Prematurity and intrauterine growth restriction (IUGR), together with congenital malformations, infections and anoxia, are the most important problems in foetal medicine, and are the main causes of perinatal morbidity and mortality. Incidence of severe IUGR is estimated at 3%–5% of pregnancies.1

Several studies have reported increased perinatal and neonatal morbidity and mortality in newborns with IUGR or low birth weight, together with an increase in cardiovascular morbidity in adulthood, a phenomenon known as foetal programming of adult disease.2–23 The neonatal morbidity and mortality described in these patients include complications related to prematurity (respiratory distress, bronchopulmonary dysplasia, necrotising enterocolitis, sepsis, low 5-minute Apgar test score, altered thermoregulation, retinopathy of prematurity [ROP], intraventricular haemorrhage, periventricular leukomalacia and neonatal death), and haematological and metabolic complications (thrombocytopaenia, coagulopathy, leukopaenia, initial hypoglycaemia, subsequent hyperglycaemia, altered cord blood lipids, cholestasis and jaundice).2–23 Increased neonatal morbidity and mortality and the foetal programming phenomena may be due to the foetal hypoxia-ischaemia presented by these IUGR patients. Hypoxia-ischaemia gives rise to haemodynamic adaptation, a phenomenon in which the brain, heart and adrenals are spared in detriment to the maturity of other organs.11,14,16,24 However, some studies seem to demonstrate that this haemodynamic redistribution does not completely spare priority organs from hypoxia-ischaemia and nutrient deficiency.25–32 Cardiovascular abnormalities have been described in IUGR patients using both echocardiography and measurement of cord blood cardiovascular dysfunction markers, specifically, increased levels of B-type natriuretic peptide (BNP).25–27 These alterations could be related to the mechanisms underlying foetal programming of cardiovascular disease in adulthood.

Very few studies have investigated the relationship between neonatal morbidity and mortality and severity of IUGR. Damodaram et al., reported an increase in risk of intrauterine and neonatal death and intraventricular haemorrhage in IUGR foetuses and newborns with both umbilical artery and venous Doppler abnormalities compared with those presenting only umbilical artery abnormalities.3

The main problem in the literature is that most studies on neonatal morbidity and mortality related to IUGR are conducted in “low birth weight for gestational age” newborns, without clearly identifying placenta-related IUGR patients, which are the ones with hypoxia-ischaemia phenomena. Another problem is that most of these studies are retrospective and include a poorly selected control cohort of adequate birth weight newborns (frequently without excluding foetuses with congenital anomalies, aneuploidies or chorioamnionitis)4,8–13 Finally, very few authors have studied early plasma markers of cardiovascular dysfunction in IUGR patients, or the impact of IUGR severity on both perinatal outcomes and the extent to which levels of cardiovascular dysfunction markers are increased.

The objectives of our study were the following: to determine differences in neonatal morbidity, mortality and cord blood levels of metabolic-cardiovascular markers in 2 well-defined cohorts of premature infants with and without IUGR; and to study the relationship between these variables and the severity of IUGR assessed by foetal Doppler scan.

Prospective cohort study: a cohort of pre-term placenta-related IUGR infants and a gestational age- and gender-matched cohort without IUGR. The IUGR cohort was formed of preterm infants with a clinical prenatal diagnosis of placenta-related IUGR based on standard weight charts and foetal Doppler scan33,34 (estimated foetal weight [EFW] below the 3rd percentile and/or within the 3rd–10th percentile with abnormal Doppler findings), born and monitored at the Hospital Vall d’Hebron between 2007 and 2010. The non-IUGR cohort was formed of preterm infants without IUGR (EFW and birth weight above the 10th percentile but below the 90th percentile according to standard foetal weight charts,33 with normal Doppler findings and no pre-eclampsia), matched with the IUGR cohort and born at the same hospital between 2007 and 2010.

Exclusion criteria for both cohorts were the following: parents’ refusal to participate; diseases affecting growth potential (embryopathies, congenital infections, chromosomopathies, genetic diseases, foetal malformations), certain maternal pathologies (type 1 diabetes mellitus, neuropathy, drug addiction, human immunodeficiency virus), chorioamnionitis, monochorionic multiple pregnancies, pregnancies not monitored at the Vall d’Hebron hospital or with no Doppler scan.

Maternal, obstetric, Doppler scan, perinatal and neonatal morbidity and mortality data were collected from all study patients (129 preterm infants: 72 with IUGR and 57 without IUGR). Severe neonatal morbidity was defined as the presence of 1 or more of the following complications: severe respiratory distress (defined as the need for intubation), intraventricular haemorrhage grade 3 or 4, patent ductus arteriosus (treated), kidney failure, necrotising enterocolitis, intestinal perforation, sepsis of vertical transmission, nosocomial sepsis, laser-treated retinopathy of prematurity (ROP), bronchopulmonary dysplasia, periventricular leukomalacia, administration of postnatal corticosteroids, administration of inotropic drugs, and/or death.

Severity of IUGR was classified on the basis of the Doppler findings, and defined as 1 or more of the following findings at the end of pregnancy: absent or reversed end-diastolic umbilical artery flow and/or abnormal ductus venosus flow due to increased ductus venosus pulsatility index or absent/reversed diastolic flow.

Whenever possible, and after obtaining the mother's informed consent (see Appendix), cord blood was collected and tested for lipid markers (cholesterol and triglyceride) and cardiovascular dysfunction markers (N-terminal pro b-type natriuretic peptide [NT-proBNP], cardiac troponin T [cTnT] and heart-type fatty acid binding protein [hFABP]). All data were entered into a separate form for each patient, and subsequently uploaded to an Excel database designed for the study. Statistical analysis was performed on STATA v. 11, with the help of the Biomedical Research Methodology Support Unit. All variables were compared between cohorts, and according to severity classification in the IUGR cohort.

In this study, morbidity, mortality and corrected gestational age at discharge (hospital stay) were higher, and somatometry was lower among placenta-related IUGR infants with respect to non-IUGR infants.

Most studies published to date report higher neonatal morbidity and mortality among IUGR infants.2–14 Specifically, the IUGR cohort shows higher incidence of severe morbidity and certain morbidities closely related with prematurity: lower 1-minute Apgar score3,9 and higher incidence of nosocomial sepsis,3,11,14 respiratory complications2–4,8–10 and ROP.2,4 However, in contrast with other authors,3,4,9,10 no statistically significant differences were observed in neonatal mortality or the rate of necrotising enterocolitis.2–4,8,9,11 Evidence of intraventricular haemorrhage and periventricular leukomalacia is contradictory in the literature. In this study, no differences were found in this regard between IUGR and non-IUGR patients, a finding that is consistent with some earlier studies.3,8,15 Several studies coincide with our findings of a higher incidence of neonatal metabolic and haematological complications among IUGR patients, including hypoglycaemia, hyperglycaemia, need for insulin, leukopaenia, thrombocytopaenia and jaundice treated with phototherapy.2,14,16–18

However, as outlined in the introduction, most studies so far have been retrospective, with a poorly defined IUGR group. This is one of the main strengths of this study, which is prospective and in which cases were limited to placenta-related IUGR patients. In addition, both cohorts were carefully defined using restrictive criteria, and were gestational age- and gender-matched. The maternal and obstetric differences between the cohorts were inherent to the pathology associated with each (IUGR and other causes of prematurity), and are consistent with the literature. As such, they should not be a limitation for this study.1,5,35–37 Moreover, the most common cause of medically indicated delivery in the IUGR cohort (foetal cause: altered foetal Doppler scan and/or altered NST) are also consistent with the literature.7,36,37

Nevertheless, this study is limited by the final sample size, which was to a large extent due to the restrictive criteria used for the selection of the two cohorts.

Another important contribution made by this study is the finding of differences in metabolic and cardiovascular dysfunction biomarkers levels in cord blood between IUGR and non-IUGR infants. These abnormalities could be related to mechanisms underlying foetal programming of cardiovascular disease in adulthood. Although little has been done to investigate this phenomenon, the cord blood lipid profile found in IUGR infants in this study is consistent with the findings of other authors, namely, a higher proportion of triglyceride and lower cholesterol level.16,17 Moreover, changes in the cardiovascular dysfunction biomarkers cTnT and NT-proBNP in new-borns with IUGR in this study were also consistent with those described by other authors. In particular, patients with IUGR presented higher levels of natriuretic peptides and cTnT compared to newborns without IUGR.38–40 Confirmation of increased levels of these markers is important, as it supports the hypothesis of early cardiovascular pathology in IUGR infants being associated with foetal programming of cardiovascular disease in adulthood. Further studies are needed to investigate the relationship between these blood cardiovascular biomarkers abnormalities and the long-term evolution of IUGR patients.

Another important finding of this study has been the direct correlation between neonatal morbidity, mortality and cord blood cardiovascular dysfunction biomarkers and the severity of Doppler scan haemodynamic abnormalities in IUGR patients.

Unfavourable perinatal outcomes and the presence of cardiovascular dysfunction biomarkers in severe IUGR patients may be due to more severe hypoxia-ischaemia in this population, shown by greater abnormalities in Doppler scan. More severe hypoxia-ischaemia would lead to greater foetal organ damage and dysfunction, thus increasing the risk of associated morbidities in both the neonatal period and in later life.2,14,16–18 Despite the paucity of studies on this phenomenon, Damodaram et al. have described an increased risk of certain morbidities among IUGR patients with both arterial and venous Doppler abnormalities.3

With regard to cord blood biomarkers, our findings echo those of the only other study to explore the association between cord blood cardiovascular dysfunction biomarkers and severity of IUGR determined by Doppler findings.38 In this case, apart from detecting higher levels of NT-proBNP, an increase in the cardiovascular dysfunction biomarkers cTnT and h-FABP in cord blood was also observed in the more severe IUGR cases. Despite the small sample size, this important finding contributes new information that could reveal the benefit of these biomarkers in detecting not only the severity of IUGR and the perinatal consequences of this pathology, but in predicting neonatal or adult cardiovascular dysfunction in these patients.

In conclusion, the main contributions of this study are the following: confirmation of increased neonatal morbidity and mortality in preterm infants with placenta-related IUGR; determination of abnormal cord blood levels of lipid and cardiovascular dysfunction biomarkers in these patients; and a direct correlation between greater risk of neonatal morbidity, mortality and abnormal cord blood biomarkers and severity of IUGR determined by Doppler findings. This study, therefore, confirms the benefit of arterial and venous Doppler scan in the management and stratification of IUGR patients, and highlights the need for prospective studies with larger cohorts with an appropriate characterization of prenatal placental abnormalities and their correlation with short- and long-term morbidity and mortality.

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  Study conducted within the framework of the project FIS PI07/1095 (2007–2010), financed by the Health Research Fund, titled “Pregnancy as a stress situation for the development of cardiovascular disease: assessment of haemodynamic and biochemical risk markers for atherosclerosis in mothers and foetuses with pre-eclampsia and/or intrauterine growth delay” (principal investigator: Elisa Llurba Olivé).

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  Scholarship granted before doctoral studies and after the internal medicine residency (IMR) by VHIR (Institut de Recerca Vall d’Hebron) to Júlia Candel Pau (2011–2014).