Foetal haemoglobin concentration at postmenstrual age is unaffected by gestational age at birth

Abstract

Background

Our aim was to determine whether the postnatal age or postmenstrual age is a more appropriate criterion for evaluating foetal haemoglobin concentrations.

Methods

Blood samples (n = 1095) were obtained from 394 infants and were divided into two groups based on gestational age at birth: <37 weeks (n = 491) and ≥37 weeks (n = 604). (1) Foetal haemoglobin concentrations divided by one month at age after birth were compared between the groups. (2) Foetal haemoglobin concentrations divided into ≤9 months from last menstruation and one month thereafter were compared between the groups.

Results

In samples from infants ≥37 weeks’ gestational age at birth, the median foetal haemoglobin concentrations were 69.5%, 21.4% and 3.6% at 0–1 month, 2–3 months and ≥5 months after birth, respectively. The median foetal haemoglobin concentrations in infants <37 weeks’ gestational age at birth were 75.5%, 62.7% and 5.1% at 0–1 month, 2–3 months and ≥5 months after birth, respectively. The median foetal haemoglobin concentrations in infants <37 weeks’ gestational age at birth were significantly higher than that in infants ≥37 weeks’ gestational age at birth at all postnatal age points. (2) There was no significant difference between the groups at all age points after nine months of postmenstrual age: 72.5 and 75.3% at 9–10 months, 25.1 and 26.6% at 11–12 months and 5.5 and 4.6% at >13 months after last menstruation in infants ≥37 and <37 weeks’ gestational age at birth, respectively.

Conclusions

Evaluation of foetal haemoglobin concentrations at postmenstrual age is unaffected by gestational age at birth.

Introduction

Foetal haemoglobin (HbF) is present in the blood of foetuses and neonates. The concentration of HbF in the blood gradually decreases after birth and is replaced with adult haemoglobin ¹ ; at six months after birth, HbF accounts for less than 1% of the total haemoglobin. HbF is reportedly elevated in chronic lung diseases and sudden infant death syndrome.^2,3 HbF concentrations could therefore be used as a predictive marker for these diseases. However, an established criterion for the HbF concentrations does not exist, because HbF concentrations at various postnatal ages show variations due to the gestational age (GA, a time elapsed between the first day of the last menstrual period and the day of delivery) at birth. ⁴ In the present study, we assessed whether the postnatal age or postmenstrual age (PMA, gestational age plus chronological age that is a time elapsed from birth) is more appropriate as a criterion for determining the HbF concentration.

Materials and methods

Blood samples (n = 1095) that were collected from 394 infants <12 months of age were analysed. No infants with sudden infant death syndrome and chronic lung disease that required home oxygen therapy were included. Infants with congenital diseases or after blood transfusion were excluded in this study, as these conditions could have influenced the HbF concentration. The blood samples were divided into the following two groups based on the GA at birth: <37 weeks (n = 491) and ≥37 weeks (n = 604). The HbF concentrations divided by one month at age after birth were compared between the groups. Additionally, the HbF concentrations divided into ≤9 months from last menstruation and one month thereafter were compared between the groups. Statistical analyses were performed using the Mann–Whitney U test. Differences were determined to be statistically significant when P < 0.05.

PMA and GA at birth were calculated from the last menstrual period and corrected by sonographic foetal measurement data, if needed.

HbF concentrations in all samples were measured by high-performance liquid chromatography using an ADAMS A1c HA-8180T (Arkray Inc., Japan) with the appropriate calibration based on the manufacture’s recommendation. The results of intra-day assay (n = 20) using a sample with a mean HbF value of 4.67% and inter-day assay (n = 20) using a sample with a mean HbF value of 4.93% gave coefficients of variation of 0.2% and 0.4%, respectively (Supplementary Table).

Results and discussion

Patient background

The median (range) of GA at birth and the birth weight of the infants were 36 (22–41) weeks and 2541 (478–4176) g, respectively. The preterm and term groups had a GA at birth of 32 (22–36) and 38 (37–41) weeks, respectively, and birth weight of 1834 (478–3460) and 2996 (2320–4176) g, respectively. The median postnatal HbF concentration at 0–1 month after birth was 72.0% regardless of GA at birth.

HbF concentrations at postnatal age

HbF concentrations at postnatal age are shown in Figure 1(a) and (c). In samples from infants ≥ 37 weeks’ GA at birth, the median HbF concentration was 69.5% at 0–1 month after birth, and gradually declined thereafter, measuring 10.9% at 4–5 months and 3.6% at ≥5 months after birth. Colombo et al. ¹ reported that the mean HbF concentration obtained using electrophoresis in 30 samples of umbilical cord blood in full-term infants was 64.8%, which was close to our result in spite of the different materials and different measurement methods used. The mean HbF concentration decreased to approximately 5% by five months of age. ¹ Garby et al. ⁵ also measured HbF concentrations from 0 to 140 days after birth in 19 infants ≥37 weeks’ GA at birth and found that the HbF concentration was 50–60% immediately after birth and decreased to approximately 5% at 100–140 days after birth. These are similar to the results obtained in our study. In samples from infants <37 weeks’ GA at birth, the median HbF concentrations were 75.5% at 0–1 month after birth, 28.2% at 4–5 months and 5.1% at ≥5 months after birth. The decrease in the HbF concentrations was delayed compared with those of infants ≥37 weeks’ GA at birth. The HbF concentration of an infant with 22 weeks’ GA at birth was approximately 30% even at six months of age (the value was over the reference range, as seen in Figure 1(a) and within the reference range, as seen in Figure 1(b)). Cottom ⁴ has shown that the HbF concentrations in umbilical cord blood are higher in infants with a lower GA. Our results also show that the HbF concentrations in infants <37 weeks’ GA at birth were significantly higher than those in infants with a GA at birth ≥37 weeks. These findings suggest that the HbF concentrations at a certain postnatal age can have variations due to the GA at birth.

Figure 1.

(a) Plots and reference ranges of HbF concentration at postnatal age. (b) Plots and reference ranges of HbF concentration at postmenstrual age. (c): HbF concentrations at postnatal age and postmenstrual age in infants <and ≥37 weeks’ GA at birth. Data are shown as median (range).

HbF concentrations at PMA

The HbF concentrations at PMA are shown in Figure 1(b) and (c). When we compared HbF concentrations between in infants with GA at birth ≥ and <37 weeks, there was no statistically significant difference between them at the age points after the PMA of nine months. The HbF concentrations at PMA were not affected by the GA at birth, which confirms the report by Colombo et al. ¹ Our results are compatible with those of a previous animal study, in which it was confirmed that the switching from foetal to adult haemoglobin production occurred at a time related to the postmenstrual age. ⁶

Conclusion

The HbF concentrations at the postnatal age are higher when the GA at birth is low. However, the HbF concentrations at the PMA did not differ according to the GA at birth. Therefore, it is better to evaluate the HbF concentration using the PMA rather than using the postnatal age.