, Hanley FL. Prostaglandin synthesis inhibition prevents placental dysfunction after fetal cardiac bypass J Thorac Cardiovasc Surg 1992;103:733-741discussion 741–742.[Abstract]
  18. 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;107:1416-1422.[Abstract/Free Full Text]
  19. Sabik JF, Heinemann MK, Assad RS, Hanley FL. High-dose steroids prevent placental dysfunction after fetal cardiac bypass J Thorac Cardiovasc Surg 1994;107:116-124discussion 124–125.[Abstract/Free Full Text]
  20. Khalil RA, Granger JP. Vascular mechanisms of increased arterial pressure in preeclampsialessons from animal models. Am J Physiol Regul Integr Comp Physiol 2002;283:R29-R45.[Abstract/Free Full Text]
  21. Kaufmann P, Black S, Huppertz B. Endovascular trophoblast invasionimplications for the pathogenesis of intrauterine growth retardation and preeclampsia. Biol Reprod 2003;69:1-7.[Abstract/Free Full Text]
  22. Chaddha V, Viero S, Huppertz B, Kingdom J. Developmental biology of the placenta and the origins of placental insufficiency Semin Fetal Neonatal Med 2004;9:357-369.[Medline]
  23. Koong LJ, Garrett WN, Rattray PV. A description of the dynamics of fetal growth in sheep J Anim Sci 1975;41:1065-1068.[Abstract/Free Full Text]
  24. 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;62:393-400.[Abstract/Free Full Text]
  25. Fenton KN, Zinn HE, Heinemann MK, Liddicoat JR, Hanley FL. Long-term survivors of fetal cardiac bypass in lambs J Thorac Cardiovasc Surg 1994;107:1423-1427.[Abstract/Free Full Text]
  26. Luks FI, Peers KH, Deprest JA, Lerut TE, Vandenberghe K. The effect of open and endoscopic fetal surgery on uteroplacental oxygen delivery in the sheep J Pediatr Surg 1996;31:310-314.[Medline]
  27. Blea CW, Barnard JM, Magness RR, Phernetton TM, Hendricks SK. Effect of nifedipine on fetal and maternal hemodynamics and blood gases in the pregnant ewe Am J Obstet Gynecol 1997;176:922-930.[Medline]
  28. Assali NS. Dynamics of the uteroplacental circulation in health and disease Am J Perinatol 1989;6:105-109.[Medline]
  29. Lumbers ER. Effects of drugs on uteroplacental blood flow and the health of the foetus Clin Exp Pharmacol Physiol 1997;24:864-868.[Medline]
  30. Hanley FL. Fetal cardiac surgery Adv Card Surg 1994;5:47-74.[Medline]
  31. Hampl V, Bibova J, Stranak Z, et al. Hypoxic fetoplacental vasoconstriction in humans is mediated by potassium channel inhibition Am J Physiol Heart Circ Physiol 2002;283:H2440-H2449.[Abstract/Free Full Text]
  32. Scott BH. Opioids in cardiac surgerycardiopulmonary bypass and inflammatory response. Int J Cardiol 1998;64(suppl 1):S35-S41.
  33. Sofianos E, Alevizou F, Zissis N, Kostaki P, Balamoutsos N. Hormonal response in thoracic surgery. Effects of high-dose fentanyl anesthesia, compared to halothane anesthesia Acta Anaesthesiol Belg 1985;36:89-96.[Medline]
  34. Rankin JH, Dhindsa DS, Metcalfe J. High gain placental cardiovascular control Proc Soc Exp Biol Med 1977;154:606-609.[Medline]
  35. Rankin JH, Goodman A, Phernetton T. Local regulation of the uterine blood flow by the umbilical circulation Proc Soc Exp Biol Med 1975;150:690-694.[Medline]
  36. Stock MK, Anderson DF, Phernetton TM, McLaughlin MK, Rankin JH. Vascular response of the fetal placenta to local occlusion of the maternal placental vasculature J Dev Physiol 1980;2:339-346.[Medline]



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