Pregnancy-specific reference intervals: should we exclude women based on body mass index?

Dear Editor

We read with interest the article by Groenendijk et al., in which normative pregnancy-specific levels are reported for 41 routine haematological and biochemical tests. ¹ We appreciated this well-executed reference study for its rigorous approach to investigating partitioning by gestational age. However, we have concerns about the use of body mass index (BMI) as an exclusion criterion.

Pregnancy is characterised by marked plasma expansion. The relative reduction in platelets, haemoglobin, urea, creatinine, transaminases, B-natriuretic peptide (BNP) and NT-pro BNP (described extensively in the published literature as well as this study) are attributed to haemodilution. Furthermore, women with a raised BMI have a greater degree of plasma expansion and thus more profound haemodilution in some cases.^2,3 In contrast, some markers are significantly elevated in overweight and obese pregnant women despite haemodilution, such as C-reactive protein, which is driven by a greater mass of secretory, pro-inflammatory adipose tissue. ⁴ BMI-specific reference intervals are not established in current clinical practice; very few have been defined and most diagnostic accuracy studies have not been powered to investigate their utility. However, it is increasingly apparent that interpreting tests in the context of BMI is important, particularly for those with extreme body mass indices.

We appreciate the importance of selecting a healthy reference population, which was probably effectively achieved by excluding women with a BMI of 25 kg/m² or more. However, in 2021, 63.5% of adults in England were overweight or obese, ⁵ and this is broadly reflected in the UK pregnant population. Indeed, Ireland (where the study originated) ranks ninth in Europe for obesity with 55% of women classified as overweight or obese. ⁶ Therefore, the results of this study cannot be generalised to around half of the intended target population of White European pregnant women. We propose that, rather than excluding women with a higher BMI in pregnancy-specific reference studies, a pragmatic approach would be to maintain wider selection criteria and to undertake appropriate subgroup analyses.