Helle Brander Eriksen 2013

In Guinea-Bissau a small thymic size at birth is a predictor for subsequent mortality, but we

lack knowledge of what determines thymic size at birth. In infants, thymic size can easily be

estimated using ultrasound, estimating the so-called thymic index. In high-mortality settings

routine vaccinations, such as the Bacille Calmette-Guérin (BCG) vaccine and measles

vaccine, reduce child mortality more than can be explained by the protection from the

target diseases. The phenomenon is called “non-specific effects”. The non-specific effects of

oral polio vaccine (OPV) and BCG on mortality was being tested in two randomized trials.

The thesis is based on three papers studying determinants thymic size at birth and the effect

of OPV and BCG vaccination at birth on subsequent thymic size. Additionally we studied the

effect of thymic size at birth on mortality and determinants of thymic growth after birth.

To study determinants of thymic size at birth (Paper I), we used a cross-sectional design

enrolling 366 normal birth weight (NBW) and 426 low birth weight (LBW) newborns.

Information on gestational and perinatal exposures was collected from hospital records and

interviews with the mother. Thymic size was measured shortly after birth. Pathological

amniotic fluid was associated with a decreased thymic size in both NBW and LBW infants.

Among NBW infants, male sex was associated with an increased thymic index. Among LBW

infants, birth season, maternal body temperature, antibiotic treatment at the time of labor,

caesarean section, number of pregnancy consultations, maternal age, Apgar score and

infant convulsion were all independent determinants of thymic index but not all

determinants of thymic size relative to weight.

To study determinants of thymic size in the follow-up period we used measurements of

thymic size in 305 NBW and 383 LBW infants who were examined at birth and again at

either 2, 4 or 6 weeks. Hospitalization during the follow-up period was associated with a

decreased thymic growth in both NBW and LBW infants. Among NBW infants, increased

thymic growth was seen in males compared to females and in infants of mothers who had

been drinking alcohol during pregnancy. Among LBW infants, maternal HIV and attendance

of health center consultations were associated with decreased thymic growth.

The effect of OPV and BCG on thymic growth was studied in two randomized trials. In the

OPV study (Paper II) we tested whether not receiving OPV at birth (no-OPV0) was associated

with increased thymic size. 511 NBW infants were randomized to no-OPV0 or OPV0. Thymic

size was measured before randomization and after 2, 4 or 6 weeks. No-OPV0 was not

associated with increased thymic index, but associated with increased thymic index relative

to weight (thymus/weight index) after 2 weeks, but not after 4 or 6 weeks. Results could

indicate that if any effect occurs, it is only within the first weeks after vaccination.

In the BCG study (Paper III) we tested whether early BCG vaccination given to LBW infants

was associated with increased thymic growth. 438 LBW infants were randomized to BCG at

birth (early BCG) or the usual postponed BCG (late BCG). Thymic size was measured before

randomization and after 4 weeks. There was no overall effect of early BCG on thymic

growth, however significantly more infants in the late BCG group died before follow-up,

which may be explained by BCG reducing mortality in the early BCG group. When excluding

infants randomized to late BCG who had received BCG during follow-up, early BCG was

associated with a larger thymic growth in infants above 2 kg.

We confirmed the previous findings of an association between thymic size and mortality. A

large thymic index was associated with decreased mortality until 6 months of age. Overall

thymic index was better at predicting mortality than weight.

In conclusion, several exposures related to stress and infections were associated with

decreased thymic size at birth and decreased thymic growth in the neonatal period. OPV

and BCG vaccination had no clear effects on thymic growth but there may have been a

transient effect of OPV and an effect of BCG in the largest infants.