Discussion

This case highlights the therapeutic dilemma of managing pregnancy in women receiving burosumab for XLH. Evidence for continued burosumab administration during pregnancy is extremely limited. While the current guidelines make a conditional recommendation for conventional therapy during pregnancy, they emphasize the importance of shared decision-making because of a lack of sufficient evidence. The patient's history of severe orthopedic complications as well as the risk of symptomatic rebound influenced our decision to continue burosumab treatment. Burosumab's efficacy in improving patient-reported outcomes such as pain and stiffness is well-established, and discontinuing it may severely compromise maternal caretaking capacity.

A striking finding was the neonate's transient, markedly elevated FGF23 level (48 700 pg/mL [SI: 1933 pmol/L]). Burosumab is an IgG1 antibody known to cross the placenta, particularly in the third trimester. We hypothesize that the extremely high FGF23 concentration is due to a combination of transplacental transfer of burosumab, which stabilizes circulating FGF23 by forming antibody-antigen complexes, and intrinsic FGF23 overproduction caused by the infant's inherited PHEX mutation. The mechanism for this elevation is likely the formation of burosumab-FGF23 immune complexes. Studies have demonstrated that burosumab binds to FGF23, preventing its degradation and clearance, resulting in an increase in total/intact FGF23 levels measured by immunoassays [8]. Furthermore, recent studies indicate that the presence of burosumab can interfere with certain commercially available FGF23 assays, resulting in markedly elevated values that do not necessarily reflect biologically active free FGF23 [9]. As a result, serial FGF23 measurements in this infant were not designed to provide a definitive assessment of disease activity. Rather, since burosumab was not administered after birth, we reasoned that the temporal decline in FGF23 levels might provide supportive information about the decreasing influence of maternally derived burosumab and help inform future treatment decisions.

The decrease of FGF23 to 151 pg/mL (SI: 6.0 pmol/L) over 7 months corresponds to the expected clearance of maternal IgG from the neonatal circulation. The persistence of elevated FGF23 at 7 months reflects the infant's intrinsic overproduction caused by an inherited PHEX mutation. Importantly, despite the in utero exposure and biochemical abnormalities, the infant did not experience adverse skeletal events, such as craniosynostosis, which has been reported in XLH [10]. The start of burosumab at 8 months was well-tolerated. Recent phase 3 trials and real-world data have demonstrated the safety and efficacy of burosumab in young children [11]. Although there were no obvious adverse skeletal findings observed during the first year of life, these findings should not be interpreted as proof of the efficacy of prenatal burosumab exposure. Interpretation of postnatal growth is limited as growth retardation in XLH is typically not visible during early infancy. Whether these findings apply to pregnancies in which the fetus does not inherit XLH is unclear. Therefore, the absence of short-term adverse outcomes does not guarantee safety, and careful neonatal monitoring is still necessary. Long-term follow-up is required to determine the significance of prenatal burosumab exposure.