New frontiers: HBOT in treatment of fetal growth deficiencies
B. Sparacia
Hyperbaric oxygen is really important in the sanitary emergency of acute care, in which its role is best defined. Present indications in obstetric pathology date back to about 15 years ago, when some soviet authors (1,4,8,9,11,13), for the first time tried to treat with HBO both acute hypoxia in labor and fetal growth delay due to placental insufficiency. Other researchers as well as ourselves proved that for this kind of affection, HBO is irreplaceable in improving both placental blood flow and O2 diffusion at the cellular level. In fact, the indications of HBO in pregnancy are represented by events with a different pathogenesis which interfere with normal supply of O2 to the fetus: some affections exist earlier than pregnancy and some others a rise as a result of pregnancy itself. Other indications depend on morbid moments close to the various apparatus of the pregnant woman's organism (Table 1).
Table 1. HBO indications during pregnancy
Maternal causes prior to the gestation period
- Hypochromic or hemolytic anemia
- Uterine pathology involving a reduction of the placental implantation surface
- Cardiopathy of various origin and anyhow cyanogen
- Pulmonary lesions HBO-compatible
Pregnancy-related causes
- Hypertensive preeclampsia syndrome
- Placental alterations reducing the exchanging function fetus/placenta
Intercurrent pathogenic causes
- Various affections: atonic ulcer, wound-healing delay, badly united fractures, etc. Carbon monoxide intoxication, etc.
Pathophysiology of HBO
Two of the main mechanisms of HBO action are the following:
- Hb oxygen-carrying function replacement when it is insufficient either for the lack of heme (anemia) or for its functional ineffectiveness (CO or meta-hemoglobinizing substance intoxication);
- the restoration of O2 diffusion from capillaries to cells when it is hindered either by a reduction in blood perfusion (ischemia) or by the extension of O2 diffusion area (pyogen membranes, reactions in the connective tissues, any type of edema, etc.).
These fundamental stages of the HBO action easily lead to the final stage of O2 delivery from lungs to tissues, so as to ensure cell respiration at mitochondrial level through oxido-reductive processes. Oxygen Pp in the mitochondria varies from 1 mBar to 6 mBars. Excessive O2 at this level may therefore interrupt the oxido reductive sequence with lethal effects on the cell. Hence, the importance of the entire arteriovenous bypass system which activate shunts in the presence of O2. If this mechanism is not sufficient, a reduction in local perfusion will take place with vasoconstrictive phenomena in wider lumen arterial vessels, but the same mechanism will work the opposite way in the case of tissular hypoxia.This vasomotor mechanism depends largely on a regulating mechanism correlated to the oxygen Pp present in the intercellular spaces. Where they are extremely limited,O2 supply at high Pp allows a rapid transition from the hypoxic state, to the normo-oxic and the hyperoxic states, but the vasoactive constrictive response will be rapid as well.
This is particularly evident in hypervascular organs such as the encephalon, where respiration under HBO entails a 13% reduction of hematic perfusion at 1 Bar, up to 25% at 3 Bars. In decreasing order the following organs are also affected: coronary arteries, retina, viscera (kidneys, uterus placenta) and limbs. In clinical medicine the vasoconstrictive phenomenon does not compromise HBO functional effectiveness, as it does work as a protection mechanism against an O2 "overdose". This mechanism, however, is not reliable because the O2 physical diffusion might sometimes exceed its effectiveness, or part. Furthermore, the balancing and restoration of normoxia, with the simultaneous presence of a reduction in blood circulation, favour a certain CO2 accumulation which, with a reflex mechanism, tends to restore normal blood flow.
If HBO rationale is based on the previously mentioned aspects, its use in the treatment of delayed fetal growth is a totally justified circulatory disorder at placental level being one of the main pathogenic mechanisms. Furthermore, if the metabolic effects of hyperbaric oxygen on cell enzymes and hemocoagulants are taken into account, the multimodal action by hyperbaric oxygen is undoubtedly important in starting the delicate treatment of fetal growth defects and, more generally, of pregnancies at risk.
This is the reason why, over the past few years we have been using HBO on a number of eclamptic patients (as illustrated in one of our previous studies or works on patients with different degrees of gestosis; but the most interesting among all is the treatment of 31 cases of delayed fetal growth with HBO at moderate bathymetry.
Pathosiology of fetal growth defects and study of the cases patients undergoing HBO.
The fundamental parameter at the basis of delayed fetal growth is the evaluation of fetal weight related to fetal age.
The diagnosis of delayed growth is generally the result of accurate echographic and echo-Doppler tests. Further contribution to the diagnosis are provided by a careful cardiotocographic study and serial biochemical endocrinological checks on estriol and HPL (Human Lactogenic Placental Hormone). This set of analyses was performed on all pregnant patients before and immediately after HBO.
Our patients were divided into two groups, including 10 and 21 patients respectively, on the basis of a treatment feature related to their gestational age. The first HBO treatments were carried out on pregnant women at an advanced gestational age, mainly because the assessment of delayed fetal growth was possible through echography.
Thanks to the echo-Doppler analysis, the serial endocrinological and amnioscopic examinations and the amnio-aspirate study, the diagnosis could be defined in an earlier period of pregnancy, and in 5 patients hyperbaric oxygenation, treatment at an earlier stage, succeeded in correcting the fetal growth defect.
In the first group of pregnant patients, five HBO treatments were performed, each lasting 60 minutes with a 1.5 ATA bathymetry on a daily basis. After being exposed to hyperbaric oxygen, a good stability of hemodynamic indexes could be observed. An increase in arterial pressure, without statistical significance, was recorded (systolic arterial pressure from 125 + 1.6 to 135 +2 mmHg) together with a heart rate reduction from 90 +2 to 82 +1.8 beats per minute and a small reduction in the respiratory rate.
The cardiotocographic and echographic analysis, at fetal level, showed a heart rate reduction (from 150 +2 to 130 +1.6 beats per minute) and an increase in fetal motor activity of about 12-14 BPM. In all the biochemical endocrinological analysis, which was carried out 24 after HBO, indicated an increase in estriol from 81 +1 to 93 +1.5 ng/ml and in HPL from 6.2 +1.5 to 7 +1.5 ng/ml.
This clinical/humoral picture suggested the extension of HBO treatment with three other sessions to be held on alternate days. Fetal weight growth, measured by means of ultrasonographic methods, failed to experience any type of acceleration because just a few days later, pregnant patients underwent surgical deliveries (Caesarean section at the 36th-38th week of pregnancy).
In 4 cases, placental morphology was characterized by a reduction in volume and presence of small infarcted areas. In 6 other cases, besides a reduced volume and more widespread infarcted areas, the funicle showed several characteristic endoluminal thrombi.
The newborns' weight ranged between 1780 and 2280 g and the neonatological indexes of fetal maturation were satisfactory. APGAR and neurological evaluation indexes suggested to keep two newborns in the normal neonatal unit and two others, in the intensive neonatology unit, due to their insufficient weight.
Neonatological examinations performed on all newborns every 2 or 3 months and up to 14 months from birth underlined normal eye grounds and growth.
This first experience has been corroborated by the study carried out on the second group of 21 patients. Thanks to the echo-Doppler examination and the analysis of the amniotic fluid, the fetal growth defect was diagnosed at an earlier stage with regard to the patients of the first group.
The pregnant patients of the second group underwent cycles of 10 HBO sessions, each lasting 60 min, at a 1.5-ATA pressure. The HBO cycles were repeated after 1-3 weeks according to their gestational age.
With regard to pregnant patients and their respective fetuses, no significant variations were recorded in biodynamic and humoral parameters, but we are convinced that the possibility to repeat HBO exposures in the future will improve fetal growth results with regard to those obtained in the first group of patients.
As in the first group, systolic pressure variations were small: from 120 +1.5 to 128 +2.5 mm/Hg; the heart rate went from 87 +3 to 82 +1.4 beats per minute; the respiratory rate dropped, remaining however within physiological limits.
In all cases, through a serial cardiotocographic analysis, a decrease of fetal heart rate was recorded: from 155 +2 to 128 +3 beats per minute; echographycally, an increase in width and frequency of fetal movements has been observed (15- 20 bpm); and the biochemical endocrinological parameters, at the end of each HBO cycle varied from 80 +2 to 94 +3 ng/ml for estriol and 6 +1.5 to 7 +2 ng/ml for HPL.
The results of these gestational parameters led us to continue HBO up to the end of the 38th week of pregnancy. The fetal (echographic test) and placental biometric (echo-Doppler) increments were sufficiently stimulated and stepped up following up on the extended HBO treatment.
In 21 patients a caesarean section was performed in the 38th gestational week. The newborns' weight ranged between 2200 and 2550 g and neonatological and maturation indexes were satisfactory. At placental level, no other special alteration was found, except for reduced volume.
Discussion and conclusions
It has been stated that the main mechanism of HBO action, which can favourably influence the pathologic retardation of fetal growth, include a) the substituting action in O2 delivery and b) the restoration of O2 diffusion from capillaries to cells. Now, however, the discussion should turn to the metabolic repercussions of the two previously mentioned fundamental actions on fetus and placenta. In growth defects and gestoses in general, the placenta is the target organ promoting any modification in a normal pregnancy. Following upon placental modifications, in the placental fetal system hypoxic conditions develop that are harmful to both fetus and mother.
When considerable interstitial hypoxia develops with a feedback mechanism, an increase of cell respiration starts. As a result, an H+ increase in the interstitial space is recorded, as well as an increment in cellular energy and molecular oxygen, while acidosis becomes ingravescent owing to the failed H+ elimination because of the limited circulatory exchanges.
Electric alterations with the depolarization of the cell membrane also occur and, as a consequence, modifications in the transmission of transmembrane signals; membrane H+ and ATPase is deactivated for both enzymatic structural alterations and high interstitial H+ concentration. The mono-oxygenic activity is stimulated and the intra and extracellular release of O2 free radicals increases. Phospholipidic peroxidation processes are thus activated together with the scavenger enzymes, and mitochondrial alterations with O2 obstruction, lactate production, and drastic ATP and AMPc reduction begin to develop.
The cell, at this stage, is deeply altered in the whole of its structures, and the reversibility of morphological and enzymatic damage depends only on the rapidity with which interstitial pO2 normalizes and an adequate blood circulation is restored so as to facilitate the metabolic exchanges that activate H+ and O2 free radicals.
By balancing tissular pO2 , trans-membrane exchanges normalize and ATP production increases, with a concomitant optimization of the O2 free radical/scavenger enzyme ratio. If these are the metabolic and circulatory modifications produced by hypoxia, which intervene in placental alterations responsible for delayed fetal growth, it is obvious that hyperbaric oxygenation, better than other therapeutical methods, can play a fundamental role in treating pregnancies at risk, assessed by echo-Doppler and serial endocrinological analyses, allowing to reach the 36th-38th week of pregnancy with an acceptable fetal growth. As we observed in these studies, this is only possible by HBO, because with the classic obstetric therapy, a pregnancy at risk is bound to end with an early delivery, seriously compromising the chances of survival of the underdeveloped fetus.
Why does HBO allow achievement of the described therapeutical objectives?
Because HBO brings about a constant increase of interstitial pO2 , even in poor circulatory conditions, allowing a blood interstice cell diffusion by virtue of the physical law of O2 dilution in plasma. Edema, which is always present in the placenta, decreases also as a result of the reduction in blood flow, which Bird and Tefler estimate at 20% with a fall in perfusion pressure of the damaged tissular zones.
Actually, vasoconstriction does not compromise HBO effectiveness, because it does acts as a defence mechanism against an "O2 overdose". This mechanism, however, is to be mistrusted because the thrust to O2 diffusion can sometimes overcome it.
The improved cellular aerobic mechanism reduces or eliminates the production of O2 free radicals, reactivates scavenger enzyme production and reduces the release of xanthine oxidase, progressively normalizing xanthine dehydrogenase. The reduced presence of free radicals brings down the production of prostaglandins, leukotrienes as well as the hyperpermeabilizing activity of serotonin and bradykinin which would make edema more harmful.
To conclude this survey of obstretic, neonatological, diagnostic and instrumental data on delayed fetal growth and of the pathophysiological data available on HBO, we may assert that this branch of gestational pathology can be successfully treated with hyperbaric oxygen.
Finally, remaining in the sector of placental insufficiencies not yet affecting fetal growth, the HBO-induced normalization of placental blood flow and, as a result, of utero-placental cell metabolism, is fundamental for a precarious gestational balance on the basis of the mother/fetus study carried out with modern technology.
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