Ann Hematol (1991) 63:210-213
AnnaLs of
Hematology 9 Springer-Verlag 1991
Original article Immunoglobulin serum levels in very low birth weight infants treated with different intravenous preparations M. Amato 1, D. Markus z, P. Hiippi 2, and P. Imbach I 1 Division of Neonatology, Children's Hospital, Aarau, Switzerland z Division of Neonatology, Department of Obstetrics and Gynecology, University of Berne, Switzerland Received April 8, 1991/Accepted June 24, 1991
Summary. Parenteral h u m a n immunoglobulin (IVIG) administration is widely used in low birth weight (LBW) infants for prevention and therapy of neonatal infection. In previous studies, I V I G preparations containing IgG and low IgM concentrations were commonly used. In this study we compare immunoglobulin serum levels in two groups of healthy preterm infants receiving prophylactically standard I V I G (Sandoglobulin, 0.1 m g / k g IgM) or IgM-enriched I V I G (Pentaglobin, 30 m g / k g IgM). Immunoglobulin levels were assayed by rate nephelometry at birth and at 3, 5, 7, and 14 days after birth. The two groups of patients were matched for gestational age (31 + 2.3 weeks), birth weight (1320 +_ 340 g), and serum IgG (4.1 +_ 1.9 g/l) and IgM (0.22 +_ 0.18 g/l) levels at birth. Significantly higher IgM levels were observed at 3 and 5 days after IgM-enriched I V I G administration (p < 0.01). Higher IgG levels were attained and persisted for 2 weeks after standard I V I G administration (p < 0.01). These data indicate different IgG and IgM target levels in LBW infants treated with different immunoglobulin preparations. Key words: Intravenous immunoglobulin serum levels - Low birth weight infants
Neonatal
Introduction The incidence of bacterial infection is predictably higher in preterm babies and contributes significantly to neonatal mortality and morbidity [14]. Although antibiotic therapy has had a dramatic effect on successful treatment, passively intravenous-administered immunoglobulin (IVIG) for prevention and therapy of neonatal infection has been proposed as adjunctive treatment in low birth weight (LBW) infants [6, 7]. Premature babies have low serum immunoglobulin (Ig) concentrations at birth Address for correspondence: M. Amato, Division of Neonatology,
Children's Hospital, CH-5001 Aarau, Switzerland
and have the highest risk of acquiring sepsis. In previous clinical studies on the prophylactic use of I V I G in LBW infants, Chirico et al. [5] found significant decrease of mortality and severity of neonatal sepsis. Nowadays, there are many theoretical reasons why boostering the serum IgM level in the newborn could lead to a more rapid and specific antibody response, reducing significantly mortality from neonatal sepsis [12]. Pharmacokinetic investigations using different I V I G preparations are required to enable individualization of Ig dosage [8]. The aim of this prospective study was to assess the kinetics of IgG and IgM levels through the first 2 weeks after birth in healthy LBW infants receiving prophylactic infusion of standard I V I G or IgM-enriched IVIG.
Patients and methods Two groups of healthy, appropriate for gestational age, preterm neonates (gestational age ranging between 26 and 34 weeks and birth weight between 850 and 1650 g) born at the Neonatal Division of the Berne University were studied. They were matched for gestational age assessed by Ballard's criteria [3], birth weight, and immunoglobulin levels measured immediately after birth. After informed parental consent was obtained, the babies were randomly allocated into two groups and treated prophylactically with standard IVIG (Sandoglobulin, pH 4 and pepsin-treated, Sandoz Products Ltd.) or IgM-enriched IVIG (Pentaglobin, beta-propiolactone treated, Biotest Pharma, Frankfurt, FRG). Human immunoglobulin is prepared from pooled human plasma by various fractionation procedures and then modified to obtain a preparation suitable for intravenous use. Sandoglobulin contains predominantly IgG (96%), antibodies of the IgM (3.6%) and IgA (0.4%) classes being lost during fractionation. Pentaglobin is a preparation containing significant amounts of IgM (12%) and IgA (12%) but less IgG (76%). Both preparations contain antiviral and antibacterial antibodies against different strains of Escherichia coli, Klebsiella pneumoniae, Streptococcus pneumoniae, Haemophilus influenzae, and staphylococcus aureus. Improved opsonic activity for Pseudomonas aeruginosa was observed using Pentagiobin [9]. In our patients, infection was excluded before treatment, by recording maternal obstetric history. Babies born after prolonged rupture of membranes (> 24 h) or with clinical or hematological signs of neonatal infection during the study period were excluded. The first group of noninfected infants (SG) was treated with standard IVIG (0.5 g/kg
211
IgM after Sandoglobulin/Pentaglobin infusion
body wt./day equivalent to 480 mg IgG and 0.1 mg IgM). The second group (PG) received beta-propiolactone treated IgM-enriched IVIG (5 ml/kg body wt./day equivalent to 290 mg IgG and 30 mg IgM). In both groups, IVIG was administered intravenously, over 2 h per day for 3 days by a syringe pump. On day 1 and after the third Ig infusion on days 3, 5, 7, and 14, blood (0.5 ml) was drawn for serum immunoglobulin measurements at the time routine blood samples were being done. Immunoglobulins were assayed by rate nephelometry using the Beckman automated immnnochemistry system. Standard human serum was used as control. The study was approved by the ethical committee of the hospital. The paired Student's t-test was used to compare the results before, during, and after IVIG infusion. The level of significance was set at 0.05.
Results
T h e e n r o l l m e n t p e r i o d e x t e n d e d f r o m D e c e m b e r 1989 to June 1990, d u r i n g which 34 p r e t e r m n e o n a t e s c o m p l e t e d the study. Seventeen were treated with S a n d o g l o b u l i n (gestational age o f 32 _+ 2.2 weeks a n d b i r t h weight o f 1390 _+ 290 g) a n d 17 were treated with P e n t a g l o b i n (gestational age o f 30 + 2.6 weeks a n d b i r t h weight o f 1240 _+ 409 g). There were no statistically significant differences between the two t r e a t m e n t g r o u p s with respect to b i r t h weight (total m e a n 1320 + 340 g), g e s t a t i o n a l age (total m e a n 31 + 2.3 weeks), 1 a n d 5 m i n A p g a r score ( m e a n 6.3 ___ 1.1 a n d 8.0 + 1.2 respectively), a n d arterial cord b l o o d p H ( m e a n 7.19 + 0.1) (p > 0.05). T h e sex dist r i b u t i o n was the s a m e for b o t h groups. Patients were c o n t i n u o u s l y m o n i t o r e d for h e a r t rate, r e s p i r a t o r y rate, a n d b l o o d pressure d u r i n g t h e infusion. I n a d d i t i o n , h e m a t o l o g i c a l , h e p a t i c a n d renal f u n c t i o n s were s t u d i e d so t h a t acute side effects o f I V I G c o u l d be evaluated. C o m p l e t e b l o o d cell count, level o f t o t a l bilirubin, b l o o d urea nitrogen, a n d s e r u m creatinine were d e t e r m i n e d in all infants before a n d after I V I G infusion. T h e p a t i e n t s were closely o b s e r v e d for any evidence o f r e a c t i o n to the t h e r a p y a n d d u r i n g the course o f their stay in the n u r s e r y for a n y evidence o f c o m p l i c a t i o n s . A s r e p o r t e d in o t h e r studies, there was n o evidence o f adverse effects related to I V I G a d m i n i s t r a t i o n .
Fig. 2. Serum IgM concentration (g/l) measured at birth and at days 3, 5, 7, and 14 after IVIG infusion in two groups of very low birth weight infants. [] IgM at birth; [] IgM day 3; [] IgM day 5, [] IgM day 7; [] IgM day 14
Table 1. IgG levels (g/l) after Sandoglobulin (SG) or Pentaglobin
(PG) infusion (values are mean • SD) Day of life
SG
PG
p-value
1 3 5 7 14
5.6• 11.7• 10.4• 9.8• 8.8•
4.8• 8.7• 7.6• 7.1• 6.0•
n.s.*
AnnaLs of
Hematology 9 Springer-Verlag 1991
Original article Immunoglobulin serum levels in very low birth weight infants treated with different intravenous preparations M. Amato 1, D. Markus z, P. Hiippi 2, and P. Imbach I 1 Division of Neonatology, Children's Hospital, Aarau, Switzerland z Division of Neonatology, Department of Obstetrics and Gynecology, University of Berne, Switzerland Received April 8, 1991/Accepted June 24, 1991
Summary. Parenteral h u m a n immunoglobulin (IVIG) administration is widely used in low birth weight (LBW) infants for prevention and therapy of neonatal infection. In previous studies, I V I G preparations containing IgG and low IgM concentrations were commonly used. In this study we compare immunoglobulin serum levels in two groups of healthy preterm infants receiving prophylactically standard I V I G (Sandoglobulin, 0.1 m g / k g IgM) or IgM-enriched I V I G (Pentaglobin, 30 m g / k g IgM). Immunoglobulin levels were assayed by rate nephelometry at birth and at 3, 5, 7, and 14 days after birth. The two groups of patients were matched for gestational age (31 + 2.3 weeks), birth weight (1320 +_ 340 g), and serum IgG (4.1 +_ 1.9 g/l) and IgM (0.22 +_ 0.18 g/l) levels at birth. Significantly higher IgM levels were observed at 3 and 5 days after IgM-enriched I V I G administration (p < 0.01). Higher IgG levels were attained and persisted for 2 weeks after standard I V I G administration (p < 0.01). These data indicate different IgG and IgM target levels in LBW infants treated with different immunoglobulin preparations. Key words: Intravenous immunoglobulin serum levels - Low birth weight infants
Neonatal
Introduction The incidence of bacterial infection is predictably higher in preterm babies and contributes significantly to neonatal mortality and morbidity [14]. Although antibiotic therapy has had a dramatic effect on successful treatment, passively intravenous-administered immunoglobulin (IVIG) for prevention and therapy of neonatal infection has been proposed as adjunctive treatment in low birth weight (LBW) infants [6, 7]. Premature babies have low serum immunoglobulin (Ig) concentrations at birth Address for correspondence: M. Amato, Division of Neonatology,
Children's Hospital, CH-5001 Aarau, Switzerland
and have the highest risk of acquiring sepsis. In previous clinical studies on the prophylactic use of I V I G in LBW infants, Chirico et al. [5] found significant decrease of mortality and severity of neonatal sepsis. Nowadays, there are many theoretical reasons why boostering the serum IgM level in the newborn could lead to a more rapid and specific antibody response, reducing significantly mortality from neonatal sepsis [12]. Pharmacokinetic investigations using different I V I G preparations are required to enable individualization of Ig dosage [8]. The aim of this prospective study was to assess the kinetics of IgG and IgM levels through the first 2 weeks after birth in healthy LBW infants receiving prophylactic infusion of standard I V I G or IgM-enriched IVIG.
Patients and methods Two groups of healthy, appropriate for gestational age, preterm neonates (gestational age ranging between 26 and 34 weeks and birth weight between 850 and 1650 g) born at the Neonatal Division of the Berne University were studied. They were matched for gestational age assessed by Ballard's criteria [3], birth weight, and immunoglobulin levels measured immediately after birth. After informed parental consent was obtained, the babies were randomly allocated into two groups and treated prophylactically with standard IVIG (Sandoglobulin, pH 4 and pepsin-treated, Sandoz Products Ltd.) or IgM-enriched IVIG (Pentaglobin, beta-propiolactone treated, Biotest Pharma, Frankfurt, FRG). Human immunoglobulin is prepared from pooled human plasma by various fractionation procedures and then modified to obtain a preparation suitable for intravenous use. Sandoglobulin contains predominantly IgG (96%), antibodies of the IgM (3.6%) and IgA (0.4%) classes being lost during fractionation. Pentaglobin is a preparation containing significant amounts of IgM (12%) and IgA (12%) but less IgG (76%). Both preparations contain antiviral and antibacterial antibodies against different strains of Escherichia coli, Klebsiella pneumoniae, Streptococcus pneumoniae, Haemophilus influenzae, and staphylococcus aureus. Improved opsonic activity for Pseudomonas aeruginosa was observed using Pentagiobin [9]. In our patients, infection was excluded before treatment, by recording maternal obstetric history. Babies born after prolonged rupture of membranes (> 24 h) or with clinical or hematological signs of neonatal infection during the study period were excluded. The first group of noninfected infants (SG) was treated with standard IVIG (0.5 g/kg
211
IgM after Sandoglobulin/Pentaglobin infusion
body wt./day equivalent to 480 mg IgG and 0.1 mg IgM). The second group (PG) received beta-propiolactone treated IgM-enriched IVIG (5 ml/kg body wt./day equivalent to 290 mg IgG and 30 mg IgM). In both groups, IVIG was administered intravenously, over 2 h per day for 3 days by a syringe pump. On day 1 and after the third Ig infusion on days 3, 5, 7, and 14, blood (0.5 ml) was drawn for serum immunoglobulin measurements at the time routine blood samples were being done. Immunoglobulins were assayed by rate nephelometry using the Beckman automated immnnochemistry system. Standard human serum was used as control. The study was approved by the ethical committee of the hospital. The paired Student's t-test was used to compare the results before, during, and after IVIG infusion. The level of significance was set at 0.05.
Results
T h e e n r o l l m e n t p e r i o d e x t e n d e d f r o m D e c e m b e r 1989 to June 1990, d u r i n g which 34 p r e t e r m n e o n a t e s c o m p l e t e d the study. Seventeen were treated with S a n d o g l o b u l i n (gestational age o f 32 _+ 2.2 weeks a n d b i r t h weight o f 1390 _+ 290 g) a n d 17 were treated with P e n t a g l o b i n (gestational age o f 30 + 2.6 weeks a n d b i r t h weight o f 1240 _+ 409 g). There were no statistically significant differences between the two t r e a t m e n t g r o u p s with respect to b i r t h weight (total m e a n 1320 + 340 g), g e s t a t i o n a l age (total m e a n 31 + 2.3 weeks), 1 a n d 5 m i n A p g a r score ( m e a n 6.3 ___ 1.1 a n d 8.0 + 1.2 respectively), a n d arterial cord b l o o d p H ( m e a n 7.19 + 0.1) (p > 0.05). T h e sex dist r i b u t i o n was the s a m e for b o t h groups. Patients were c o n t i n u o u s l y m o n i t o r e d for h e a r t rate, r e s p i r a t o r y rate, a n d b l o o d pressure d u r i n g t h e infusion. I n a d d i t i o n , h e m a t o l o g i c a l , h e p a t i c a n d renal f u n c t i o n s were s t u d i e d so t h a t acute side effects o f I V I G c o u l d be evaluated. C o m p l e t e b l o o d cell count, level o f t o t a l bilirubin, b l o o d urea nitrogen, a n d s e r u m creatinine were d e t e r m i n e d in all infants before a n d after I V I G infusion. T h e p a t i e n t s were closely o b s e r v e d for any evidence o f r e a c t i o n to the t h e r a p y a n d d u r i n g the course o f their stay in the n u r s e r y for a n y evidence o f c o m p l i c a t i o n s . A s r e p o r t e d in o t h e r studies, there was n o evidence o f adverse effects related to I V I G a d m i n i s t r a t i o n .
Fig. 2. Serum IgM concentration (g/l) measured at birth and at days 3, 5, 7, and 14 after IVIG infusion in two groups of very low birth weight infants. [] IgM at birth; [] IgM day 3; [] IgM day 5, [] IgM day 7; [] IgM day 14
Table 1. IgG levels (g/l) after Sandoglobulin (SG) or Pentaglobin
(PG) infusion (values are mean • SD) Day of life
SG
PG
p-value
1 3 5 7 14
5.6• 11.7• 10.4• 9.8• 8.8•
4.8• 8.7• 7.6• 7.1• 6.0•
n.s.*
