Adults Born Preterm: Long-Term Health Risks of Former Very Low Birth Weight Infants
Background: Advances in neonatology now enable increasing numbers of very low birth weight neonates (<1500 g) to survive into early adulthood and beyond. What are the implications for their long-term care?
Methods: Selective literature search on the outcome of very low birth weight neonates in adulthood (“adults born preterm”).
Results: Robust data are available on the pulmonary, metabolic, cardiovascular, renal, neurocognitive, sensory-visual, social-emotional, mental, reproductive, and musculoskeletal long-term risks. On the somatic level, elevated rates have been documented for asthma (odds Ratio [OR] 2.37), diabetes mellitus (OR 1.54), and chronic renal disease (hazard ratio [HR] 3.01), along with the cardiovascular and cerebrovascular sequelae of a tendency toward arterial hypertension. On the psychosocial level, the main findings are deficits in romantic partnerships (OR 0.72) and a lower reproduction rate (relative risk [RR] male/female 0.24/0.33). The affected women also have an elevated risk of preterm delivery.
Conclusion: A risk profile with both somatic and psychosocial aspects can be discerned for adults who were born prematurely, even if some of these risks are present in low absolute numbers. As the ability to compensate for latent deficits declines with age, such adults may suffer from “premature aging as the late price of premature birth.” A holistic approach to care with personalized prevention strategies—which for most of them was discontinued at discharge from pediatric follow-up—therefore seems appropriate in adulthood as well.
Thanks to advances in neonatology, the mortality rate in preterm infants has continuously declined in recent years. Even in preterm infants born in the 23rd–24th gestational week (GW), that is to say, at the border of viability, one can expect a survival rate of 60–80%; having said that, between a quarter and a third of surviving neonates suffer immediate neurological sequelae (1, 2, e1, e2, e3, e4).
These patients are only the most striking representatives of the large group of infants born prematurely, that is, before the completed 37th week of gestation—a group that accounts for approximately 10% of all births worldwide. In turn, around 10% of these are born with a birth weight < 1500 g, corresponding to a gestational age of < 30 GW, and are referred to as “very low birth weight infants” (VLBWI) (3, e5, e6).
In the short and medium term, the majority of preterm infants can lead a full or largely unimpaired life. However, irrespective of organic disabilities, which are mostly diagnosed at an early age, other functional deficits sometimes occur that typically do not become apparent until an age is reached at which corresponding skills are required (2, e7). There is no cut-off value for behavioral disorders and learning disabilities of this kind, which represent a burden on families that should not be underestimated. Indeed, it is far more the case that special educational needs, for example, increase from the 37th GW downwards with each week of prematurity, reaching a rate of 50–60% among the smallest preterm infants (4). Here, the causes of preterm birth, in addition to the degree of prematurity, determine the prognosis: whereas perinatal infections, for example, increase the risk of neurological sequelae, intrauterine growth restriction may promote later metabolic syndrome through what is referred to as fetal programming (5).
Although neonatal intensive care had already been introduced in the 1960s, it was initially doomed to fail in many cases primarily due to the newborn respiratory distress syndrome that occurs before the 30th GW. It was not until the introduction of surfactant replacement therapy to treat fetal lung immaturity in the 1980s that the treatment of very low birth weight infants succeeded—and has been continuously perfected ever since (e8, e9). As a result, a growing number of people belonging to this group will reach medium to advanced age in the coming years.
Many of these patients will have undergone pediatric follow-up ending at the latest in adolescence and, thus, in a phase of life at which most have achieved, at least subjectively, a satisfactory quality of life (6, e10, e11). When they seek medical advice again for new health problems as they grow older, they will introduce their former preterm birth into the conversation with degrees of importance that vary from individual to individual. The primary care physicians or specialists being consulted will then ask themselves what objective significance the history of preterm birth could have for their now adult patients—as well as in terms of the possible impact on their ongoing care.
In order to help answer this question, we selected in a targeted manner articles with the term “adults born preterm” that addressed the long-term outcome (> 20 years) of very low birth weight infants (< 1500 g). The most robust data can be found in meta-analyses and birth registry studies, which are particularly common in Scandinavian countries. Although relative increases in risk are usually argued here, the statistical significance of which sometimes contrasts to some extent with the low absolute incidences and prevalences, a relevant risk profile can be discerned from these studies and can be subdivided into 10 somatic and psychosocial categories.
Even after surfactant therapy for respiratory distress syndrome and despite ever less invasive ventilation, a highly variable percentage (10–70%) of very low birth weight infants develop primarily inflammation-mediated and likely genetically underpinned bronchopulmonary dysplasia (BPD) (e12, e13). Although the cardinal symptom, a persistently elevated oxygen requirement, usually resolves with age, a 15–20 percentage point reduction in forced expiratory volume in 1 s (% FEV1), as evidenced by an extensive meta-analysis (7), remains following BPD (Table 1) and can progress to (manifest) chronic obstructive pulmonary disease (COPD) (8, 9, e14). As early on as in young adulthood, some former very low birth weight infants exhibited severe asthma in a Norwegian study (10), at a prevalence of 1.5–2.5% compared to approximately 0.5% in full-term newborns (adjusted OR 2.4) (Table 1).
Based on the observation that patients with coronary heart disease often had low birth weights, Barker (11) arrived at his ground-breaking hypothesis on the intrauterine origin of metabolic syndrome. It would appear that the growth-retarded fetus is programmed for a “thrifty” metabolism to such an extent that even a normal substrate intake can have the effect of an excessive intake in later life and, through obesity, hyperglycemia, and hyperlipoproteinemia, lead to atherosclerosis and its sequelae (12, e15, e16). For example, in a Finnish study (13), former very low birth weight infants already exhibited at 18–27 years a 6.7% higher 2-h blood glucose (95% confidence interval [CI]: [0.8; 12.9]) despite a 40.0% (CI: [17.5; 66.8]) higher insulin level compared to full-term infants. Latent insulin resistance is a precursor of manifest diabetes mellitus. Although it was rare overall in a Swedish VLBWI collective (14) aged 26–37 years, diabetes was seen to develop (with an adjusted odds ratio of 1.5) significantly more frequently (Table 2).
According to a large meta-analysis (15), former very low birth weight infants exhibit systolic/diastolic arterial blood pressure that is on average 3.4/2.1 mm Hg higher, representing a further risk factor for cardiometabolic diseases (Table 2). The propensity to arterial hypertension given attention not so much for its severity as for its regular occurrence (12, 16, e17) is explained by, among other factors, the fact that the wall stiffness in the large arteries is increased and the capillary bed rarefied (e18). In addition, cardiac magnetic resonance imaging (MRI) demonstrated altered geometry of the left ventricular myocardium (e19). All these risk factors likely contribute to the (slightly) increased risk (adjusted HR 1.22) for coronary heart disease found in a Swedish study (17) on adults aged 30–43 years following preterm birth before the 34th GW (Table 2). This result corrected earlier statistics that had found no significant increase in risk (18), and was used by authors and editorialists to recommend cardiac prevention for the affected group of individuals (17, 19).
As is true for the lungs and the brain, it is also true for the kidneys that, following preterm birth, their maturation (nephrogenesis) takes place partially extrauterine—with possible consequences in terms of organ size and function (e20, e21). In addition, there appear to be close interactions with cardiovascular status (16), be it that the (unduly small) kidney contributes to arterial hypertension or that it is (additionally) damaged by metabolic and hemodynamic factors. In a large Swedish cohort study (20), former very low birth weight infants had an adjusted HR of 3.01 for chronic kidney disease in young adulthood (Table 2). The incidence rose from 4.5 to 13 (per 100,000 patient-years), prompting the study authors to warn of a silent epidemic of chronic kidney disease in this patient group (21). This concern applies especially to young women with regard to possible transgenerational nephrogenic complications of pregnancy (22).
Neurological risks in adults born preterm include severe early-onset organic brain complications as well as less severe learning disabilities that come to light in the further course. In addition to this, and much like the cardiovascular risk, cerebrovascular diseases occur more frequently. A Swedish study (18) found an HR of 1.89 in this regard in former very low birth weight infants, corresponding to an increase in incidence to 0.13% compared to 0.07% in former full-term infants (Table 3). In addition, MRI studies of former preterm infants identified structural abnormalities in individual areas of the brain that are presumably the result of (cerebral) brain development occurring under unnatural extrauterine environmental conditions. In neuropsychological tests, these correlated with abnormal cognitive and executive functions (e22, e23, e24). Finally, the internal architecture of the brain also appears to be able to change in adaptation to existing sensory deficits (23).
Sensory (visual) risk
These sensory deficits primarily include visual disturbances that largely result from the “retinopathy of prematurity” (ROP) typical at the ocular level in the smallest preterm infants, despite all the advances in prevention and treatment (e25). A cohort study of >3 million Swedish citizens (24) described an increased adjusted HR for retinal detachment in former preterm infants (<28 GW): before screening eye examinations were introduced in neonatology in 1987, it was 19.2, and subsequently still 8.95—at incidences of 1.6 and 0.18%, respectively, compared to 0.1 and 0.02%, respectively, in former full-term infants (Table 3). In addition, there are also other visual impairments following preterm birth, for example, of visual acuity, convergence, and stereopsis, which—together with the disorders of central nervous visual processing recently observed more frequently—may be contributing, undetected, to presumed cognitive deficits (25, e26, e27).
At the intersection between neurosensory and mental health risks, one finds socio-emotional problems that, although in themselves without pathological significance in the narrower sense, can still be life-determining (e28). According to the groundbreaking research conducted by Wolke and coworkers, although most very low birth weight infants later develop “in an adaptive manner and within the normal range” (26), they tend—due to various minor performance deficits and significantly compounded by negative experiences with peers (bullying) (e29)—to be anxious, socially withdrawn, and more rarely achieve full occupational and financial independence. Also, with a pooled OR of 0.72, a remarkably high number of adults born prematurely did not experience a romantic partnership, as shown in an extensive meta-analysis (27, e30) of numerous cohort and registry studies (Table 4). These and other abnormalities impair not only quality of life, but also contribute to the manifestation of mental illness (28).
In extremely low birth weight infants (< 1000 g), internalizing problems fail to decline between the second and the fourth decade of life, as would be expected (29, e31), which is consistent with the depressive symptoms often complained of in self-help groups. The psychiatric diagnoses typical of preterm birth include—in addition to autism spectrum disorders, which are closely associated with the abovementioned socio-emotional abnormalities—attention deficit hyperactivity disorder (ADHD) (e32, e33). A recent meta-analysis (30) found a pooled relative risk for ADHD of 3.04 with a striking prevalence of 21.5% in the group of former very low birth weight infants (Table 4). Eating disorders, which are well known from pediatric follow-up, have been little studied as yet—although recent data suggest they occur in up to 20% of former very low weight infants (31). Their progression to anorexia nervosa have already been noted in the past (e34).
With remarkable concordance, epidemiological studies conducted in several countries have found a lower reproductive rate in adults born preterm (32, e35, e36). In a Norwegian study (32) of extremely preterm women, only 25% had had children by the age of 28–37 years compared to 68% of women born full-term. This phenomenon depends on the degree of prematurity and affects males even more than females (Table 4). Whether this can be attributed to somatic causes in addition to the abovementioned problems of partner selection (27) remains an unanswered question. In addition, former preterm women have an increased risk for experiencing preterm births themselves. This could be as a result of the fact that metabolic syndrome predisposes to diabetic or hypertensive complications of pregnancy (22, e37). According to a Canadian study, however, this phenomenon also appears to exist independently of epigenetic factors of this kind (33).
Little is known about the long-term consequences of preterm birth on the musculoskeletal system. Since the introduction of osteopenia of prematurity prevention using adequate calcium, phosphate, and vitamin D supplementation, pathologic fractures have become rare on preterm intensive care units (e38). However, decreased bone density of the femoral neck has been repeatedly reported in former preterm infants, particularly after intrauterine growth restriction (e39, e40, e41), thereby suggesting an increased risk for fractures in advanced age. In an Australian study (34), preterm birth (by ≥ 2 GW) was associated with an adjusted HR of 2.53 for hip arthroplasty at age ≥ 40 years, with incidences of 3.8% versus 2.1% in the baseline population (Table 5). Finally, motor handicaps or physical inactivity may contribute to musculoskeletal symptoms in adults born preterm.
The studies cited here are subject to three caveats: First, the majority of very low birth weight infants have only now reached middle adulthood, where health problems—measured in absolute numbers—are still minor, and a significant relative increase in risk could be due to a handful of patients with particularly unfavorable outcomes. As such, it is unclear whether the current risk profile will be substantiated or will level out in older age. Second, many of the oldest patients followed-up were born before the introduction of surfactant replacement therapy, at a time when neonatal intensive care was far more limited and, at the same time, more invasive than today. Therefore, this article on the current outcome of infants born preterm at that time should not be interpreted as a description of the—presumably and hopefully in many points more favorable— future prognosis of today’s preterm infants. Third, a number of questions that are equally of interest in this context, such as concerning cancer or dementia, cannot be answered as yet due to the lack of sufficient follow-up time.
Nevertheless, the available data make it possible to identify a risk profile that is characterized by a combination of somatic and psychosocial factors that varies in an age-dependent manner (5, 26): initially, neurocognitive deficits and problems of social integration appear to predominate, making occupational independence difficult and hindering successful family formation. Then, the predisposition to metabolic syndrome may promote the early onset of cardiovascular disease, while the reduced pulmonary reserve may bring patients to the limits of their respiratory capacity faster than is usual in the physiological aging process. Consistent with this, not all (e42, e43) but some recent molecular biological studies (35, e44) in adults born preterm have found shorter telomere length. Thus, premature aging may be the price that affected individuals pay later in life for preterm birth not only at the systemic level, but also at the cell biological level (8, 16, e14, e45).
The growing number of patients that reach adulthood at all thanks to advances in medicine is reminiscent of the transition problems known in rare (metabolic) diseases (36, e46)—with the difference that preterm birth is not only much more frequent compared to the rare diseases in question, but that most preterm infants are also not subject to seamless ongoing treatment. The result of this, however, is that when they subsequently seek medical advice once again, the continuity of their former preterm follow-up care has been discontinued and is sorely missed by at least some of the affected individuals (37, e47). There is an analogy to be made here to adults with congenital heart disease (ACHD) for whom so-called ACHD centers were set up, likewise around 30 years after the early days of pediatric cardiac surgery (38, e48)—again with the difference that in preterm infants it is less a matter of previously unknown organ complications and more one of a novel, perinatal risk profile.
To assess this risk profile, a differentiated medical history is first required, for which some key questions are listed in Table 6. It is generally true that not all preterm births are alike, and that possible subjective (mis-)attributions can be differentiated from objective risk constellations based only on the degree of prematurity and the causes of preterm birth. Whether specialist neonatology outpatient clinics for adults born preterm, much like the ACHD centers mentioned above, may be able to help with this differentiation in the future—at least in particularly complex cases—remains to be seen. If risks can be demonstrated, one can expect to see increased vulnerability to exogenous noxious agents (pulmonary function) (8, 9, 10, e13, e14) or lifestyle factors (cardiometabolic risk) (e15, e16, e49). This in turn leads to consequences for personalized prevention (12, 19, 21, 39, 40, e50), which, in this case, must also take into account the special interrelationship between somatic and psychosocial factors. However, it is even more important to recognize that (extremely) preterm birth represents a chapter of life for those affected that can never be completely closed. Therefore, adults born preterm can benefit in particular from holistic, long-term, and, in the best sense of the word, general practitioner care.
Conflict of interest statement
Prof. Singer received research funding from Drägerwerk AG and speaker’s fees from Chiesi GmbH.
Dr. Perez received study support (third-party funding) from the Werner-Otto-Stiftung Hamburg.
Mrs Thiede declares that no conflict of interest exists.
Manuscript received on 2 July 2020, revised version accepted on 22 February 2021.
Translated from the original German by Christine Rye.
Prof. Dr. med. Dominique Singer
Sektion Neonatologie und Pädiatrische Intensivmedizin
20246 Hamburg, Germany
Cite this as:
Singer D, Thiede LP, Perez A: Adults born preterm:
long-term health risks of former very low birth weight infants.
Dtsch Arztebl Int 2021; 118: 521–7.
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