Discussion
Prematurity remains the leading cause of neonatal morbidity and mortality. Intrauterine growth restriction is another first-line cause of the adverse neonatal prognosis, both as a single pathology or in association with prematurity. According to studies, there is a concordant relationship between preterm birth and intrauterine growth restriction.5 Intrauterine growth restriction shows chronic fetal distress based on placental dysfunction, with placental abnormal vascularization leading to hypoperfusion, ischemia, and release of reactive oxygen species in the context of oxidative stress.
Both prematurity and intrauterine growth restriction have an increased incidence among pregnancies complicated with preeclampsia6, results that are consistent with the data in the literature. In this context, we decided to highlight the unfavorable short-term prognosis of prematurity, as well as intrauterine growth restriction, in both preterm and term infants with low birth weight.
According to the results obtained, the frequency of premature births in the Emergency University Hospital of Bucharest, a multidisciplinary hospital in which multiple complex cases are addressed, was approximately 13%. The cases of complicated preterm infants with intrauterine growth restriction accounted for 6.5% of all premature births recorded in the clinic during the 3 years of study and about 1% of all births. The cases of newborns with low birth weight for the gestational age accounted for about 2% of all births recorded during the study period. Thus, the data obtained are consistent with reports in the literature; the proportion of intrauterine growth restriction among preterm births is higher than that among term births.5
Another parameter that was consistent with the published reports is the predominance of female fetal sex in cases of intrauterine growth restriction 7,8 and the predominance of male sex among premature births. However, the difference was not significant; therefore, according to the results, we can consider the following conclusions of the study by Quinones et al,9 focusing mainly on the influence of fetal sex on the perinatal prognosis of cases of intrauterine growth restriction: fetal sex is not associated with unfavorable perinatal prognosis in cases of intrauterine growth restriction.
The purpose of the analysis of the values of the Apgar index as a marker of the immediate neonatal adaptation was to objectively highlight the difference of adaptation, especially in the case of premature infants with low weight for gestational age and those infants with weight corresponding to their gestational age. The values obtained were not different from expectations, more specifically, the adaptation of preterm infants with low weight for the gestational age was the most deficient, with a median value of 7. Figure 1 shows that there were no values that deviated significantly from the value of the median, with the distribution being proportional. However, the degree of adaptation was higher in the group of premature infants with weight corresponding to the gestational age, as expected. In figure 2, it appears that the values of the Apgar index were higher in this group. However, in the single cases of small Apgar index, the median assigned to group 2 was 8. The most favorable adaptation was noted in the newborns in group 3. In groups 2 and 3, maximum values of the Apgar score were noted.
Birth by caesarean section predominated in all study groups, with a statistically significant difference noted among the 3 groups. This is justified by the fact that birth by cesarean section of premature infants is associated with lower neonatal mortality10, which is explained by the possibility of early and promising neonatal intensive care.11 Additionally, in this context, it is worth mentioning that the birth weight is inversely proportional to the rate of neonatal complications, in which the impact of the vaginal birth decreases with increasing fetal weight.12 Even though premature birth is not an absolute indication of cesarean delivery, this mode of birth provides a better prognosis for preterm infants by avoiding prolonged labor and allowing for a less traumatic birth.12
Regarding obstetric factors, it is not surprising that we obtained a higher incidence of pelvic presentation among preterm infants; however, the incidence of pelvic presentation among low-weight newborns for gestational age was slightly higher than that in the general population. The data at the general population level show an incidence of caesarean section of 4%-40% among term births an 25%-60% among premature births, which is inversely proportional to the gestational age. As can be seen in Figure 3, the incidence of pregnancy-induced hypertension predominates in cases of growth restriction, both in premature newborns and particularly in newborns with term growth restriction. This situation is also characteristic of preeclampsia, except that it prevails in preterm infants with intrauterine growth restriction and low weight for gestational age. These results confirm the results of other studies, namely that placental functional disorders belong to the group of progressive multifactorial pathologies that present deteriorating signs and symptoms over time.
Fetal malformations predominated in the group of premature newborns with growth restriction, which is consistent with published reports on the association of fetal malformations with intrauterine growth restriction13,14and prematurity.15The umbilical cord pathology, mainly the true cord knot, did not have a significant association with intrauterine growth restriction, which is consistent with the data in the literature; however, this association has not been fully established and is still being studied16,17,18. Regarding the multiple nuchal cord, a statistically significant association has not yet been evidenced between these condition and adverse neonatal prognosis.19According to the results obtained in our study, the incidence of multiple nuchal cord was higher in the groups with growth restriction.
Essentially, the purpose of our study is to show that intrauterine growth restriction, a condition closely related to placental dysfunction, is a common diagnosis that is associated with an increased risk of perinatal mortality and morbidity. The fetal response consists in circulatory adaptations, respectively brain-sparing reflected by the value of cerebroplacental ratio, which has a better predictability index of adverse outcomes especially in fetuses with intrauterine growth restriction 20. The meta-analysis published in 2016, which had the aim to evaluate the perinatal predictability value of cerebroplacental ratio concluded that abnormal cerebroplacental ratio is associated with increased rates of unfavorable perinatal outcome, having a moderate-high specificity and sensitivity21. An abnormal cerebroplacental ratio was associated with higher rates of need of neonatal intensive care and neonatal complications and suggest a poorer perinatal outcome of fetuses with intrauterine growth restriction21. Regarding the normalization of the cerebroplacental ratio, the results of a recent sub-analysis which started from the hypothesis that normalization of this ratio associates a poorer perinatal outcome due to the loss of the compensatory mechanism of brain sparing, showed that there is no additional worsening of the perinatal prognosis given by this normalization22. Recent studies have analyzed the impact of the abnormal cerebroplacental ratio on neurodevelopmental outcome in fetuses with intrauterine growth restriction. Meher et al in his review suggested that the brain sparing phenomenon has not only a protective benefit but is associated with a poorer psychomotor development at one and two years caused by implied cerebral hypoxia23.
In the context of the results obtained, as well as of the discussions regarding the advantages of the expectant management for both short and long-term outcome, the decision regarding choosing the most appropriate time for termination of the pregnancy becomes even more difficult. Thus, each case should be treated individually with a therapeutic behavior guided by the main pathology but also the associated one in order to reduce the rate of iatrogenic prematurity among the fetuses with intrauterine growth restriction but also to offer them the best prognosis.
Further, with reference to Table 4, which contains the frequency and comparative analysis of all the neonatal complications studied for the 3 groups, one can observe the objective impact of intrauterine growth restriction during the immediate neonatal period.
Thus, as discussed in the results chapter, the highest frequency of neonatal complications occurred in study group 1. Statistical significance was obtained for the following complications: cardio-vascular arrest (P <0.001), acute respiratory failure (P <0.001), ulcer-necrotic enterocolitis(P <0.001), hypoxia present in 58% of premature cases with growth restriction and in 23% of cases of gestational age weight (P <0.001), respiratory distress (P <0.001), cerebral edema (P = 0.004), intraventricular hemorrhage (P <0.001), cerebral hemorrhage (P = 0.003), pulmonary hemorrhage (P <0.001), neonatal infection (P <0.001), hypoglycemia(P <0.001), retinopathy (P <0.001), anemia (P <0.001), hemorrhagic disease (P = 0.002), disseminated intravascular coagulation (P <0.001), disease of hyaline membranes (P <0.001), neonatal sepsis (P = 0.002), need for intensive neonatal therapy (P <0.001), and death (P <0.001).
Intrauterine growth restriction is associated with an increased risk of both antenatal and neonatal complications. There is an increased negative impact on prognosis when fetuses with intrauterine growth restriction are born premature. In our study, newborns with low weight for gestational age had an increased incidence in complications in comparison to newborns with adequate weight, specifically: cardio-vascular arrest, 0.1% in the general population and 1% in the present study; acute respiratory failure, 0.45% in the general population and 2% in the present study12; however, respiratory distress, cerebral edema, ulcer-necrotic enterocolitis, pulmonary hemorrhage, persistence of the arterial canal, cerebral hemorrhage, seizures, retinopathy, hemorrhagic disease, disseminated intravascular disease, and hyaline membrane disease were absent in term infants with low birth weight for gestational age, indicating that these newborns have a good neonatal adaptation by leaving an environment already unfit for their well-being, i.e. intrauterine.