With these unsettling questions, Dr. Dati expressed a growing sense of unease with the outcomes of newborn screening. The staff saw many patients for whom newborn screening brought diagnostic ambiguity as well as symptomatic patients who did not seem to improve. And for the asymptomatic patients, there was always a lingering suspicion that per- haps these patients would have remained unaffected anyway. What was the public health impact of newborn screening? Are we, as the name of the parent advocacy group suggests, saving babies through screening? The ensuing discussion at the staff meeting offered a refl ective diversion from the standardized case reports typically shared in staff meetings.
Dr. Silverman spoke fi rst. He had the longest career in newborn screen- ing. He explained that from the onset of the expansion, he had known that for the most severe disorders associated with the worst outcomes, such as MMA and propionic acidemia, newborn screening was unlikely to make a difference in outcomes. These conditions were, in his words, “guilty by- standers” of newborn screening. “You may treat these patients a little ear- lier,” he explained, “but it will not change the outcome much.” He added that with “milder” fatty acid oxidation disorders, such as MCADD, the out- comes seem to be better. But, he added, “the jury is still out” on whether some children diagnosed with disorders such as cobalamin C defi ciency, 3- MCC, or carnitine defi ciency truly benefi t because with intervention at an early age, we never know if they would have developed symptoms.
While focusing on the diverse consequences of newborn screening for families and geneticists, we have remained agnostic about the offi cial goal of newborn screening: to save babies through secondary prevention. Most of the immediate consequences of newborn screening do not directly per- tain to lives saved. What stands out in clinic visits is the management of di- agnostic uncertainty when newborn screening raises a red fl ag, or prognos- tic uncertainty in the care of symptomatic infants. Still, for public health offi cials and policymakers, newborn screening constitutes a health policy decision justifi ed by the expectation of a reduction of morbidity and mor- tality. In this chapter, we turn to the lifesaving promise underlying newborn screening. Our starting point is the presumption that newborn screening does not save lives by itself. In the most fortunate of circumstances, new- born screening offers an opportunity for saving lives, but making a dif- ference in health outcomes depends on a mixture of luck and hard work. Complicating causal narratives about newborn screening’s lifesaving po- tential, we will argue that the window of opportunity to save lives may close prematurely due to remaining inequities in the US healthcare system.
study design does not allow us to evaluate the extent to which newborn screening has saved lives. Answering such epidemiological questions would require a different methodology. Because expanded newborn screening was implemented so recently, there is little data about long- term clinical outcomes. Data from pilot studies in the United States and elsewhere sug- gest that while infants diagnosed through newborn screening do experi- ence better health outcomes than those diagnosed clinically, they may still experience signifi cant morbidity and mortality.1 In this chapter, we will
focus on how the opportunity to save lives can be maximized, and point to some recurring barriers. Even then, our analysis is suggestive rather than defi nitive: we have not measured health outcomes but we can point to some social, cultural, and economic factors that likely impact lifesaving.
There are four logical possibilities that link newborn screening to health outcomes, as indicated in table 1. We use “doing well” and “doing poorly” as heuristics to indicate a stable or improving health course and a deterio- rating health trajectory, respectively, recognizing that we are simplifying complex, multicausal processes. First, as Dr. Silverman’s comments at the meeting and the situation of Marisa Hidalgo suggest, some children did poorly despite the advance knowledge provided by newborn screening.2
In such cases, the main effect of newborn screening was to reduce the di- agnostic odyssey once the children developed symptoms, and its inevitable counterpart, a period of “blissful ignorance”3 during which parents could
enjoy their as yet asymptomatic newborns unencumbered by the knowl- edge that their child had a life- threatening condition. As we discussed in the previous chapters, the goal of screening in such cases was to begin treatment promptly, address symptoms vigilantly, and keep the child out of the hospital for as long as possible. Newborn screening advocates hoped that earlier attention to metabolic diseases and a better understanding of their natural histories might lead to more effective therapies in the future. At this point, however, children might die in spite of early detection, as did three infants in our study, including Marisa, who passed away several
table 1. Four possible outcomes of expanded newborn screening
Positive outcome Negative outcome Newborn screening makes
a difference
Child doing well because of NBS
Child doing poorly because of NBS
Newborn screening is incidental
Child doing well regardless of NBS
Child doing poorly regardless of NBS
months after the meeting we described in the beginning of the chapter. Researchers at Children’s Hospital, Boston, also documented four sud- den deaths in children with MCADD, despite identifi cation via newborn screening. As the authors note, “While the frequency of sudden death in MCADD has probably been reduced by NBS it has not been eliminated.”4
Such cautionary tales demonstrate that even with early diagnosis, manag- ing metabolic disorders is not a straightforward clinical task.5
Second, although it is impossible to know for sure without doing a ran- domized controlled trial, there is very likely a corollary at the other end of the lifesaving continuum: children who did well but whose good health might not be attributable to preventive measures. For these children, di- etary regulation and other therapies were likely incidental to favorable outcomes. There is some evidence for this claim because the incidence rates of metabolic disorders have been signifi cantly higher since the imple- mentation of expanded newborn screening, which suggests that many pa- tients with these disorders went undetected prior to population screening and went on to live healthy, symptom- free lives. As we discussed earlier, newborn screening has also lead to the diagnosis of metabolic disorders in asymptomatic mothers who had not been treated for their conditions but nevertheless had done fi ne.
One child in our study who fi t into this category was Paul Wong, a boy diagnosed with GA1. Unlike Bailey Baio and Mike Honan, who had ele- vated metabolite levels with only one mutation, Paul’s mutation analysis identifi ed two mutations implicated in the disease and left no ambiguity that he indeed had the condition. Dr. Silverman explained his situation to a visiting medical student: “Paul was picked up on newborn screen- ing as having glutaric acidemia type 1, and he defi nitely has it. His values, though, are not particularly high, the values of the telltale metabolites, but they were high enough for us to be fairly certain. And some patients, at least intermittently, are completely normal metabolically. We chose to se- quence his glutaric- CoA dehydrogenase genes, and found two presumed pathological indications. . . . So he’s got that. The Wongs sweated for two years. Two years is very important. After two years, damage does not fre- quently occur, at least acute damage, and after four years, virtually never.” Paul had a fraternal twin brother who offered a ready comparison for his development. Based on language development, motor skills, and other developmental landmarks, Paul seemed ahead of his brother, which sug- gested that Paul was “normal.”
The Wongs credited Dr. Silverman with saving their son’s life. They even took a picture of Paul in Dr. Silverman’s arms. Yet Dr. Silverman ex-
pressed reluctance to take credit for saving this child. He explained dur- ing a clinic visit, “We don’t know if newborn screening is preventing any- thing in a kid like Paul. What we know is one thing: it scares the hell out of the parents.” Paul’s mother agreed: “Yeah, it sure did.” Dr. Silverman con- tinued: “I think now with the fact that he’s doing this well and he’s doing as well as his not- identical twin brother and that he hasn’t had any epi- sodes is very reassuring.” Dr. Silverman then added that unlike for PKU, in which every untreated sibling had mental retardation, “from the earli- est days of GA1, we had retarded kids who had normal siblings with the same mutations.” Thus, some children diagnosed with GA1 did well with- out dietary treatment. Dr. Silverman could not be sure whether Paul was one of them or whether he did well because of the treatment. As Dr. Dati observed dryly in a meeting, “The kids with nondisease usually do fi ne.”
A logical third group exists: those who undergo preventive measures that may harm them. We do not have evidence for such outcomes in our study, but the early history of PKU screening indicates that some patients were harmed because they had been unnecessarily deprived of essential nutrients. The full extent of iatrogenesis during the 1960–1970s is diffi cult to reconstruct because the medical literature is biased against publishing accounts of medical error.6 Some case reports suggest failure to thrive,
listlessness, and skin rashes in a few false positive PKU patients who were deprived of phenylalanine.7 Similarly, past screening programs for histi-
dinemia and the resulting low histidine diet may have caused psycholog- ical stress, unnecessary blood draws, and uncertainty about the future.8
Monica mentioned that she occasionally had to talk pediatricians and parents out of implementing a restrictive diet as a preventive measure in cases where newborn screening results had not yet been confi rmed. She also gave an example of potential iatrogenic harm in a child who screened positive for GA1. “You know, we actually were really scared that this was going to be a true positive, so we started the kid on diet, even though we didn’t have a diagnosis,” she recalled. “But we fi gured, ‘Okay, it’s just going to be a diet until we fi gure out, we’d just rather be safe than sorry, you know, just start this diet.’ And then the kid started losing weight, be- cause they started . . . I think we freaked them out about the protein and everything, and so the kid stopped breastfeeding and then they fi gured they would just give more formula. But the formula is not a complete for- mula . . . we fi gured out what was going on and we said, ‘No, no, no. You know, go back, add formula, regular formula.’ And I think at that time we’d fi gured out, the repeat test came back normal. So: ‘Okay. Just go back. You know, go back to regular formula and everything.’ ”
The fourth possibility consists of the patients for whom there exists an opportunity for lifesaving preventive measures. This is the group of great- est interest to us, and we will devote the rest of this chapter to them. Since newborn screening is premised on the assumption that early interven- tion can save lives, geneticists and families had to take advantage of this early opportunity to intervene. Besides forming a working relationship with the genetics team, parents had to be vigilant every day. We offer the hypothesis that for some children with a positive newborn screen, the un- relenting work of parents and the genetics team could make a lifesaving difference. It is impossible to prove this conclusively because we do not know the counterfactual outcome of geneticists and parents not stepping up to the plate. We fi nd some evidence in our data that acting on advance knowledge could tip the balance for fortunate children, presuming that the parents maintained an unwavering focus on keeping their child alive. Much of this mundane work to keep a child healthy is all- encompassing, infi nite, and labor intensive. Clinicians delegate this work to parents but most of it remains invisible. Our goal here is to bring this critical yet often overlooked work into the open.
At the same time, parents’ ability to keep the child alive was further circumscribed by certain features of the US healthcare system. In the con- text of the US healthcare economy, newborn screening is unusually demo- cratic: every child is screened regardless of the family’s ability to pay. Om- nipresent inequities in the healthcare system, however, created structural barriers for some families that can offset the lifesaving benefi ts of screen- ing. The problems related to accessing services, obtaining dietary inter- ventions, follow- up testing, and transportation. Again, we do not have defi nitive evidence that healthcare barriers by themselves result in compli- cations but our data indicate that such barriers may prematurely close the window of opportunity to make a difference in health outcomes. We sug- gest that an increasing complexity of problems and of coordinating care among multiple stakeholders combined with a lack of resources to cir- cumvent barriers can have a negative impact on health outcomes.
The Window of Opportunity
The geneticists’ reference point for the potential success of newborn screening was their long experience with PKU. They had followed some patients with PKU for several decades and had observed how controlled phenylalanine levels could prevent mental retardation. The geneticists saw