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Effect of early postpartum use of the contraceptive implants, NORPLANT®, on the serum levels of immunoglobulins of the mothers and their breastfed infants
CONTRACEPTION
EFFECT OF IMPLANTS, GLOBULINS
K.A.
EARLY POSTPARTUM USE OF NORPLANTR, ON THE SERUM OF THE MOTHERS AND THEIR
Abdulla’,
Departments
of
Pathologyz,
Sawsan M.M. Obstetrics
Faculty of P.O.
Box
I. Elwan’, Shaabanl*
THE CONTRACEPTIVE LEVELS OF IMMUNOBREASTFED INFANTS
H.S.
and Gynecology' Medicine, Assiut 30 Assiut, Egypt
Salem’
and
and Clinical University,
ABSTRACT Ten breastfeeding NORPLANTR inserted
women had the contraceptive implants The between days 30 and 39 postpartum. in the serum immunoglobulins IgG, IgM and IgA were measured of the mothers and the infants before insertion and five A control group of breastfeeding mothers who months later. did not use any contraception or used local barrier methods Although there were changes in the were similarly studied. immunoglobulin levels with time in both mothers and infants, there were no group differences; this indicates that the use of NORPLANTR does not influence these factors of humoral immunity.
*
To
whom
Submitted Accepted
correspondence
for publication for publication
should
be
adressed.
September 4. 1965 September 30, 1985
SEPTEMBER 1985 VOL. 32 NO. 3
261
CONTRACEPTION
INTRODUCTION From the immunological standpoint, the postpartum period is a turbulent time: the mother is recovering from the effects of pregnancy and the infant is striving to build up the immunity system necessary for postnatal life. The use of hormonal contraception at,this time may influence either process. Moreover the postnatal period is a time when the risk of contracting infection is increased for both the mother and her infant. Epidemiological studies have shown an increased prevalence of viral infections, such as varicella and urinary tract infections, among combined oral contraceptive users (1,2). However, these morbidities were not judged of sufficient magnitude to be considered a health hazard. It has been demonstrated that the use of the combined contraceptive pill (COC) and depot-medroxyprogesterone acetate diminished the capacity to produce antibody to a discrete antigen like the tetanus toxoid (3). The use of COC was also shown to produce changes in certain immunoglobulins (4,5). The present study assesses the changes in the major immunoglobulins IgG, IgM, and IgA in mothers and their breastfed infants when the use of levonorgestrel-releasing implants, NORPLANTR, is initiated shortly after delivery.
MATERIAL AND METHOD NORPLANTR implants were inserted subdermally in ten breastfeeding mothers between days 30 and 39 postpartum. They received full information about the method, including the uncertainty of its effect on lactation. They had had normal deliveries and each was breastfeeding one healthy infant who weighed, at that time, 3500 g or more. The women agreed to give a preinsertion blood specimen and allowed a venous sample to be taken from their infants after the purpose of the study was explained to them. Each woman and her child were clinically followedcup at monthly intervals up to the end of the sixth postpartum month when venous blood specimens were taken again from her and her infant. Ten control women of the same inclusion criteria were examined in parallel. They either used no contraception or used the vaginal occlusive diaphragm or the condom. The main characteristics of the studied group are given in Table I. The infants received the routine immunization schedule and none of them had any significant illness during the follow-up. The serum of the blood samples was separated and kept frozen at-ZO'C until assayed for IgG, IgM and IgA, by the rate nephelometric technique (6) using the immunochemistry analyzer (Beckman).
262
SEPTEMBER 1985 VOL. 32 NO. 3
CONTRACEPTION
Table I: Mother and infant characterstics
on admission
NORPLANTR mean -+ SD Age Parity Living Weight Height Infant Infant
children (Kg) (cm) weight (gm) length (cm)
29.5 5 3.9 62.8 163 4120 54.3
Barriers/none mean + SD
+ 4.62 7 1.63 T 1.29 I7.18 7 4.16 T 374 7 1.06 -
29.5 4 3.6 62.5 162.6 4260 54.3
+ + T 7 y T 2
4.67 1.7 1.43 9.61 3.6 349 1.42
RESULTS Table II gives the mean serum concentrations of IgG, IgM and IgA in NORPLANTR users and the control group at admission to the study and by the end of the sixth postpartum month. There was a significant rise in the concentration of IgG and IgA concenta significant decline in IgM in both groups. ration declined after 6 months postpartum in both the study and control groups but the difference was statistically There were no signisignificant for the former group only. ficant differences between the two groups in the admission values of any of the immunoglobulins or in the changes that occurred after five months. Table II: Serum concentrations (mg/dL) of immunoglobulins in breastfeeding mothers who used NORPLANTR implants and in those who used no contraception or barrier methods IgG mean+SD -
IgM mean+SD -
IgA mean+SD -
NORPLANTR
1251~330
207+60 -
210+57 -
Barriers/none
1341~226
216+53 -
214+81
NORPLANTR
1417L447**
169~32""
201+62* -
Barriers/none
1419~268"
177+50*** -
200270
Admission: day 30-40 postpartum
Sixth postpartum month
Statistically different from admission values: *** = P <.OOl. ** = P <.Ol, * = P<.O5,
SEPTEMBER 1985 VOL. 32 NO. 3
263
CONTRACEPTION
The serum concentrations of the three immunoglobulins in the infants of the NORPLANTR-using mothers and the controls are given in Table III. There were no group differences at the time of admission to the study. IgG concentration slightly declined during the first six postpartum months, but IgM and IgA showed a marked increase between the first and sixth postpartum months. There were no group differences, either at admission or at the end of the study, in any of the three immunoglobulins. Table III: Serum concentrations (mg/dL) of immunoglobulins in infants breastfed by mothers who used NORPLANTR implants and in those whose mothers used no contraception or barrier methods
IgG
IgM
IgA
mean+SO -
mean+SO
mean+SD -
NORPLANTR
500+80
52+7 -
17+5 -
Barrier/none
504+97 -
50+7 -
18+4 -
NORPLANTR
487+92 -
73+10*** -
32+11***
Barrier/none
480+64 -
73+14*** -
29+6*** -
Admission
Six months postpartum
Statistically
different
from admission
values:
*** = P <.OOl.
DISCUSSION The changes in maternal immunoglobulin levels observed in the present study between the time of admission to the study and the end of the sixth postpartum month were similar to those previously described for the normalization of plasma protein levels after parturition (7). The levels were also not different from those found in non-nursing women before and after six months of NORPLANTR use (8). The use of NORPLANTR implants by nursing mothers did not influence the level of circulating immunoglobulins in any way that could contribute to increased susceptibility to infection. Similarly, the changes in the three immunoglobulins observed in the breastfed infants during the study are similar to the physiological changes expected during this time of evolution of the infants'immunological system (9). In both groups of infants, those of NORPLANTR-using mothers and those of the controls, there was a slight decrease in IgG and a marked increase in IgM and IgA. Since there were no significant differences between the groups in the magnitude of immunoglobulin changes, the study gave no
264
SEPTEMBER
1985 VOL. 32 NO. 3
CONTRACEPTION indication that NORPLANTR use predisposed infants to increased risks of contracting infection. However, it must be noted that the levels of immunoglobulins in the body are only one aspect of the immune system and there may be no correlation between the factors measured and the other aspects of this system (10). The present study findings that use of NORPLANTR contraceptive implants during breastfeeding does not influence the humoral immunity of the infants are reassuring since it has been demonstrated that levonorgestrel released from the implants reaches the blood of breastfed infant (11). They confirm the finding, by the same group of investigators, that there is no increase in the risk of infant morbidity as a result of NORPLANTR use by breastfeeding mothers (12).
ACKNOWLEDGEMENT This study was supported grant No. GA SIE 8119.
by the Rockefeller
Foundation
REFERENCES 1. Royal College of General Practitioners: Oral contraceptives and health. Pitman Publishing Corporation,London, P. 100, (1974) 2. Takahashi, M. and Loveland, D.6.: Bacteriuria and oral contraceptives. Routine health examination of 12076 middle-class women. 3AMA 227, 762 (1974) 3. goshi, U.M., Rangnekar, K.N., and Rao, S.S.: Effect of Ovulen and depoprovera on primary and secondary immune response in mice and rats. 3. Reprod. Fertil. 27: 310-314, (1971) 4. Horne, C.H., Weir R.J., Howie P.W. and Goudie R.B. Effect of combined oestrogen-progestogen oral contraceptives on serum-levels of42-macroglobulin, transferrin, albumin and IgG. Lancet 1: 49-50. January 10 (1970) 5.
Mendenhall, H.W. Effect of oral contraceptives on serum protein concentrations. Am. 3. Obstet. Gynaec. 106: 750-753 (1970)
6. Sternberg, 3.C. A rate nephelometer for measuring specific proteins by immunoprecipitin reactions. Clin Chem 23: 1456-1464 (1977) 7. Laurell, C.B., Kullander S. and Thorell 3. Rate of plasma protein normalization after parturition and withdrawal of Stand. 3. Clin. Lab. Invest. 26: oral contraceptives. 345-348 (1970) 8. Shaaban, M.M., Elwan, S.I., El-Sharkawy, M.M. and Farghaly, A.S. Effect of subdermal levonorgestrel contraceptive implants, NORPLANTR, on liver functions. Contraception 30: 407-412 (19841
SEPTEMBER1985VOL.
32N0.3
265
CONTRACEPTION
9. Allansmith, M., McClellan, B.H., Butterworth, M., and Maloney, 3.R. The development of immunoglobulin levels in man. 3. Pediatr. 72: 276-290 (1968) 10. Ramalakshmi, B.A., Jagadeesan, V. and Prema, K. Immune studies in oral contraceptive users. Contraception 20: 417-425 (1979) 11. Shaaban, M.M., Odlind, V., Salem, H.T., Abdallah, K.A. and Gomaa, A.A. Levonorgestrel concentrations in maternal and infant serum during use of subderaml levonorgestrel contraceptive implants, NORPLANTR.by nursing mothers. In preparation for publication. 12. Shaaban, M.M., Salem, H.T. and Abdullah K.A.: Influence of levonorgestrel contraceptive implants, NORPLANTR, initiated early postpartum upon lactation and infant growth. Submittedto Contraception.
266
SEPTEMBER 1985 VOL. 32 NO. 3
EFFECT OF IMPLANTS, GLOBULINS
K.A.
EARLY POSTPARTUM USE OF NORPLANTR, ON THE SERUM OF THE MOTHERS AND THEIR
Abdulla’,
Departments
of
Pathologyz,
Sawsan M.M. Obstetrics
Faculty of P.O.
Box
I. Elwan’, Shaabanl*
THE CONTRACEPTIVE LEVELS OF IMMUNOBREASTFED INFANTS
H.S.
and Gynecology' Medicine, Assiut 30 Assiut, Egypt
Salem’
and
and Clinical University,
ABSTRACT Ten breastfeeding NORPLANTR inserted
women had the contraceptive implants The between days 30 and 39 postpartum. in the serum immunoglobulins IgG, IgM and IgA were measured of the mothers and the infants before insertion and five A control group of breastfeeding mothers who months later. did not use any contraception or used local barrier methods Although there were changes in the were similarly studied. immunoglobulin levels with time in both mothers and infants, there were no group differences; this indicates that the use of NORPLANTR does not influence these factors of humoral immunity.
*
To
whom
Submitted Accepted
correspondence
for publication for publication
should
be
adressed.
September 4. 1965 September 30, 1985
SEPTEMBER 1985 VOL. 32 NO. 3
261
CONTRACEPTION
INTRODUCTION From the immunological standpoint, the postpartum period is a turbulent time: the mother is recovering from the effects of pregnancy and the infant is striving to build up the immunity system necessary for postnatal life. The use of hormonal contraception at,this time may influence either process. Moreover the postnatal period is a time when the risk of contracting infection is increased for both the mother and her infant. Epidemiological studies have shown an increased prevalence of viral infections, such as varicella and urinary tract infections, among combined oral contraceptive users (1,2). However, these morbidities were not judged of sufficient magnitude to be considered a health hazard. It has been demonstrated that the use of the combined contraceptive pill (COC) and depot-medroxyprogesterone acetate diminished the capacity to produce antibody to a discrete antigen like the tetanus toxoid (3). The use of COC was also shown to produce changes in certain immunoglobulins (4,5). The present study assesses the changes in the major immunoglobulins IgG, IgM, and IgA in mothers and their breastfed infants when the use of levonorgestrel-releasing implants, NORPLANTR, is initiated shortly after delivery.
MATERIAL AND METHOD NORPLANTR implants were inserted subdermally in ten breastfeeding mothers between days 30 and 39 postpartum. They received full information about the method, including the uncertainty of its effect on lactation. They had had normal deliveries and each was breastfeeding one healthy infant who weighed, at that time, 3500 g or more. The women agreed to give a preinsertion blood specimen and allowed a venous sample to be taken from their infants after the purpose of the study was explained to them. Each woman and her child were clinically followedcup at monthly intervals up to the end of the sixth postpartum month when venous blood specimens were taken again from her and her infant. Ten control women of the same inclusion criteria were examined in parallel. They either used no contraception or used the vaginal occlusive diaphragm or the condom. The main characteristics of the studied group are given in Table I. The infants received the routine immunization schedule and none of them had any significant illness during the follow-up. The serum of the blood samples was separated and kept frozen at-ZO'C until assayed for IgG, IgM and IgA, by the rate nephelometric technique (6) using the immunochemistry analyzer (Beckman).
262
SEPTEMBER 1985 VOL. 32 NO. 3
CONTRACEPTION
Table I: Mother and infant characterstics
on admission
NORPLANTR mean -+ SD Age Parity Living Weight Height Infant Infant
children (Kg) (cm) weight (gm) length (cm)
29.5 5 3.9 62.8 163 4120 54.3
Barriers/none mean + SD
+ 4.62 7 1.63 T 1.29 I7.18 7 4.16 T 374 7 1.06 -
29.5 4 3.6 62.5 162.6 4260 54.3
+ + T 7 y T 2
4.67 1.7 1.43 9.61 3.6 349 1.42
RESULTS Table II gives the mean serum concentrations of IgG, IgM and IgA in NORPLANTR users and the control group at admission to the study and by the end of the sixth postpartum month. There was a significant rise in the concentration of IgG and IgA concenta significant decline in IgM in both groups. ration declined after 6 months postpartum in both the study and control groups but the difference was statistically There were no signisignificant for the former group only. ficant differences between the two groups in the admission values of any of the immunoglobulins or in the changes that occurred after five months. Table II: Serum concentrations (mg/dL) of immunoglobulins in breastfeeding mothers who used NORPLANTR implants and in those who used no contraception or barrier methods IgG mean+SD -
IgM mean+SD -
IgA mean+SD -
NORPLANTR
1251~330
207+60 -
210+57 -
Barriers/none
1341~226
216+53 -
214+81
NORPLANTR
1417L447**
169~32""
201+62* -
Barriers/none
1419~268"
177+50*** -
200270
Admission: day 30-40 postpartum
Sixth postpartum month
Statistically different from admission values: *** = P <.OOl. ** = P <.Ol, * = P<.O5,
SEPTEMBER 1985 VOL. 32 NO. 3
263
CONTRACEPTION
The serum concentrations of the three immunoglobulins in the infants of the NORPLANTR-using mothers and the controls are given in Table III. There were no group differences at the time of admission to the study. IgG concentration slightly declined during the first six postpartum months, but IgM and IgA showed a marked increase between the first and sixth postpartum months. There were no group differences, either at admission or at the end of the study, in any of the three immunoglobulins. Table III: Serum concentrations (mg/dL) of immunoglobulins in infants breastfed by mothers who used NORPLANTR implants and in those whose mothers used no contraception or barrier methods
IgG
IgM
IgA
mean+SO -
mean+SO
mean+SD -
NORPLANTR
500+80
52+7 -
17+5 -
Barrier/none
504+97 -
50+7 -
18+4 -
NORPLANTR
487+92 -
73+10*** -
32+11***
Barrier/none
480+64 -
73+14*** -
29+6*** -
Admission
Six months postpartum
Statistically
different
from admission
values:
*** = P <.OOl.
DISCUSSION The changes in maternal immunoglobulin levels observed in the present study between the time of admission to the study and the end of the sixth postpartum month were similar to those previously described for the normalization of plasma protein levels after parturition (7). The levels were also not different from those found in non-nursing women before and after six months of NORPLANTR use (8). The use of NORPLANTR implants by nursing mothers did not influence the level of circulating immunoglobulins in any way that could contribute to increased susceptibility to infection. Similarly, the changes in the three immunoglobulins observed in the breastfed infants during the study are similar to the physiological changes expected during this time of evolution of the infants'immunological system (9). In both groups of infants, those of NORPLANTR-using mothers and those of the controls, there was a slight decrease in IgG and a marked increase in IgM and IgA. Since there were no significant differences between the groups in the magnitude of immunoglobulin changes, the study gave no
264
SEPTEMBER
1985 VOL. 32 NO. 3
CONTRACEPTION indication that NORPLANTR use predisposed infants to increased risks of contracting infection. However, it must be noted that the levels of immunoglobulins in the body are only one aspect of the immune system and there may be no correlation between the factors measured and the other aspects of this system (10). The present study findings that use of NORPLANTR contraceptive implants during breastfeeding does not influence the humoral immunity of the infants are reassuring since it has been demonstrated that levonorgestrel released from the implants reaches the blood of breastfed infant (11). They confirm the finding, by the same group of investigators, that there is no increase in the risk of infant morbidity as a result of NORPLANTR use by breastfeeding mothers (12).
ACKNOWLEDGEMENT This study was supported grant No. GA SIE 8119.
by the Rockefeller
Foundation
REFERENCES 1. Royal College of General Practitioners: Oral contraceptives and health. Pitman Publishing Corporation,London, P. 100, (1974) 2. Takahashi, M. and Loveland, D.6.: Bacteriuria and oral contraceptives. Routine health examination of 12076 middle-class women. 3AMA 227, 762 (1974) 3. goshi, U.M., Rangnekar, K.N., and Rao, S.S.: Effect of Ovulen and depoprovera on primary and secondary immune response in mice and rats. 3. Reprod. Fertil. 27: 310-314, (1971) 4. Horne, C.H., Weir R.J., Howie P.W. and Goudie R.B. Effect of combined oestrogen-progestogen oral contraceptives on serum-levels of42-macroglobulin, transferrin, albumin and IgG. Lancet 1: 49-50. January 10 (1970) 5.
Mendenhall, H.W. Effect of oral contraceptives on serum protein concentrations. Am. 3. Obstet. Gynaec. 106: 750-753 (1970)
6. Sternberg, 3.C. A rate nephelometer for measuring specific proteins by immunoprecipitin reactions. Clin Chem 23: 1456-1464 (1977) 7. Laurell, C.B., Kullander S. and Thorell 3. Rate of plasma protein normalization after parturition and withdrawal of Stand. 3. Clin. Lab. Invest. 26: oral contraceptives. 345-348 (1970) 8. Shaaban, M.M., Elwan, S.I., El-Sharkawy, M.M. and Farghaly, A.S. Effect of subdermal levonorgestrel contraceptive implants, NORPLANTR, on liver functions. Contraception 30: 407-412 (19841
SEPTEMBER1985VOL.
32N0.3
265
CONTRACEPTION
9. Allansmith, M., McClellan, B.H., Butterworth, M., and Maloney, 3.R. The development of immunoglobulin levels in man. 3. Pediatr. 72: 276-290 (1968) 10. Ramalakshmi, B.A., Jagadeesan, V. and Prema, K. Immune studies in oral contraceptive users. Contraception 20: 417-425 (1979) 11. Shaaban, M.M., Odlind, V., Salem, H.T., Abdallah, K.A. and Gomaa, A.A. Levonorgestrel concentrations in maternal and infant serum during use of subderaml levonorgestrel contraceptive implants, NORPLANTR.by nursing mothers. In preparation for publication. 12. Shaaban, M.M., Salem, H.T. and Abdullah K.A.: Influence of levonorgestrel contraceptive implants, NORPLANTR, initiated early postpartum upon lactation and infant growth. Submittedto Contraception.
266
SEPTEMBER 1985 VOL. 32 NO. 3