Assessment of Gestational Age and Birthweight in Patients with Metabolic Conditions Included in CLIR
Biochemical/Metabolic and Therapeutics
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Primary Categories:
- Public Health Genetics
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Secondary Categories:
- Public Health Genetics
Introduction:
Previous studies have suggested that infants with inborn errors of metabolism (IEMs), particularly long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) deficiency and mitochondrial trifunctional protein (MTP) deficiency, are more likely to be born preterm and with low birthweight (BW). Previous analyses assessing the incidence of prematurity in fatty acid oxidation (FAO) disorders and other IEMs have been limited by small sample sizes and/or binning of newborn screening (NBS) disorders into broad IEM categories. This project utilized a large NBS database to evaluate the relationship between LCHAD/MTP deficiency, and other NBS conditions, with gestational age (GA) and BW.
Methods:
Cases included all true FAO disorders, amino acidopathies (AA), organic acidopathies (OA), and urea cycle disorders (UCD) submitted to Collaborative Laboratory Integrated Reports (CLIR; http://clir.mayo.edu) from January 2015 to April 2024 for which age at collection (hours), GA (weeks, w), BW (grams, g), and sex were available. The control group consisted of NBS cases submitted to CLIR as short-chain acyl-CoA dehydrogenase (SCAD) deficiency, SCAD heterozygote, or SCAD polymorphism(s) (n=443). Cases were excluded from analysis if there were <10 cases of a particular IEM. Cases were assigned to preterm and low birthweight (LBW) categories according to the World Health Organization (WHO) designations. Statistical analysis included descriptive statistics, student’s t-tests, and Chi squared tests.
Results:
4,520 cases met the inclusion criteria, including 1,586 FAO disorders, 1,496 AAs, 1,178 OAs, and 260 UCDs. Across all IEM cases reviewed, the mean GA was 39w and BW was 3251g. The GA and BW of infants with an IEM were similar (p>0.05) to the control group (GA 39w, BW 3242g) when analyzed as broad IEM categories: FAO disorders (GA 39w, BW 3289g); AAs (GA 39w, BW 3283g); OAs (GA 39w, BW 3175g); UCDs (GA 39w, BW 3185g). However, when analyzed as individual conditions, LCHAD/MTP deficiency (n=68) was the IEM most notably associated with lower GA (36w; p=3.6x10-7) and BW (2416g; p=8.9x10-12) compared to controls. Of the LCHAD/MTP deficiency cases, 40% (27/68) were born preterm (<37w), inclusive of 15 moderately preterm births (32-37w), 9 very preterm births (28-32w), and 3 extremely preterm births (<28w), while only 10% (44/443) of controls were born preterm (X2=55, p=<1x10-5). Similarly, 49% (n=33/68) had LBW (<2500g), of which 15% (n=5/33) were very LBW (1000-1500g) and 15% (n=5/33) were extremely LBW (<1000g); comparatively, only 7% (n=33/443) of controls exhibited LBW (X2=93, p<1x10-5). The GA and BW of other FAO disorders were similar (p>0.05) to that of controls.
Conclusion:
This study utilized a large dataset to evaluate associations between IEMs, GA, and BW, and suggests that LCHAD/MTP deficiency is most strongly associated with preterm birth and lower BW. These associations were not observed in other FAO disorders, suggesting an underlying disease mechanism specific to LCHAD/MTP deficiency. The association with preterm birth and lower BW in LCHAD/MTP deficiency may be secondary to the pathophysiology of maternal HELLP (hemolysis, elevated liver enzymes, and low platelet count) syndrome and maternal acute fatty liver of pregnancy (AFLP), which are also unique features of this FAO disorder. This study more clearly delineates the incidence and degree of prematurity and LBW in LCHAD/MTP deficiency, which will inform future prenatal counseling efforts for at-risk patients and families. The data analyzed in this study did not include gestational nor maternal history data that potentially contributes to these findings; future work is needed to determine if prematurity and LBW are independent findings in LCHAD/MTP deficiency or more commonly observed in cases with significant pregnancy complications, such as HELLP syndrome and/or AFLP.
Previous studies have suggested that infants with inborn errors of metabolism (IEMs), particularly long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) deficiency and mitochondrial trifunctional protein (MTP) deficiency, are more likely to be born preterm and with low birthweight (BW). Previous analyses assessing the incidence of prematurity in fatty acid oxidation (FAO) disorders and other IEMs have been limited by small sample sizes and/or binning of newborn screening (NBS) disorders into broad IEM categories. This project utilized a large NBS database to evaluate the relationship between LCHAD/MTP deficiency, and other NBS conditions, with gestational age (GA) and BW.
Methods:
Cases included all true FAO disorders, amino acidopathies (AA), organic acidopathies (OA), and urea cycle disorders (UCD) submitted to Collaborative Laboratory Integrated Reports (CLIR; http://clir.mayo.edu) from January 2015 to April 2024 for which age at collection (hours), GA (weeks, w), BW (grams, g), and sex were available. The control group consisted of NBS cases submitted to CLIR as short-chain acyl-CoA dehydrogenase (SCAD) deficiency, SCAD heterozygote, or SCAD polymorphism(s) (n=443). Cases were excluded from analysis if there were <10 cases of a particular IEM. Cases were assigned to preterm and low birthweight (LBW) categories according to the World Health Organization (WHO) designations. Statistical analysis included descriptive statistics, student’s t-tests, and Chi squared tests.
Results:
4,520 cases met the inclusion criteria, including 1,586 FAO disorders, 1,496 AAs, 1,178 OAs, and 260 UCDs. Across all IEM cases reviewed, the mean GA was 39w and BW was 3251g. The GA and BW of infants with an IEM were similar (p>0.05) to the control group (GA 39w, BW 3242g) when analyzed as broad IEM categories: FAO disorders (GA 39w, BW 3289g); AAs (GA 39w, BW 3283g); OAs (GA 39w, BW 3175g); UCDs (GA 39w, BW 3185g). However, when analyzed as individual conditions, LCHAD/MTP deficiency (n=68) was the IEM most notably associated with lower GA (36w; p=3.6x10-7) and BW (2416g; p=8.9x10-12) compared to controls. Of the LCHAD/MTP deficiency cases, 40% (27/68) were born preterm (<37w), inclusive of 15 moderately preterm births (32-37w), 9 very preterm births (28-32w), and 3 extremely preterm births (<28w), while only 10% (44/443) of controls were born preterm (X2=55, p=<1x10-5). Similarly, 49% (n=33/68) had LBW (<2500g), of which 15% (n=5/33) were very LBW (1000-1500g) and 15% (n=5/33) were extremely LBW (<1000g); comparatively, only 7% (n=33/443) of controls exhibited LBW (X2=93, p<1x10-5). The GA and BW of other FAO disorders were similar (p>0.05) to that of controls.
Conclusion:
This study utilized a large dataset to evaluate associations between IEMs, GA, and BW, and suggests that LCHAD/MTP deficiency is most strongly associated with preterm birth and lower BW. These associations were not observed in other FAO disorders, suggesting an underlying disease mechanism specific to LCHAD/MTP deficiency. The association with preterm birth and lower BW in LCHAD/MTP deficiency may be secondary to the pathophysiology of maternal HELLP (hemolysis, elevated liver enzymes, and low platelet count) syndrome and maternal acute fatty liver of pregnancy (AFLP), which are also unique features of this FAO disorder. This study more clearly delineates the incidence and degree of prematurity and LBW in LCHAD/MTP deficiency, which will inform future prenatal counseling efforts for at-risk patients and families. The data analyzed in this study did not include gestational nor maternal history data that potentially contributes to these findings; future work is needed to determine if prematurity and LBW are independent findings in LCHAD/MTP deficiency or more commonly observed in cases with significant pregnancy complications, such as HELLP syndrome and/or AFLP.