Copyright 2007 R. Klimek

Prediction of the birth term
Marek Klimek

Whenever, wherever, we have hope and dream, the hope will certainly be realized and bring the brighter future in perinatal medicine
S.Sakamoto
(Pre-Perintal Psycho-Medicine 1992)

see: Klimek M.: Prediction of the birth term and course of the labor. Archives of Perinatal Medicine 7 (3), 24-29, 2001

Introduction

Ultrasonographic measurements of selected fetal parameters by means of existing devices are exact and precise; it is only their interpretation that is false. When making physical measurement of one of 100 fetuses in 37^th week of pregnancy even by means of the best and unfortunately common percentile scales one cannot conclude if the fetus has to be deliver in days or weeks.

Both fetus and mother in the last 3-4 days of pregnancy undergo rapid pre-labor changes necessary to delivery and sudden child's adaptation to extrauterine life [13,15,24,25,41]. Labor which starts one week before its own individual term (preterm) as well as delayed due to disturbance of it's initiation (postponed pregnancy) is possible in the large six-week range (37^0/7 - 43^2/7). Obstetricians cannot equally relate the same calendar week of very late pregnancy those fetuses, which will indeed be born during this period (e.g. 41^st or 43^rd). Thus, a preterm birth can occur even at 42^nd week just as a postterm birth is possible even at 38^th week owing to failed feto-maternal mechanism of labor initiation.
At the beginning of the period of the norm, the increase in morbidity and mortality is caused not only by labors of multifetal pregnancies, but mainly by lack of help necessary for undiagnosed true preterm births. Reversibly, at the end of the period of the norm (≥ 41^st week) premature induction in over ten percent of labors causes iatrogenic prematurity because of statistical , not individual postdatism.
Adjustment of the existing ultrasound devices to the requirements of the modern medical thermodynamics was patented first in Poland and later in Europe (European Patent No 0 557 831) which not only proves the originality of the method of ultrasonographic fetal biometry and birth prognosis with the accuracy of several days but should primarily force the manufacturers and designers of the faulty scales to change forthwith their way of doing things due to the growing hazard for human health [9 - 11,13,15-23].
In contemporary clinical practice even the most sophisticated ultrasonographic imaging equipment fails to provide in advanced pregnancy more accurate information relating to individual birth date than Naegele's Rule (95% confidence interval ± 3 weeks) using only the knowledge of the LMP date. In 1985 S.Campbell and co-workers [5] verified Naegele's Rule on 4 000 BPD measurements though their ultrasonographic interpretation contained a cardinal error committed, unfortunately, as recently as 1994 [6]. The error lies not in the technologically superior equipment but rather in the application of its programs. Their authors so far have failed to react to critical publications that appeared to date [7,28,29,30,31,32,33,35]. For example, the 40^0/7-6/7 week on the calendar scale may represent for all observed babies only one of three different possibilities: 1) the 40^th week for the babies in which delivery is to occur (i.e. birth only for 30% cases), but 2) some babies to be delivered during the 37^th week are actually three weeks overdue, while 3) those to be delivered during the 42^nd week still have two more weeks prior to birth. Therefore pregnancy dating scale which is incorporated in USG programs [4,5,7,8,38-40] can only provide a statistically probable range of delivery since calendar time (called horizontal time due to its linear appearance) is not directly connected to the fetuses' rate of maturity [12,14,16,17,26,27,33,35].
The object of this paper is to draw attention to the responsibility of industry for programming their products, if their use could entail medically harmful effects. Instrument, which is advertised as the one that enables to asses fetal age, must not obtain data differing by 1 or 2 weeks in the average values of pregnancy duration, depending on which scale was chosen by the manufacturers. And reversibly, a physician who observes closely the development of pregnancy from the last menstrual period, will not acquire data for e.g. 42^0/7 week, because some scales end at week 40 or 41.
The six-week period of birth occurrence in a human being is too big for obstetrical management to be determined only by statistical methods. An increase in instrumental deliveries and lack of progress in lowering the number of premature births associated with increased fetal morbidity and mortality are the consequence of this approach.
Biometric scales of few fetal parameters used in ultrasound devices are not correlated with one another therefore the result that assessment of fetal age can differ even in average values by 2 weeks depending on the examined parameter e.g. femur length, head or cranium circumference. It is caused by the fact that it is not the absolute value of the examined parameters and the postmenstrual pregnancy duration which determine the birth term and the condition of the newborns but the constant growth rate of all spatial fetal parameters.

Maturity quanta
Maturity is not a phenomenon like three other measurable fetal dimensions, but it is a consequence of space-time distribution of mass and energy in fetus. At the atomic level each subsequent new indivisible unit (quantum) of fetal maturity appears at a particular time which is inseparable from maturing fetal structure. Delivery occurs when a full quanta of fetal maturity has been completed. Thus, accordingly to the quickness of appearance of the consecutive quanta some fetuses are already mature at 37^0/7 postmenstrual weeks of gestation while the other ones have to mature until 43^2/7 (95% of confidence limits).
Technical quantization differs from physical one by the fact the scale of examined parameters is set on macro level in such a way as to make them multiples of a selected measure (quantum) in our case - points. Physicians' error consist in fact that in spite of the proven simplicity of maturity quantization and its expression in point scale, doctors attempt to measure it on the scale of grams or centimeters or - even worse - of gestational days or weeks. However, it is enough to understand the meaning of the three categories of pregnancy time to eliminate many iatrogenic actions.
In figure 3 and 4 the calendar time is marked on the horizontal X-axis, where the starting points is the date of conception or of the last menstruation. The developmental time, is measured on the vertical Y – axis and in physics adopts the designation “imaginary time”. Every fetus during the period of maturation (developmental time) must acquire a specific amount of maturity quanta sufficient for self-dependent life. The rate of fetal maturation depends on the frequency of appearance of maturity quanta and therefore the biological time, which is the sum of developmental time and intraquantal intervals, is longer and is located on the diagonal line.

Computer-aided prognosis of childbirth
By means of an ultrasonographic device we take a measurement of biophysical event such as fetal maturation which is subject to be quantizied. Thus, we have to relate the results to the individual time of examined fetus; this is done on the Y axis together with the mass and height instead of calendar horizontal scale (X axis). It suffices to compare a measurement made in 37^th or later week to any previous examination ≥ 28^th week. Then even the same absolute increase in an examined parameter during 2-3 weeks enables to divide fetuses into fast (predicted labor in 37^th-38^th week), regular (predicted labor in 39th-40th week) and slowly (predicted labor in ≥ 41^st week) maturating once.
Fetal growth means increase in the size of any of its parts occurring in the process of gestational maturation simultaneously with the mother's adaptation to the labor. Therefore, new computer-aided ultrasonographic with enzymatic monitoring of advanced pregnancy (≥ 28 weeks) enables to specify the kind of fetal growth rate (fast, regular, slow) and therefore to estimate the expected date of delivery (EDD) and newborn's state. The results of two (or more) examinations can be input into the computer program to obtain prognoses of observed pregnancy and birth prognosis.
Enzymating monitoring of pregnancy is based upon the rule that the constant increase of the oxytocinases level until delivery proves the proper course of pregnancy. In healthy woman the continuous increment of blood oxytocinase level until labor is observed in 81% of cases, decreases of levels on several days before labor - in 12%, and it is irregular with variable profile in 7% only 5 and 6)..

As far back as 1930 it has been demonstrated by K. Fekete that the serum of pregnant women was capable of abolishing the uterus-stimulating activity of posterior pituitary extracts. In late forties this feature was linked with enzymes activity called oxytocinase (E. W. Page, K. Semm, E. Werle, G. Effkeman, A. Hevelke, K. Buthmann), but the obtained results have not been adapted in clinical practice.
In 1957 H. Tuppy and H. Nesvadba described the principles of chemical assay of the enzyme. They used as substrate L-cystine-di-ß-naphtylamide indicating erroneously a 1% concentration of solution of sodium nitrate instead of 0,1% what precluded the determination of oxytocinase. In 1961 R. Klimek and M. Pietrzycka revised the methodical error and made the first attempt at establishing an international unit of enzyme activity: µmol/l/min [36].
The following years brought an increasing interest in assessment of aminopeptidase activity in obstetrics (B. Berde, J. Berhard, P. Fylling, G. Graff, T. Hashimoto, H. Kleiner, R. Klimek, S. E. H. Melander. Z. B. Miller, W. Muller-Hartburg, A. P. M. van Oudeusden, A. M. Riad, A.M. Rutenburg, G. Ryden, S. Sakamoto, I. Sjoholm, E.E. Smith, F. Sorm, M. A. Titus, P. Wilken et al.). The European especially Scandinavian authors were leading ones in this field. Unfortunately in 1966 C. Babuna and E. Yenen published a wrong study on the modification of the original chemical assessment of oxytocinase [1,2], which in fact hindered investigations of enzyme monitoring in pregnancy. Three years later R.Klimek delivered a paper in which these laboratory mistakes were corrected. Owing to refusing its publication in Am. J. Obstet. Gynecol. (also this journal published his other clinical studies [3,34] it was published in a biochemical journal which was readily available for the clinicians.
Finally, the introduction of new methods of pregnancy monitoring, e. g. human placental lactogen, sonography as well as divergences of opinion on oxytocinase application resulted in groundless neglect of the study on cystine-aminopeptidase activity of pregnant women serum. The continuation of our investigation on the use of various substrates and buffers resulted in the clinical verification of chemical methods that could be applied in the monitoring of pregnancy for the prediction of delivery.
Oxytocinase and its isoenzymes reflect the present state of the mother, the child and the placenta – the three being inseparable until the labor components of pregnancy. Maternal blood levels of cystine-aminopeptidases (CAP1 and CAP2) show high correlation with the fetal and placental mass as well as the fetal maturity level.
Maternal blood levels of cystine-aminopeptidases (CAP1 and CAP2) in the 4 consecutive weeks of the sixth gestational month were correlated with the fetal maturation rate. The study covered 395 pregnant women with a retrospective division in two groups according to whether labor took place in 39th week or later. A statistically significant (p<0.001) increase of both enzymes (CAP1 from 3.1±1µmol/l/min to 3.5±1µmol/l/min, and CAP2 from 3±0.8µmol/l/min to 3.7±1µmol/l/min) was found. The average values of the enzymes are statistically significantly higher (p<0.001) already in the 6th month in the pregnancies which ended in ≥ 39th week, respectively CAP1 3.5±0.9µmol/l/min : 3.1±0.9 µmol/l/min, t=4.4 and CAP2 3.3±0.8µmol/l/min : 3±0.8µmol/l/min, t=3.7. Also according to auxological laws 30 days before the labor, fast maturating fetuses have statistically significantly highest enzymatic values (7.2±2.4 µmol/l/min : 5.6±1.9 µmol/l/min).
The constant increase of oxytocinase and isooxytocinase in maternal blood up to the time of delivery in 81% of pregnancies and potential stabilization of its level during the last two weeks of pregnancy in further 12% of cases are the most sensitive indicators of the proper development of fetuses. Enzymes levels and the rate of their increases enable to predict the probable birth term with all the more accuracy, the more similar the subsequent values of the enzymatic determinations. Their low level during pregnancy proves the hypothalamo-hypophyseal hypofunction and is a pathognomonic symptom in the habitual abortions caused by such insufficiency. Decrease in levels instead of the normal constant increase precedes by several weeks intrauterine death of the fetus which reaches 70% when untreated in such neuroendocrine gestoses. The substitutive ACTH-depot therapy makes possible to end every pregnancy successfully, but with statistically lower (p<0.01) values of CAP1 and CAP2 by 0.2µmol/l/min till the 23rd gestational week and later two times higher differences in CAP2 level and 5 times higher for CAP1 level.
The object of this summary is to highlight the importance of enzymatic monitoring which serves as the basis of the biochemical diagnostics in all fields of medicine except for obstetrics. This is particularly odd, as the first enzyme used in medicine was the placenta-produced „defensive pregnancy enzyme” discovered by E.Abderhalden.
The same difference of various sets of ultrasound measurements corresponds to different angles, depending on the elapsed time between consecutive exams. Thus, the same absolute increase of measured ultrasonic parameters between serial measurements at the 1st and 2nd examination do not have a distinctive quality, but decisive is the angle at which growth line will take place over a known period of time.
Under physiological conditions all tested parameters of individual fetus have the same rate of maturity, but using angular growth rate, computer-aided method gives us clear differentiation between measurements of slow and fast maturing fetuses. There are highly significant correlation and straight regression curves for calendar scale as well as obviously curve for biological age within the last 12 gestational weeks of individual fetuses. (Figure 8)
Figure 8 Fast (F), regular (R) and slow (S) fetal maturation according to calendar and biological gestational age

Conclusions
The quantum thermodynamics makes possible prediction of the birth term with the accuracy of ±3-4 days. Owing to this we consider premature each end of pregnancy which occurs ≥ 1 week before, and post-term if the labor does not occur ≥ 1 week after the individual term. In each of three components of pregnancy (fetus, mother and placenta with the fetal membranes) several days before the birth term there occur clinically noticeable changes which enable verification of the clinical prognoses of birth date and the course of labor done with computer-aided method 28 weeks of gestation.

References

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