newborn screening in southeastern europe

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Newborn screening in southeastern Europe Urh Groselj a , Mojca Zerjav Tansek a , Andraz Smon a , Natalija Angelkova b , Dana Anton c , Ivo Baric d,v , Maja Djordjevic e , Lindita Grimci f , Maria Ivanova g , Adil Kadam h , Vjosa Mulliqi Kotori i , Hajrija Maksic j , Oana Marginean k , Otilia Margineanu l , Olivera Milijanovic o , Florentina Moldovanu m , Mariana Muresan n , Simona Murko a , Michaela Nanu m , Barbka Repic Lampret a , Mira Samardzic o , Vladimir Sarnavka d , Aleksei Savov g , Maja Stojiljkovic p , Biljana Suzic q , Radka Tincheva h , Husref Tahirovic r , Alma Toromanovic s , Natalia Usurelu t , Tadej Battelino a,u, a University Children's Hospital Ljubljana, UMC Ljubljana, Ljubljana, Slovenia b University Children's Hospital Skopje, Skopje, Macedonia c Clinical Hospital for Children Sfanta Maria, Iasi, Romania d Department of Pediatrics, University Hospital Center Zagreb, Zagreb, Croatia e Mother and Child Health Care Institute of Serbia, Belgrade, Serbia f University Hospital Center Mother Teresa, Tirana, Albania g National Genetics Laboratory, Soa, Bulgaria h University Pediatric Hospital Soa, Soa, Bulgaria i Pediatric Clinic, University Clinical Center Pristina, Pristina, Kosovo j University Clinical Center Sarajevo, Sarajevo, Bosnia and Herzegovina k Clinical Hospital of Targu Mures, Romania l Clinical Hospital for Children Luis Turcanu, Timisoara, Romania m Mother and Child Health Care Institute Alfred Rusescu, Bucharest, Romania n Clinical Hospital for Children Iuliu Hateganu, Cluj-Napoca, Romania o Institute for Sick Children, Clinical Center of Montenegro, Podgorica, Montenegro p Institute of Molecular Genetics and Genetic Engineering, University of Belgrade, Belgrade, Serbia q Children Hospital Banja Luka, Banja Luka, Republic of Srpska, Bosnia and Herzegovina r Department of Medical Sciences, Academy of Sciences and Arts of Bosnia and Herzegovina, Sarajevo, Bosnia and Herzegovina s Department of Pediatrics, University Clinical Center Tuzla, Tuzla, Bosnia and Herzegovina t Institute of Mother and Child, Centre of Reproductive Health and Medical Genetics, Chisinau, Republic of Moldova u Department of Pediatrics, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia v University of Zagreb, School of Medicine, Zagreb, Croatia abstract article info Article history: Received 16 July 2014 Received in revised form 21 July 2014 Accepted 22 July 2014 Available online 1 August 2014 Keywords: Newborn screening Survey Southeastern Europe The aim of our study was to assess the current state of newborn screening (NBS) in the region of southeastern Europe, as an example of a developing region, focusing also on future plans. Responses were obtained from 11 countries. Phenylketonuria screening was not introduced in four of 11 countries, while congenital hypothyroidism screening was not introduced in three of them; extended NBS programs were non-existent. The primary challenges were identied. Implementation of NBS to developing countries worldwide should be considered as a priority. © 2014 Elsevier Inc. All rights reserved. 1. Introduction Newborn screening (NBS) programs were rst introduced around 50 years ago, based on a groundbreaking work of Dr. Robert Guthrie [1]. Currently, NBS is a well established practice in most developed countries worldwide, while it is less uniformly implemented in devel- oping countries, which represent most of the southeastern Europe [211]. Timely identication and appropriate measures in the case of a positive screening result can help in reducing disabilities and even mor- talities in the affected newborns [12,13]. With the right choice of screened disorders NBS is clearly cost-effective, also in the context of a developing country [1416]. A NBS program consists of six components: screening test, short term follow-up, diagnosis, treatment, management and evaluation [17]. Molecular Genetics and Metabolism 113 (2014) 4245 Corresponding author at: University Children's Hospital Ljubljana, UMC Ljubljana, Ljubljana, Slovenia. Fax: +386 1 2320190. E-mail address: [email protected] (T. Battelino). http://dx.doi.org/10.1016/j.ymgme.2014.07.020 1096-7192/© 2014 Elsevier Inc. All rights reserved. Contents lists available at ScienceDirect Molecular Genetics and Metabolism journal homepage: www.elsevier.com/locate/ymgme

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Molecular Genetics and Metabolism 113 (2014) 42–45

Contents lists available at ScienceDirect

Molecular Genetics and Metabolism

j ourna l homepage: www.e lsev ie r .com/ locate /ymgme

Newborn screening in southeastern Europe

Urh Groselj a, Mojca Zerjav Tansek a, Andraz Smon a, Natalija Angelkova b, Dana Anton c, Ivo Baric d,v,Maja Djordjevic e, Lindita Grimci f, Maria Ivanova g, Adil Kadam h, Vjosa Mulliqi Kotori i, Hajrija Maksic j,Oana Marginean k, Otilia Margineanu l, Olivera Milijanovic o, Florentina Moldovanu m, Mariana Muresan n,Simona Murko a, Michaela Nanu m, Barbka Repic Lampret a, Mira Samardzic o, Vladimir Sarnavka d,Aleksei Savov g, Maja Stojiljkovic p, Biljana Suzic q, Radka Tincheva h, Husref Tahirovic r, Alma Toromanovic s,Natalia Usurelu t, Tadej Battelino a,u,⁎a University Children's Hospital Ljubljana, UMC Ljubljana, Ljubljana, Sloveniab University Children's Hospital Skopje, Skopje, Macedoniac Clinical Hospital for Children “Sfanta Maria”, Iasi, Romaniad Department of Pediatrics, University Hospital Center Zagreb, Zagreb, Croatiae Mother and Child Health Care Institute of Serbia, Belgrade, Serbiaf University Hospital Center “Mother Teresa”, Tirana, Albaniag National Genetics Laboratory, Sofia, Bulgariah University Pediatric Hospital Sofia, Sofia, Bulgariai Pediatric Clinic, University Clinical Center Pristina, Pristina, Kosovoj University Clinical Center Sarajevo, Sarajevo, Bosnia and Herzegovinak Clinical Hospital of Targu Mures, Romanial Clinical Hospital for Children “Luis Turcanu”, Timisoara, Romaniam Mother and Child Health Care Institute “Alfred Rusescu”, Bucharest, Romanian Clinical Hospital for Children “Iuliu Hateganu”, Cluj-Napoca, Romaniao Institute for Sick Children, Clinical Center of Montenegro, Podgorica, Montenegrop Institute of Molecular Genetics and Genetic Engineering, University of Belgrade, Belgrade, Serbiaq Children Hospital Banja Luka, Banja Luka, Republic of Srpska, Bosnia and Herzegovinar Department of Medical Sciences, Academy of Sciences and Arts of Bosnia and Herzegovina, Sarajevo, Bosnia and Herzegovinas Department of Pediatrics, University Clinical Center Tuzla, Tuzla, Bosnia and Herzegovinat Institute of Mother and Child, Centre of Reproductive Health and Medical Genetics, Chisinau, Republic of Moldovau Department of Pediatrics, Faculty of Medicine, University of Ljubljana, Ljubljana, Sloveniav University of Zagreb, School of Medicine, Zagreb, Croatia

⁎ Corresponding author at: University Children's HosLjubljana, Slovenia. Fax: +386 1 2320190.

E-mail address: [email protected] (T. Battelin

http://dx.doi.org/10.1016/j.ymgme.2014.07.0201096-7192/© 2014 Elsevier Inc. All rights reserved.

a b s t r a c t

a r t i c l e i n f o

Article history:Received 16 July 2014Received in revised form 21 July 2014Accepted 22 July 2014Available online 1 August 2014

Keywords:Newborn screeningSurveySoutheastern Europe

The aim of our study was to assess the current state of newborn screening (NBS) in the region of southeasternEurope, as an example of a developing region, focusing also on future plans. Responses were obtained from 11countries. Phenylketonuria screeningwas not introduced in four of 11 countries, while congenital hypothyroidismscreening was not introduced in three of them; extended NBS programs were non-existent. The primarychallenges were identified. Implementation of NBS to developing countries worldwide should be considered asa priority.

© 2014 Elsevier Inc. All rights reserved.

1. Introduction

Newborn screening (NBS) programs were first introduced around50 years ago, based on a groundbreaking work of Dr. Robert Guthrie[1]. Currently, NBS is a well established practice in most developed

pital Ljubljana, UMC Ljubljana,

o).

countries worldwide, while it is less uniformly implemented in devel-oping countries, which represent most of the southeastern Europe[2–11]. Timely identification and appropriate measures in the case of apositive screening result can help in reducing disabilities and evenmor-talities in the affected newborns [12,13]. With the right choice ofscreened disorders NBS is clearly cost-effective, also in the context of adeveloping country [14–16]. ANBS program consists of six components:screening test, short term follow-up, diagnosis, treatment, managementand evaluation [17].

Table 1Demographics and newborn screening program characteristics in southeastern Europe.

Total pop.(Mil.)

GDP per cap.in 2012 (USD)

Screened/allNb in 2012

No. ofscreeningcenters

Diseases mandatoryscreened(y of introduction)

Age whenscreened(h)

Lab. methodsin NBSP

NBSP costs(per Nb)

Plans to expandNBSP in next 5 y

Which diseasesplanned to beadded to NBSP

Main obstacle(s)perceived inexpanding NBSP

Perceived urgencyof expanding NBSP(5 = highest;1 = lowest)a

Albania 2.83 9403 −/35,295 0 None – – – Yes CH; PKU FR; LW 5Bosnia–Federation ofBosnia and Herzegovina(without Sarajevo)

2.07 9392b 16,915/nd 1 CH (2005); PKU(2005)d

48–96 D (CH); F(PKU)

8 EUR In 2 y CAH; CF FR 3

Bosnia–Rep. of Srpska 1.33 9392b 9907/9978 1 CH (2007); PKU(2007)e

48–72 D (CH); F(PKU)

8 EUR In 3–4 y CAH, CF, GALT FR; SI; LM; 4

Bosnia–Sarajevo 0.44 9392b 5152/nd 1 CH (2000); PKU(2006)

24 (96 ifCS)

D (CH); F(PKU)

12 EUR In 1 y CF FR; O; LS 2

Bulgaria 7.36 16,041 62,496/69,121 1 CH (1993); PKU(1979); CAH(2010)

72 D (CH); F(PKU)

3 EUR After 2 y CF FR; LS; LM 3

Croatia 4.28 20,961 41,606/41,700 1 CH (1985); PKU(1986)f

72 D (CH); G(PKU)

5 EUR In 1 y CUD; GA1;IVA; LCHADD;MSUD;MCADD;VLCADD;

FR 5

Kosovo 1.74 8436 −/34,262 0 None – – – In 1 y First CH; laterPKU, CAH

FR; O 5

Macedonia 2.06 11,834 nd/23,752 1 CH (2002) 48–96 D (CH) b2 EUR Np Np nd 4Moldova 3.50 4219 36,654/39,641 1 CH (1989–1993);

PKU (1989)N48 D (CH); F

(PKU)1 EUR In 1 y CH (again) FR; LS 5

Montenegro 0.63 14,358 −/8156 1 CH (2007) 48–96 D (CH) 1.6 EUR Np – FR; SI; LS 4Romania 18.91 18,063 159,039/

201,1045 CH (1979); PKU

(1979; wholecountry 2011)

48–72 D (CH); F(PKU)

2.5 EUR In 2 y GALT, CAH FR; LS 3

Serbia 7.18 11,801 52,094/67,257c 2 CH (1983); PKU(1983)

48–72 D (CH); F(PKU)

4 EUR Np Np FR; LS; O 4

Slovenia 2.05 28,476 21,888/21,938 1 CH (1981)PKU (1979)g

48–72 D (CH); F(PKU)

10.6 EUR In 3 y GA I; IVA;LCHADD;MCADD;MSUD;VLCADD

FR; O; LW 5

List of abbreviations: h—hours; cap.—capita; Lab.—laboratory; NBSP—newborn screening program; No.—number; Mil.—millions; Nb—newborn; Np—not planned; nd—no data; CW—country wide; FR—financial resources; LS—lack of staff; O—organization; LM—latermanagement; SI—small incidences; LW—lack of (political)will; y—year; CS—cesarean section; D—Delfiamethod; F—fluorimetricmethod; G—Guthrie's test; CAH—congenital adrenal hyperplasia; CH—congenital hypothyroid-ism; CF—cystic fibrosis; CUD—carnitine uptake defect; GALT—classic galactosemia; GAI—glutaric acidaemia type I; IVA isovaleric acidaemia (IVA)/2-methylbutyrylglycinuria; LCHADD—long-chain L-3-hydroxyacyl-CoA dehydrogenase deficiency/trifunctional protein; MCADD—medium-chain acyl-CoA dehydrogenase deficiency; MSUD—maple syrup urine disease; PKU—phenylketonuria; VLCADD—very long-chain acyl-CoA dehydrogenase deficiency.

a On a scale from 1 to 5; 1 meaning the lowest urgency and 5 the highest urgency.b Data for all Bosnia and Herzegovina.c Number of newborns in Serbia without Vojvodina region in 2012 was 49,325.d CH from 2000 in Tuzla region; PKU from 2001 in Tuzla region.e PKU from 1986 in Banja Luka region.f PKU from 1978 in Zagreb region.g PKU from 1975 in Trbovlje region.

43U.G

roseljetal./Molecular

Genetics

andMetabolism

113(2014)

42–45

44 U. Groselj et al. / Molecular Genetics and Metabolism 113 (2014) 42–45

Successful implementation of all components can be difficult, espe-cially in developing countries and regions. There have been previous re-ports of non-existent screening programs in different regions, forexample in the Asia Pacific region [4], Middle East and North Africa[18], and Latin America [19].

Since scarce data exist on NBS in the region of southeastern Europe,the aim of our study was to assess the current state of NBS in the regionof southeastern Europe (i.e. Balkan Peninsula countries), as an exampleof a developing region, focusing also on future plans.

2. Methods

The survey was performed involving identified professionals from11 countries from southeastern Europe: Albania, Bulgaria, Bosnia andHerzegovina, Croatia, Kosovo, Macedonia, Moldova, Montenegro,Romania, Serbia and Slovenia. A questionnaire was designed to assessthe demographics of each country and main characteristics of its NBSprogram and their plans for the future.

The participantswere identified in threeways: through our previousprofessional cooperation, through a review of existing literature and re-sources, and as suggested by other local professionals. The question-naires were distributed to the participants by e-mail (and also all theresponses were collected by e-mail). The distribution and collection ofthe questionnaires took place from December 2013 to March 2014and final clarifications were received in June and July 2014. A singlecompleted questionnaire was obtained from each country; the only ex-ception was Bosnia and Herzegovina where three separate responses(from Sarajevo Canton, from Federation of Bosnia and Herzegovina,and from Republic of Srpska) were obtained and included due to theircurrent political situation and consequently NBS practice. The responsi-ble participants of survey from each country were listed as coauthors ofthe study.

3. Results

Responses from11 countrieswere included; their cumulative popula-tion was approx. 52.5 million. The GDP per capita ranged from around4000 (Moldova) to 28,000 USD (Slovenia). The number of newbornsin 2012 ranged from 8156 (Montenegro) to 201,104 (Romania). Thenumber of NBS centers ranged from none to five (Romania) (Table 1).

Phenylketonuria (PKU) screening was not introduced in four of 11countries (Albania, Kosovo, Macedonia, Montenegro), while congenitalhypothyroidism (CH) screening was not introduced in three of the 11countries (Albania, Kosovo, Moldova). Screening for congenital adrenalhyperplasia (CAH)was introduced only in Bulgaria. In at least two coun-tries (Bulgaria, Romania) with established NBS over 10% of newbornswere reportedly not screened (Table 1).

Interestingly, the costs of NBS per newborn varied widely, from 1 to12 EUR, with amedian of 4 EUR. No country had introduced an expand-ed NBS program, while a few countries were planning to introduce it inthe following years. A main obstacle perceived in expanding NBS waslack of financial resources. The mean perceived urgency of expandingNBS programwas 4.0 (on a scale from 1 to 5, 5 meaning the highest ur-gency) (Table 1).

The NBS program was country-wide in all the countries exceptBosnia and Herzegovina, where it was regionally organized. In five ofnine countries with any established NBS program, it was financed bytheMinistry of Health (MH), while in the rest it was financed by the na-tional health insurance systems (NHIS) or the financing was combinedby both. Seven of the 11 countries reported not to participate in any in-ternational cooperation program on NBS.

4. Discussion

This was the first study to specifically assess the NBS characteristicsin the region of southeastern Europe, involving 11 countries from the

region, with a cumulative population of approx. 52.5 million. The in-cluded populations are thought to be ethnically and genetically veryheterogeneous. Also the economic backgrounds of the included coun-tries were very heterogeneous, four of the 11 countries had an annualGDP per capita of under 10,000 USD and nine of the 11 countries hadunder 20,000 USD.

All countries that have NBS programs in this region, exceptMoldova, screen for at least CH, most of them also for PKU.Moldova already screened for CH from 1989 to 1993, and plans toscreen for it again in a few years. These were also some of the firstconditions that countries worldwide have started to screen for [1,20,21]. The most worrying fact shown by our survey was that the PKUnewborn screening was not yet introduced in four of the 11 countries,and CH screening in three of 11 countries. In addition, in threeother countries where the NBS program was established over 10% ofnewborns were not screened.

A lot of difficulties were reported with the introduction and subse-quent expansion of NBS. All countries list as themain problem lack of fi-nancial resources, which prevents the purchase of necessary equipmentand reagents. Interestingly, despite the great heterogeneity of the eco-nomic backgrounds of the included countries, some of the countrieswith the lowest annual GDP per capita (as Moldova) maintained betterstandards of NBS as compared to some other countries with relatively 2to 3-times higher annualGDPper capita. Thus, the economic standard ina particular country may not be the only important factor influencingthe state of the NBS program, which we believe was an important andencouraging finding of the study. Interestingly, the reported costs ofNBS varied widely among the countries; the median reported cost pernewborn was 4 EUR.

Most of the included countries had less than 40,000 births annuallywith Montenegro having even less than 10,000. None of them weresending their samples to a NBS center abroad, which could be a possiblesolution for some small European countries like Liechtenstein [6,7].Since many countries reported also a lack of staff and expertise amongthe main obstacles to expand NBS, a very sound possibility could be es-tablishing regional NBS centers, covering at least 50,000 newborns an-nually. However, due to great cultural, political, economic and ethnicheterogeneity of the region, it would seem very difficult for this to beaccomplished.

The developed countries now routinely use tandemmass spectrom-etry (MS/MS) for NBS for inherited errors of metabolism [6,7,22]. Thismethod is very useful for NBS because of its short run time and abilityto screen for several diseases in one run [23]. This enabled a major ex-pansion of screened disorders to up to 30 [6,7]. At this time, none ofthe countries in southeastern Europe usesMS/MS for NBS. In the follow-ing years, only a few countries (Croatia, Romania, Slovenia) reportedplans to implement MS/MS in their NBS programs due to the expectedexpansion of screened diseases.

In conclusion, this was the first study to specifically assess theNBS characteristics in 11 countries from southeastern Europe,showing the region facing important challenges. At least neonatalPKU and CH screenings should be introduced throughout the region.In addition, we firmly believe that implementation of basic standardsof NBS to developing countries worldwide should be considered as apriority. In addition,we firmly believe that implementation of basicstandards 177 of NBS to developing countries worldwide should beconsidered as a 178 priority [24].

Conflict of interest

Authors declare no conflicts of interest.

Acknowledgments

The study was supported in part by the Slovenian National ResearchAgency grants J3-2412, J3-9663 and P3-0343.

45U. Groselj et al. / Molecular Genetics and Metabolism 113 (2014) 42–45

References

[1] R. Guthrie, A. Susi, A simple phenylalanine method for detecting phenylketonuria inlarge populations of newborn infants, Pediatrics 32 (1963) 338–343.

[2] B.L. Therrell, J. Adams, Newborn screening in North America, J. Inherit. Metab. Dis.30 (2007) 447–465.

[3] V. Sarnavka, Novorođenački skrining, Pediatr. Croat. 48 (Suppl. 1) (2004) 197–203.[4] C.D. Padilla, B.L. Therrell, Newborn screening in the Asia Pacific region, J. Inherit.

Metab. Dis. 30 (2007) 490–506.[5] A. Smon, U. Groselj, M.Z. Tansek, A. Bicek, A. Oblak, M. Zupancic, C. Krzisnik, B.R.

Lampret, S. Murko, S. Hojker, T. Battelino, Newborn screening in Slovenia, Zdrav.Vestn. (2014) (in press).

[6] J.G. Loeber, P. Burgard, M.C. Cornel, T. Rigter, S.S. Weinreich, K. Rupp, G.F. Hoffmann,L. Vittozzi, Newborn screening programmes in Europe; arguments and efforts re-garding harmonization. Part 1. From blood spot to screening result, J. Inherit.Metab. Dis. 35 (2012) 603–611.

[7] P. Burgard, K. Rupp, M. Lindner, G. Haege, T. Rigter, S.S. Weinreich, J.G. Loeber, D.Taruscio, L. Vittozzi, M.C. Cornel, G.F. Hoffmann, Newborn screening programmesin Europe; arguments and efforts regarding harmonization. Part 2. From screeninglaboratory results to treatment, follow-up and quality assurance, J. Inherit. Metab.Dis. 35 (2012) 613–625.

[8] H. Tahirovic, A. Toromanovic, Neonatal screening for congenital hypothyroidism inthe Federation of Bosnia and Herzegovina: eight years' experience, Eur. J. Pediatr.168 (2009) 629–631.

[9] H. Tahirovic, A. Toromanovic, History, present and future of laboratory for detectionof congenital metabolic diseases of the Department of Pediatrics in Tuzla,(in Bosnian), Paediatr. Today 1 (2005) 1–9.

[10] M. Samardzic, N. Gligorovic-Barhanovic, N. Popovic, M. Popovic-Samardzic, New-born screening program for congenital hypothyroidism in Montenegro, Paediatr.Today 9 (2013) 158–162.

[11] T. Battelino, C. Krzisnik, K. Pavlin, Early detection and follow up of children withphenylketonuria in Slovenia, Zdrav. Vestn. 63 (1994) 25–28.

[12] C.D. Van Karnebeek, S. Stockler, Treatable inborn errors of metabolism causing intel-lectual disability: a systematic literature review, Mol. Genet. Metab. 105 (2012)368–381.

[13] B. Wilcken, M. Haas, P. Joy, V. Wiley, F. Bowling, K. Carpenter, J. Christodoulou, D.Cowley, C. Ellaway, J. Fletcher, E.P. Kirk, B. Lewis, J. McGill, H. Peters, J. Pitt, E.Ranieri, J. Yaplito-Lee, A. Boneh, Expanded newborn screening: outcome inscreened and unscreened patients at age 6 years, Pediatrics 124 (2009)241–248.

[14] A.E. Carroll, S.M. Downs, Comprehensive cost-utility analysis of newborn screeningstrategies, Pediatrics 117 (2006) 287–295.

[15] L.E. Cipriano, C.A. Rupar, G.S. Zaric, The cost-effectiveness of expanding newbornscreening for up to 21 inherited metabolic disorders using tandem mass spec-trometry: results from a decision-analytic model, Value Health 10 (2007)83–97.

[16] E. Sladkevicius, R.J. Pollitt, A. Mgadmi, J.F. Guest, Cost effectiveness of establishing aneonatal screening programme for phenylketonuria in Libya, Appl. Health Econ.Health Policy 8 (2010) 407–420.

[17] Serving the family from birth to the medical home. Newborn screening: a blueprintfor the future - a call for a national agenda on state newborn screening programs,Pediatrics 106 (2000) 383–427.

[18] A.A. Saadallah, M.S. Rashed, Newborn screening: experiences in theMiddle East andNorth Africa, J. Inherit. Metab. Dis. 30 (2007) 482–489.

[19] G.J. Borrajo, Newborn screening in Latin America at the beginning of the 21st century,J. Inherit. Metab. Dis. 30 (2007) 466–481.

[20] R.A. MacCready, M.G. Hussey, Newborn phenylketonuria detection program inMassachusetts, Am. J. Public Health Nations Health 54 (1964) 2075–2081.

[21] E. Harms, B. Olgemöller, Neonatal screening for metabolic and endocrine disorders,Dtsch. Arztebl. Int. 108 (2011) 11–21.

[22] H.L. Levy, Newborn screening by tandemmass spectrometry: a new era, Clin. Chem.44 (1998) 2401–2402.

[23] D.H. Chace, Mass spectrometry in newborn and metabolic screening: historicalperspective and future directions, J. Mass Spectrom. 44 (2009) 163–170.

[24] U. Groselj, M. Zerjav Tansek, T. Battelino, Fifty years of phenylketonuria newbornscreening—A great success for many, but what about the rest? Mol. Genet. Metab.113 (2014) 11–13.