Indian Pediatrics 2002; 39:282-288  

Transaplacentally Transmitted Anti-Measles Antibodies in Term and Preterm Infants

From the Department of Pediatrics, Army Hospital (R&R), Delhi Contonment 110 010, India.

Correspondence to: Dr. A.T.K. Rau, Department of Pediatrics, Kasturba Medical College, Mangalore 575 001, India.

Manuscript received: October 11, 2000;
Initial review completed: November 23, 2000;
Revision accepted: August 1, 2001;

Measles is the most common vaccine preventable cause of death in the world. The WHO estimates that 8.703 million disability adjusted life years (DALY) due to measles and 0.256 million measles associated deaths still occur each year in Southeast Asia(1). The mainstay of measles control is the measles vaccine. Since 1976, the WHO has recommended that measles vaccine be integrated into routine health services and be administered at 9 months of age in developing countries(2). This recommendation is based on studies demonstrating sero conversion rates of over 90% in children 9 months of age or older in developing countries(3).

In India, measles vaccine, administered at 9 months, has been incorporated in the national immunization programme since 1985-86(4). However, 10-15% of measles infection occurs in infants at the age of 6-8 months(5), that is, before they can be immunized against measles. Therefore, the question arises whether administration of the vaccine be preponed in order to protect this group of infants. However, all infants are naturally protected against measles by trans-placentally transmitted antibodies derived from the mother(6), and become susceptible to the infection when these antibodies fall to non-protective levels. Till the time these antibodies persist in the infant, measles vaccine cannot be given, as these antibodies would interfere with its uptake and subsequent seroconversion(7,8). Trans-placental anti-body transfer occurs mainly in the last few weeks before birth and the level of antibody in a neonate is reportedly directly proporltional to gestational age(9). Numerous studies in term infants have demonstrated that trans-placentally acquired anti measles antibodies decay to non-protective levels by 7 months of age in developing countries(3). Therefore, measles vaccine administered around this time, theoretically, would be effective in these infants.

However, keeping in mind that the degree of antibody transfer is related to gestational age, it can be presumed that due to early interruption of intrauterine life, preterm infants are likely to have lower antibody titres at birth and are likely to become seronegative earlier than term infants. Very few studies have been done to verify this hypothesis. If this is so, it stands to reason that, preterm infants would require the vaccine earlier and also, would seroconvert adequately if given the vaccine at an earlier age than term infants. In view of the above, this study was undertaken to estimate and compare the levels of anti measles antibodies in term and preterm infants at birth and five months of age and determine if the levels of these antibodies behave similarly in the two groups of children.

The study was conducted on 123 term and 164 preterm infants, born consecutively, in the Army Hospital (Delhi). After clearance from the eithics committee of the hospital, verbal informed consent from both or any one parent was obtained. Gestational age at birth was assessed from the last menstrual period and ultrasound scan reports (where available) and correlated with the Dubowitz criteria(10). Each of the infant was allotted a serial number at birth and 10 ml of cord blood was collected in two sterile bottles (5 ml each) and serum separated by centrifugation at 1500 rpm for 2 minutes. One sample (A) was subjected to immunoglobulin profile test (IgG, IgM and IgA levels) by immuno turbidometric methods (Orion Diagnostica, Finland), While the other was labeled as B and stored at –20ºC. Each baby was thereafter followed up periodically at the well baby clinic and at the 5th month of postnatal life, another blood sample (C) was collected by venepuncture, from each infant and stored in a similar manner. Initial cord blood samples of those infants who died, were lost to follow up or received blood or blood products, in between birth and 5 months, were discarded (23 term and 64 preterm infants) and the subjects eliminated from the study.

On completion of collection, the samples were subjected to estimation of antimeasles IgG antibodies levels by sandwich ELISA method(11) using kits supplied by M/s. Panbio, Sydney, Australia. All samples were tested simultaneously using identical lots of reagents and then subjected to photo calori-metric estimation of optical density(OD). The results were compared with the positive and negative controls supplied by the manu-facturers to test for validity. Inter-test variability was minimized by the use of positive quality control serum sample obtained from a diagnosed case of measles. Depending on the OD levels, the samples were grouped into 3 categories: (i) Positive: OD level >1.4; (ii) Weakly positive: OD levels between 0.7-1.4; and (iii) Negative: OD levels <0.7.

The results were analyzed by standard statistical methods(12).

The mean gestational age of the hundred term infants in this study was 39.2 weeks (SD 2.14) while the mean weight, length and occipitofrontal circumference were 3352 g (SD 340.12), 48.6 cm (SD 2.4) and 34.6 cm (SD 1.65), respectively. Corresponding figures for the 100 preterm infants studied, were 32.78 weeks (SD 2.06), 1859.7 g (SD 350.15), 44.3 cm (SD 2.5) and 31.3 cm (SD 1.48), respectively. The male/female ratio was 1.04: 1 in term and 1:1.7 in preterm infants. The number of infants studied in each of the groups (term and preterm) were 100. Of the preterm infants, 6,12,10 and 22 infants (total = 50) were assessed at 29, 30, 31 and 32 weeks of gestation, respectively while 7, 14, 20 and 9 infants were assessed at 33, 34, 35 and 36 weeks of gestation, respectively.

A scrutiny of the levels of antimeasles antibodies in term and preterm infants at birth and 5 months (Table I) indicates that while all term and 92% preterm infants were sero-positive at birth, only 3% of preterm infants were seropositive at 5 months compared to 49% term babies. This difference was statistically significant (p <0.05).

The Optical Densities (OD) obtained when estimating antimealses antibody levels in both term and preterm babies (Table II) indicated that, while at birth, both term and preterm neonates had comparable levels of transplacentally transmitted IgG levels (p >0.05), the level was lower in preterm infants at 5 months of age as compared to term infants of the same age (p <0.05).

Comparison of OD levels in term babies at birth and 5 months and in preterm babies at birth and 5 months revealed that while in term babies there was no significant (p >0.05) decline in antibody titres over a period of 5 months from birth to 5 months of gestational age, the levels in preterm babies showed a marked decline over the same period (p <0.05).

Study of the OD levels in the two groups of preterm infants at birth and 5 months (Table III) indicates that though there were lower levels of antimeasles antibodies in preterm infants in the age group of 29-32 weeks at birth and 5 months, it was not statistically significant when compared to the infants in group B.

Table I__ Status of Antimeasles Antibodies in Both Group of Infants

The levels of antimeasles antibodies in the two groups showed a difference in both groups at birth and at 5 months. However, the results, only in the later age were found to be statistically significant. Almost all the preterm infants were seronegative at 5 months of age, whereas, only half the term neonates were found to be so at 5 months of age.

Studies conducted on term infants from developed countries(8,13-16) show that maternally derived measles antibodies in term neonates persist through the first year of life and decline to undetectable levels only after the first birthday. As this interferes with seroconversion when measles vaccine is administered, in developed countries, measles immunization is recommended at 15 months of age.

In India, the current recommendation is to give measles immunization at 9 months of age because prevalence of measles among infants is high(1,4), and the disease is accompanied by serious complications and significant mortality, more so amongst malnourished children. Job et al.(17) recorded the age-specific antibody response in order to evaluate this recommendation. They found sero-conversion rates of 84%, 94% and 98% in infants immunized between 6-8, 9-11 and 12-15 months respectively. Hence, extrapolating backwards, at 5 months, seroconversion rates would be even less indicating significant persistence of maternal antibodies at this age.

In another study in the Congo(18), a serological survey of 252 infants aged 2-9 months showed that the proportion of detectable antibody dropped from 95.8% at 2 months of age to 48.5% at 4 months and to 8.2% at 7-8 months of age. This correlated very well with out study, which has shown that only 49% of term infants remain positive by 5 months of age.

A study in southern California(14) demonstrated a seroconversion of 27.3% at 7 months, 45.4% at 8 months, 69.2% at 9 motnhs, 72.7% at 10 months and 82.2% at 11 months. This series had not studied preterm infants before 6 months of age. However, extrapolating backwards, it can be assumed that seroconversion at ages less than 7 months would be lower than 27.3%. In contrast, in the present study, we observed that 97% of preterms were seronegative by 5 months and we expect all these infants to seroconvert if vaccinated at this age. Although both the studies confirm the view that early interruption of intrauterine life in the preterm infant is likely to affect maternal IgG transfer, the timing of the fall is different in the two studies. Again, this difference may be explained by the fact that the former study had been undertaken in a developed country, while the present study was carried out in a developing country where the fall of maternal antibody level is postulated to occur faster(19).

However, very few studies have been conducted on preterm infants. In one such study in Chicago(20), it was demonstrated that 26% of preterm infants were seronegative at 3 months. In our study, 97% were seronegative by 5 months of age. This difference can be attributed to the fact that this study has been conducted in a developed country where the rate of waning of maternal antibody is slower than in a developing country. The authors also found that the amount of antibody transferred in preterm neonates at 37 weeks was significantly lower (p <0.005) than the amount of antibody transferred in full term infants. They concluded that gestational age was the single most important factor in transplacental antibody transfer between mother and child. In the present study, no statistically significant difference was noted in the maternal antibody transfer in term and preterm infant at birth as well as in the two groups of preterm infants of 28-32 weeks and 33-36 weeks, though quantitatively, samples from preterm infants showed larger number of weakly positive results as compared to those from term babies. Therefore, from the present study, it can be derived that, though important, gestational age is not the only factor affecting tansplacental antibody transfer and it is postulated that the level of antimeasles antibody present in the mother at the time of delivery, besides maternal age, birth weight of the baby and naturally acquired vaccine induced immunity in the mother may also be significant factors affecting the same. Further studies to evaluate the importance of each factor would be required.

Further, in this study, it was found that there is a statistically significant decline in the antimeasles IgG antibody levels between birth and five months in preterm infants but not in term infants as seen by the decline in optical density readings. It was also found that at 5 months of age, 97% of preterm infants were seronegative in contrast to only 51% of term infants. The fall in maternally derived antibodies in term and preterm infants occurs due to normal catabolism of the antibodies with the passage of time. The time taken for the decay of these antibodies is directly proportional to the extent of initial titres at birth and these preterms may become seronegative much earlier. The early decay of maternal IgG in preterm infants could be due to the fact that preterm infants are often sick and repeated blood sampling for diagnostic tests in them results in the removal of antibody containing plasma and replacement by packed RBC’s does not replace the antibody loss. Additionally, the higher incidence of sepsis in sick preterms and the hyper catabolic state in this condition could cause faster catabolism of these antibodies in these infants(21). However, these aspects were minimized in this study by eliminating those infants who fell sick in the postnatal period.

Regarding the optimal age of immunization of these infants, we have seen that at 5 months of age, 97% of preterm infants and 51% of term infants are likely to seroconvert. The vaccination failure rate thus would be 3% and 49% for preterms and terms infants, respectively. Presently, the vaccina-tion failure rate at 9 months in developing countries is about 5-10%(17). For successful uptake of vaccine, two conditions should be fulfilled. Firstly, maternal antibodies should be absent and/or should not interfere with uptake. Secondly, the immune system of the patient must be capable of mounting an adequate immune response. We have already seen in the present study that most preterm infants lose their maternal antimeasles antibody by 5 months of age. As far as the second factor is concerned, Pabst et al.(22) have pointed out that the capacity to produce antibodies to a variety of antigens increases as a function of age. Thus, it is possible that an immature immune system would cause diminished antibody response to measles vaccine in preterm infants. However, a few studies on the response of preterm infants to other vaccines like Rubella and Varicella(19,21,23) have demonstrated that by about 4 months of age, the response of preterms was comparable to term infants. This comparable immune response can be explained by the fact that by virtue of their early exposure to extrauterine life, the immune system of a preterm neonate matures rapidly and may be capable of mounting the immunological response required for satisfactory uptake of vaccine(24). Therefore, it is quite possible that the antibody response to vaccine given at 5 months of age would be adequate. However, further studies, which actually demonstrate the presence of pro-tective antibodies after vaccination in these neonates, would be required to corroborate the same.

To conclude, a statistically significant decline in transplacentally transmitted anti-measles antibodies was seen in preterm infants over a period of 5 months after birth unlike in term infants over the same period but no significant correlation in statistical terms was observed between gestational age and antibody status.

The authors wish to thank Maj. Gen. B.M. Aiyanna, Commandant, Army Hospital (R&R) and Lt. Gen. R. Jayasawal, DGAFMS for their able guidance and constant encouragement in completing the study.

Contributors: ATKR designed the study, selected the patients, interpreted the results and drafted the manuscript; he will act as guarantor for the paper. AD collected the samples, analyzed them and helped in interpreting the results and drafting the final paper. CGW helped in interpreting the data and drafting the paper. GSC carried out the tests, PKS coordinated and supervised the study.

Funding: Armed Forces Medical Research Committee, Project 89/90.

Competing interests: None stated.

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