Plasmapheresis of pregnancy rhesus-conflict and haemolytic disease of fetus and newborn

Despite of introduction of anti-D prophylaxis into clinical practice, RhD alloimmunization still presents a problem to date. The purpose of this study was to determine the effectiveness of plasmapheresis and blood exchange-transfusion to diminish content of unconjugated bilirubin and free haemoglobin in newborn. The second purpose was to study the possibility of plasmapheresis in pregnant women to prevent hemolytic disease of the fetus and newborn (HDFN).

Subsequent clinical and laboratory investigation confirm that plasmapheresis was more effective and safe then blood exchange-transfusion (BET) to treat HDFN and plasmapheresis in pregnant women was rather effective to prevent HDFN.

Key words: hemolytic disease, newborn, plasmapheresis

 

Introduction

 Development in the children of the haemolytic disease of newborns (HDN) who were born from women with a Rhesus factor sensitization reaches 63%. At 7% of women high degree brings a Rhesus factor sensitization to the complicated course of pregnancy, pre-natal and perinatal pathology. So, the delay of pre-natal development of a fetus of the 2-3rd degree comes to light in 8,4% of cases. However at concentration of pregnant women with this pathology in specialized institutions the number of children with symptoms of a pre-natal hypotrophy increases to 15–20%. HBN frequency in the Russian Federation fluctuates from 0,1 to 2,5% and doesn't change within the last 10 years [1, 2]. In the European countries on 200–300 childbirth one case of HBN falls. According to maternity hospital of Taganrog, one case met HBN on average on 280 childbirth.

The most immunogene among all of the erythrocyte anti-genes of system a Rhesus factor is an anti-gene of D which in 95% of cases is the reason of a severe course of the haemolytic disease of a fetus (HDF). Intensity of process of destruction of erythrocytes is shown in size of a titres of antibodies to anti-genes of erythrocytes; i.e. the more intensively erythrocytes.hemolysis at higher such titres. But clinically such regularity comes to light not always. In practice accurate correlation between a titres of antibodies and disease severity it is observed only at the first pregnancy. Major importance in development of HBP and HBN have a Rhesus factor antibody, belonging to class G globulins. There are 4 subclasses IgG (IgG1, IgG2, IgG3, IgG4). They are actively transfer  to a fetus and increase the level of maternal antibodies in a fetus blood. Mainly IgG1 and IgG3 by values of its titres it is possible to determine degree of risk of an erythrocytes hemolysis  have clinical value [3].

Serious forms of a hyperbilirubinemia at newborns at the bilirubin level over 310-340 µmol/l (at prematurely born 170 µmol/l) with risk of development of a kernicterus can be eliminated only by means of BET [2, 4]. One of the modern ways of treatment of HBN there is also the plasmapheresis (PA) who is carried out in the mode of a synchronous plasma exchange. The PA appeared in the effective way of newborn children treatment at a hyperbilirubinemia because of HBN, and also from the complicated pre-natal infection, septic complications [5].

Objective of this research was studying of influence of PAS and BET at the haemolytic disease of newborns (HDN) on dynamics of the indirect bilirubin (IB) and free hemoglobin (FH), and also a comparative assessment of newborn children on clinic-laboratory indicators after carrying out PA and BET and newborn children after the carried-out PA to their mothers about a Rhesus factor sensitization during pregnancy with a high Rhesus factor antibodies titres.

Materials and methods.

The analysis of 70 clinical records is carried out newborn children with HDN of Taganrog maternity houses from 1997 till 2013 in which treatment the PA and BET were applied.

All newborn children in this research are divided into three groups:

  The 1st group – 37 newborn children to whom was carried out the syringe membrane plasma exchange (PA) on the 2nd and the 4th days of life by earlier developed technique [5]. PFM-800 and "Rosa" plasma filters were used. Indications for PAS newborn children were:

•• After carrying out BET a gain IB over 5-7 µmol/l for an hour.

•• The indicator of IB exceeds 300 µmol/l and with a tendency to further increase, despite conservative therapy.

The system with the plasma filter has the volume of own filling is 35 ml (to 10% of the circulating blood volume - CBV). Before blood sampling the highway was filled with the fresh frozen plasma (FFP). For a session PA 240±12,5 ml of an autoplasma in volume to 2 circulating plasma volume (CPV) with synchronous replacement of FFP (of about 110% from removed). In total 2 sessions of PA were carried out on the 2nd and the 4th days after the birth.

The 2nd group – 16 newborn children, to which mothers during pregnancy about a Rhesus factor isosensitization in the presence the Rhesus factor antibodies was carried out course PA since 22–24 weeks of pregnancy from 3 to 5 sessions with an interval of 1-2 weeks. For one session of PA deleted to 600-800 ml of an autoplasma.Completion was carried out by isotonic solution of sodium of chloride of 400 ml + a hydroethyl starch of 300 ml. The total amount of remote plasma for course PA made 1-1,5 CPV. Frequency rate of the PA procedures depended on dynamics of a Rhesus factor antibodies titres. PFM-800 and "Rosa" membrane plasma filters were used [5, 6, 7]

The 3rd group (control) – 17 newborn children to whom in treatment of HDN only BET was applied. Indications for BET were:

•• the IB level in the umbilical blood after the birth from above 50 µmol/l;

•• an hourly gain of IB in the 1st days lives over 5,5 µmol/l;

•• if for 6 h the IB 170 level µmol/l (from 30 µmol/l from an umbilical cord at the birth).

Use of the table (the international center of University of the State of Kentucky) of the IB level at newborn children with various body weight in the first days of life for indications to CPV which was carried out at the rate of 170–200 ml/kg of body weight (to 2,5 CBV) [1, 4].

Course BET consisted of two operations in the 1-3rd days of life of children. In the first days of life at children the average hourly the gain of IB made 12,6±1,6 µmol/l, therefore to all of them BET was carried out.

For the basis of studying of efficiency detoxication methods at HDN clinical and laboratory indicators were used. Clinical indicators included an assessment of dynamics of neurologic symptoms for the 1st, 3rd, 5th days of children life with HDN. Control pulse frequency, arterial pressure, electrocardiogram, respiration, Sat02 and body temperatures of the newborn by means of the Siemens cardiomonitor.

Laboratory diagnostics included:

•• definition of IB [9] as basic HDN marker;

•• free hemoglobin (FH) [10] as indicator of stability of cellular membranes of erythrocytes, FH defined before operations PA and BET.

To all newborn children CBV was calculated. CPV was carried out on a formula: CPV = CBV – CBV × Hematocrit/100 [7, 8].

The comparative analysis of need of the transfer of children of the 1st, 2nd and 3rd groups to the newborns pathology department and average day numbers of newborns in chamber of intensive therapy is carried out.

For calculation of value of average data and their mistakes were used methods of descriptive statistics. For a correctness of application of these or those methods of the statistical analysis previously for all selections of quantitative and quality indicators tests for a distribution normality were carried out. In case of confirmation of a normality

Distributions of selection for check reliability of a zero hypothesis parametrical methods (Student's t-criterion), otherwise – nonparametric methods were used (Mann-Whitney's criterion, Kolmogorova-Smirnov). Usually distributed data are submitted as "median±quantile.

Deviations", unusually distributed data – "median±quartile (a probable deviation)" and categorical data – raw data and as frequencies.

Reliability level for all analyses it was established as p<0.05. (Kolmogorova-Smirnov)

Results and discussion

It is established that despite performance of BET in the first days at newborn children of the 1st and 3rd groups, significant growth in IB by the end of 2 days (tab. 1) that demanded sessions of PA in the 1st and BET in the 3rd groups is noted.

Tabl. 1

The IB changes after the birth at children of the studied groups

Group

Initial IB

1st day

2nd day

3rd day

4th day

5th day

1

175.9±5.1

315.9±35.1

350.1±13.4*

164,5±12,5*

85,5±10,5*   

56,5±4,5*

2

290,1±12,9    

290,1±12,9    

224,4±10,1*, **

125,1±16,9*,**

  

66,2±15,3*,**    

42,3±5,2*,**

3

173,5±33,5    

309,5±33,5      

390,3±10,2

305,4±15,6    

195,3±15,7     

116,5±5,5

Note. * – p <0,05 in comparison with 3 gr., ** – p <0,05 in comparison with 1 gr..

At the same time, at children of the 2nd group, where to their mothers in treatment a Rhesus factor sensitization at pregnancy the course of membrane PA was applied, were more stable indicators of IB by the end of 2 days and it is reliable below (p<0,05), than at children of the 1st and 3rd groups. This group of children also had the minimum hourly gain of IB and BET wasn't required to them.

The analysis of the conducted research showed essential decrease in IB (p <0,05) in the 1st group and, especially, in the 2nd group of children to which mothers courses PA, in comparison with control 3rd group were conducted that is presented in tab. 2.

Tabl. 2.

The FH dynamics before and after operations PA and BET

Groups

1st operation

2nd operation

Before

After

Before

After

1

2.3±0.2

1.3±0.1*

1.1±0.1

0.5±0.3*

3

2.5±0.2

3.5±0.3

2.2±0.3

3.6±0.3

Note. * – p <0,05 in comparison with 3 gr.

Newborn children of the 1st and 2nd groups didn't need transfer to department of pathology of newborns.

At an assessment of dynamics of neurologic symptoms at newborn children with HDN for the 1st, 3rd, 5th and 12th days of life in basically and control groups of essential differences wasn't. Rough focal neurologic symptoms at children it wasn't observed.

At research of indicators of haemodynamics and respiration at children with HDN, analyzing protocols of operations PA and BET, it became clear that at 2 children during BET were noted considerable fluctuations of pulse rates, arterial pressure, Sat02, breath frequency, microcirculation deterioration, convulsive readiness. Upon termination of operation these complications were required to be stopped by medicamentous therapy. In group with PA during operations any frustration of haemodynamics it wasn't noted.

The FH level at the newborn studied groups is presented in tab. 2. There is pay attention initially high level FH which after sessions of PA returned to normal, however after BET observed still its bigger increase (in the 2nd group FH didn't investigate).

It is probable that more considerable decrease in the FH level after operations PA could promote and more positive dynamics of decrease in bilirubin at these children.

As condition of children of the 1st and 2nd groups was more stable, in their transfer to office of pathology newborns weren't need. It was reflected also in quantity days on one newborn child, carried out in of intensive care unit of maternity hospital and department of newborn pathology that made:

•• the 1st group – 6,5±0,5 days;

•• the 2nd group – 5,2±0,3 days;

•• the 3rd group – 11,8±0,7 days.

There wasn't any lethal cases from HDN in all groups. Complications during PA it wasn't observed too.

Clinical example:

Ulyana M., 26, on March 14, 2010. The 2nd childbirth from the 3rd pregnancy at term 38 weeks (at the first pregnancy the child with HDN, was carried out by BET, and now the girl is 8 years old. At the second pregnancy the fetus stood on early term). The pregnant woman has B(III) blood type Rh (–), at the father child - A (II) Rh (+). This pregnancy proceeded with an isosensitization on a Rh-factor with the advent of antibodies titre by 20th week of pregnancy in November, 2009 to 1:124, haemolytic IgG1 and IgG3 were noted. In November-December, 2009 in the pathology of pregnancy department the pregnant woman spent 5 sessions of a membrane plasma exchange with an interval at first 2 times in week, then once a week with decrease in  antibodies titres  till 1:8 (in December the titre already was 1:4).For a session of a membrane plasma exchange 600–800 ml of an autoplasma was removed.

In January and February, 2010 at the pregnant woman increase of antibodies titres 1:124 with identification of IGg1and IgG3 was noted again. Sessions of a membrane plasma exchange in January and February with dynamics of decrease in a antibodies titres to 1:8 were carried out. Dynamic research ultrasonography of fetus pathology wasn't revealed.

Childbirth took place without complications – the boy with the body weight of 3100 g, an assessment across Apgar 1min – 7 points, 5 min. – 8 points. Laboratory: IB from an umbilical blood it is no more than 24 µmol/l also to the end of the first days of 120 µmol/l. For the 5th day the child was discharged from maternity hospital home together with mother in a satisfactory condition (!!!) with indirect bilirubin of 64 µmol/l. Signs of essential HDFN at a fetus during pregnancy and at the newborn in this case it wasn’t noted. After the birth it wasn't required to the newborn child of neither BET, nor a membrane plasma exchange in view of preventive carrying out a plasma exchange during pregnancy.

Conclusion

1.                     The plasma exchange is shown to children, needing repeated BET that allows to achieve faster dynamics of decrease in IB from newborn children with HDN.

2.                     BET promotes removal of defective erythrocytes, but doesn't release adequately an organism from a Rhesus factor antibodies, bilirubin and free hemoglobin as they are distributed not only in circulation, but also in interstitial space.

3.                     The developed method of syringe membrane plasma exchange for newborn children with use of PFM-800 and "Rosa" plasma filters it appeared by the simplest and safe method of treatment of HDN.

4.                     In control group for receive adequate decrease in IB required it was necessary to carry out 2 sessions of BET, but thus the risk of the serious transfusion complications increases and the maintenance of FH accrues.

5.                      The condition of haemodynamics and respiration were noted more stable by PA application, unlike BET.

6.                     Preventive appointment membrane plasma exchange in time pregnancies at the raised antibodies titres with threat of HDFN allows considerably to lower IB at the birth at children, not resorting to BET.

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