Newborn screening for sickle cell disease assessed by IQWiG in Germany

On behalf of the Federal Joint Committee (G-BA), the Institute for Quality and Efficiency in Health Care (IQWiG) investigated whether a systematic test of newborns for sickle cell disease (SCD) in Germany would make sense.

The hereditary SCD affects the red blood pigment hemoglobin, which transports the oxygen in the blood: by genetic changes of hemoglobin, the red blood cells deform in a sickle-shaped way and disintegrate faster than healthy cells. This leads to anemia, poor blood circulation of the body, and clogged blood vessels. As a result, essential organs, and also the defense reaction of the body are chronically damaged up to a fluid loss, lack of oxygen, fever, and infections, which can also lead to death. However, the disease is asymptomatic until about the third month of life.

Especially children in the first years of life are very susceptible to life-threatening infections. Therefore, the goal of neonatal screening on SCD is to identify and treat the affected children as early as possible. The German guideline of the consortium of the Society of Pediatric Oncology and Hematology (GPOH) therefore recommends not only preventive behavioral measures for SCD treatment (such as informing the parents about signs and the correct reaction to acute complications), but also a prophylaxis against infection including vaccinations and a lifelong structured long-term monitoring and treatment of those affected.

A systematic literature search was carried out in the databases MEDLINE, Embase, and Cochrane Central Register of Controlled Trials. In parallel, a search for relevant systematic reviews in the databases MEDLINE, Embase, Cochrane Database of Systematic Reviews and HTA Database was carried out.

As a result, 1 study (1 document) regarding the screening chain and for a separate assessment of appropriate diagnostic test procedures, 8 studies (9 documents) were identified as relevant. No ongoing studies have been identified.

Results - mortality:

• According to the King 2007 study, in the intervention group (neonatal screening for SCD in combination with an advanced diagnosis and with further intervention), 0.01% of newborns died from SCD-S / S (homozygous SCD) by the age of 1, compared to 0.10% in the comparison group (no screening strategy or diagnosis without further measures). There was a clear group difference and a dramatic effect with an odds ratio of 0.09 (95% CI [0.03, 0.30]) and a p-value <0.001. This can be used to derive an indication of benefit in favor of neonatal screening for SCD in combination with advancing the diagnosis and other intervention measures compared to no screening
• The data in the 2nd and 3rd year of life showed a mortality rate of 0.01% in the intervention group, whereas in the comparison group it increased to 0.14% (2nd year of life) and 0.17% (3rd year of life). The respective odds ratios for the group difference were, each with p-values <0.001, up to the 2nd year of age at 0.06 (95% CI [0.02, 0.20]) and up to the 3rd year of age at 0, 04 (95% CI [0.02, 0.15]). The results up to the age of 5 years also show a dramatic effect. The mortality rate was 0.02% in the intervention group and 0.19% in the comparison group. The odds ratio for the group difference was 0.09 (95% CI [0.04, 0.22]) with a p-value <0.001. The mortality rates up to 10 years of life were not statistically significant

Results – assessment of screening methods:

• No false-positive results were detected in case of the examination via MS / MS (tandem mass spectrometry) (Boemer 2011, Lobitz 2018; PPV 100, 95% CI: [78.5 and 64.6, 100], respectively), HPLC (high performance liquid chromatography) Colombatti 2019, Grosse 2016, Lobitz 2014; PPV 100, 95% CI: [51.0, 64.6, and 78.5, respectively] 100]) and IEF (isoelectric focusing) (Lin 2004; PPV 100; 95% CI: [20.7; 100] in a positive tested newborns) methods
• The ELISA (enzyme-linked immunosorbent assay) method (Boemer 2006; PPV 2.4, 95% CI: [0.8, 6.8]) and a PCA (principal component analysis analysis) (Kunz 2016; PPV 3.2, 95% CI: [1.1; 9,0]) showed false-positive results in the 2 included studies
• However, due to the small number of newborns studied per study, the significance of the PPV was very limited. A pooled effect cannot be calculated due to the different index tests
• The endpoint mortality results indicated a benefit of newborn screening on SCD in combination with advanced diagnosis and treatment compared to no SCD screening. The results of the diagnostic grade studies show (Shafer 1996, Soares 2012, Sommet 2016, Streetly 2008, Streetly 2009, Telfer 2007) that the MS / MS method and HPLC are suitable for identifying newborns with SCD.

Therefore, the positive predictive value (PPV) of individual studies indicates that there are tests with high specificity: MS / MS and HPLC: all identified babies in these procedures were actually affected by SCD.

SCD can be diagnosed with a simple blood sample - as well as the other target diseases that are already integrated into the German Newborn Screening according to the Children's Guideline of the G-BA: At the 36th to 72nd hour of life a blood sample of the newborn is taken and examined for various diseases. The SCD test could, thus, easily be included in the analysis.

According to a survey based on routine data from AOK-insured children of the birth cohorts 2009 and 2010, early diagnosis of SCD in the first or second quarter of life is currently only available in 15.4% of cases in Germany. In the US, England, France, Spain, the Netherlands and Belgium, newborn screening for SCD has already been established for some time.

The Institute published the preliminary report on newborn screening for SCD in April 2019. In the subsequent commenting process, four comments were added to the final report but did not lead to the conclusion change.

The full report in German can be found here.

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