Recent advances in perinatal care offer a reasonable chance of survival to preterm infants in the developed world. Even among extremely preterm infants, the mortality rate has decreased in the last two decades . Despite this improvement, the outcome of extremely preterm infants remains uncertain. Preterm delivery at the limits of viability up to 25+6/7 weeks of gestation, in the so-called “gray zone”, significantly contributes to neonatal and infant mortality, morbidity and subsequent physical and neuro-developmental impairment , , , . Therefore, the decision to provide intensive care to the most extremely preterm infant is challenging. Ethical and economic issues, as well as the will of the parents, need to be taken into consideration. The limits of viability is defined as a stage of fetal maturity that ensures a reasonable chance of extra-uterine survival. In the Czech Republic, the official threshold is 24+0/7 weeks of gestation. In agreement with the parents, the neonatal team can initiate care for children of even fewer gestational weeks. To let parents participate in deciding on the extent of care provided, neonatologists must fully and comprehensibly inform them about the infant’s prognosis. It is widely accepted that gestational age at delivery has the greatest impact on future outcome , , . However, estimating the likelihood of a favorable outcome by gestational age alone can be misleading as there are other factors with potential impact as well . The proactive approach involving the induction of lung maturity, delivery by cesarean section and immediate initiation of resuscitation may improve the prognosis of these extremely preterm infants , , , .
In this retrospective study, we aimed to evaluate the short-term outcome of deliveries around the limits of viability and to determine the factors that contribute to mortality and short-term morbidity of the most extremely premature infants.
The retrospective cohort study was performed at a single, regional tertiary level obstetric and neonatal intensive care unit (NICU) with approximately 4800 births and 500 NICU admissions every year. Care for all pregnancies from 24+0/7 weeks of gestation was initiated. In pregnancies that are likely to end up in delivery before 24+0/7 weeks of gestation, informed parental consent with a proactive approach to the infant was required. The proactive approach consists of induction of fetal lung maturity, delivery by cesarean section (if indicated) and active stabilization by the neonatal team in the delivery room. It was discussed with parents by a perinatal team consisting of a senior obstetrician and a senior neonatologist. In the case of parental refusal of intensive care, the newborn is not admitted to the NICU and is provided with comfortable care in the delivery room.
All live-born infants delivered between 22+0/7 and 25+6/7 weeks of gestation were included in the study. The study period extended from January 2009 until December 2015. Data of all inborn babies of the aforementioned gestational age were recorded, including those who died in the delivery room.
Determination of the gestational age of the fetus was based on an ultrasound screening examination in the first trimester. In cases where combined screening was not performed, the gestational age was calculated from the mother’s last menstrual period.
Perinatal and neonatal data of individuals meeting the inclusion criteria were obtained from the hospital medical records database and the internal neonatal morbidity database.
Perinatal data and management
Data that were extracted and further analyzed included clinical and laboratory markers of inflammation in pregnant women before delivery, the occurrence of preterm premature rupture of membranes (PPROM) and obstetric interventions, such as antibiotic and tocolytic treatment. In cases of imminent preterm delivery in the above mentioned period of gestation, intravenous antibiotic therapy was initiated. Intravenously administered hexoprenaline was used for tocolysis in symptomatic patients at risk of preterm delivery for the time necessary for induction of lung maturity. Data of initiated and completed induction of fetal lung maturity were obtained. The corticosteroid regimen used in our department involved intramuscular administration of two 12 mg doses of betamethasone given 24 h apart. Complete induction of lung maturity refers to cases in which a total dose of 24 mg betamethasone was applied and delivery occurred at least 24 h from the last dose of corticosteroid injection, but within 1 week. Furthermore, cases of placental abruption were noted, as they may have an additional serious negative impact on neonatal mortality and morbidity. The mode of delivery was recorded, and placentas were histologically evaluated and scored for chorioamnionitis.
Neonatal data and management
Infants were resuscitated by the neonatal team, which consisted of two neonatal doctors and two neonatal nurses, using internal department protocol that respects the International Liaison Committee on Resuscitation recommendations using a neonatal resuscitator (Neopuff). Respiratory distress syndrome (RDS) was managed according to European consensus guidelines on the management of RDS, including the administration of a surfactant (Curusurf® poractant alfa) by the intubate-surfactants-rapid-extubation method . Further treatment was carried out at the NICU under conditions arising from current knowledge in neonatology in pursuit of unit standard procedures, including non-invasive ventilatory support and the standardized protocol of early feeding by mother’s milk and a rapid dose increase of enteral nutrition.
Mortality and morbidity
All cases of pre-discharge deaths and their causes and circumstances were recorded. Neonatal morbidity was evaluated according to current diagnostic criteria , , , , , . Cerebral ultrasonography was performed to identify cases of intraventricular hemorrhage (IVH), periventricular leukomalacia and ventriculomegaly. Cases of necrotizing enterocolitis (NEC) and spontaneous intestinal perforation (SIP), as well as all episodes of early and late onset sepsis (EOS, LOS), were recorded. Neonatal mortality and pre-discharge morbidity were related to maternal inflammation, the administration of antenatal corticosteroids and the mode of delivery.
Infants that survived were scored for bronchopulmonary dysplasia (BPD) according to the National Institute of Health (U.S.) criteria. The international classification of retinopathy of prematurity (ICROP) was used for evaluating the retinopathy of prematurity (ROP). Survival without major morbidity was defined as surviving until discharge without severe IVH (grade 3–4), NEC requiring laparotomy, BPD (moderate or severe) and ROP stage 3 or higher. The long-term outcome of surviving infants is currently monitored at a specialized clinic; however, it is not a part of this study because not all the infants included have reached the age for examination.
A Pearson correlation matrix involving all studied variables was created. Parameters that showed a significant correlation to mortality and severe morbidity were identified and thereafter included in a multivariate logistic regression model. Odds ratios (OR) and their 95% confidence intervals (CI) were calculated. Non-significant correlations were not included in the multivariate logistic regression analysis. The analysis was performed using IBM SPSS Statistics for Windows, Version 22.0 (Armonk, NY: IBM Corp.).
We acquired perinatal and neonatal data for all 166 infants meeting the inclusion criteria. Table 1 shows perinatal characteristics, interventions and placental histology of studied pregnancies and newborns. We recorded 34.9% of infants born from multiple pregnancies including two infants that were born from one recorded triplet pregnancy. The mean birth weight in the studied population was 656±102 g. The lowest birth weight measured for an infant who received intensive care was 360 g, whereas the highest birth weight in the studied population was 1100 g. The infants that were small for their gestational age (SGA; e.g. birth weight ≤10th centile) at delivery represented 6% of newborns. PPROM complicated 30.1% of the cases. Positive maternal C-reactive protein (>10 mg/L) and leucocytosis (>10/mL) prior to delivery were common. Occurrences of both in the same individual were found in 42.2% of cases. Maternal temperature ≥37°C was recorded in 11.4%. We identified 12.1% cases of placental abruption with no apparent association to PPROM. Nearly 88% of the patients received antenatal intravenous antibiotic treatment and 67.5% received tocolytic treatment. We initiated the induction of lung maturity in 84.1% of the patients and 37.3% of the patients received a complete course of corticosteroids. A total of 85.5% of preterm deliveries were spontaneous and 14.5% were iatrogenic. The most common indication for iatrogenic preterm delivery was bleeding from placental abruption, which accounted for 87.5%. Another three iatrogenic preterm deliveries, representing 12.5%, occurred because of early-onset severe preeclampsia, which was accompanied by intrauterine growth restriction in two of the cases. We delivered the majority (60.8%) of infants by cesarean section. Nearly 43% of the infants were delivered by cesarean section at 22 and 23 completed gestational weeks, whereas 69% were delivered at 24 and 25 completed gestational weeks. The mean birth weight of infants born by cesarean section was higher than in those born vaginally (671±101 g vs. 637±98 g). We did not record any cases of instrumental vaginal delivery.
The pathologist found different stages of placental inflammation in 60.6% of the cases. One placenta was not examined. Chorioamnionitis, purulent chorioamnionitis and funisitis were present in the placentas of 15.2%, 20.6% and 24.8% of newborns, respectively. There was a correlation between the elevation of laboratory markers of inflammation and the presence of histologically verified intra-amnial infection (P<0.0001).
Table 2 shows the delivery outcome of the studied cohort. We recorded four cases of death in the delivery room: three due to parental refusal of neonatal intensive care before 24+0/7 weeks of gestation, and one due to unsuccessful resuscitation. All the live-born, extremely preterm neonates required resuscitation and the vast majority of the neonates had to undergo intubation. Umbilical artery pH was acquired in 53.6% of the cases; the mean umbilical artery pH was 7.3. In 4.5% of the cases, the pH was less than 7.2. Afterwards, we admitted all surviving neonates to the NICU.
During the study period, we recorded 21 cases of stillbirths in gestational ages between 22+0/7 and 25+6/7 weeks, mostly due to intrauterine death before admission to our department. These cases were not included in our study.
Table 3 summarizes the mortality, causes and circumstances of death of infants admitted to the NICU. The average survival until discharge was 73.5% and corresponded to the gestational age. The most common cause of death in the studied cohort was IVH. It accounted for 46.5% of the causes of death. We recorded no death from IVH after 25 completed gestational weeks. The second most prevalent cause of death was NEC. Other causes included respiratory failure and early or late onset of sepsis. There was no case of major birth defects in our group.
Most of the infants (58.1%) died after the withdrawal of intensive care following the development of severe IVH or NEC. The rate of the decision to withdraw intensive care decreased with gestational age. A total of 41.9% infants died despite full intensive care, with half of these deaths occurring during full cardiopulmonary resuscitation. The proportion of early and late neonatal mortality did not differ significantly, and the post-neonatal mortality rate was low. The average length of hospitalization among infants who died was 13 days, and the longest recorded hospital stay prior to death was 77 days; this infant, with grade 4 IVH, died of ventriculitis.
The association between survival and other variables was expressed by Pearson correlation coefficient. We found a significant correlation between mortality and gestational age (P<0.001), birth weight (P<0.001), the completed course of antenatal corticosteroid treatment (P=0.002) and cesarean section (P=0.001). For those variables that showed a significant correlation to mortality and therefore to survival, multivariate logistic regression analysis was performed (see Table 4 for the results). We calculated that every additional gestational week in this period of pregnancy was associated with a 2.3 times increase for the chance of survival (OR=2.3; 95% CI 1.346–3.971; P=0.012) and the completed course of antenatal corticosteroids with a 3.2 times increase (OR=3.2; 95% CI 1.262–8.275; P=0.014).
Although the mortality rate was lower after the cesarean delivery, the multivariate logistic regression analysis did not prove to have a significant effect on survival (OR=2.077; 95% CI 0.929–4.645; P=0.075) or grade 3 and 4 IVH (OR=2.284; 95% CI 0.922–5.658; P=0.074).
We found no statistically significant correlation between mortality rate and placental inflammation (P=0.680), elevated maternal temperature prior to delivery (P=0.680), elevated markers of inflammation in the maternal serum (P=0.290), PPROM (P=0.711), SGA (P=0.790) or male sex (P=0.433).
Table 5 summarizes neonatal morbidity. RDS occurred in all newborns and required surfactant administration in 92.2% of the cases. Severe grades of IVH were more common in infants born at 22 and 23 completed weeks of gestation and it significantly contributed to neonatal mortality. The incidence of severe grades of IVH decreased rapidly after 24 completed weeks of gestation. Cases of NEC and SIP occurred in all gestational weeks and often required a laparotomy. Early or late onset sepsis complicated half of the cases with no apparently higher incidence in any gestational week. In total, sepsis occurred in 42.6% of the infants.
All infants born at 22 completed gestational weeks and 92.5% at 23 completed gestational weeks either died or suffered from moderate or severe BPD. The incidence of ROP stage 3 or higher was greater in lower gestational weeks, and reached 50% and 23.8% at 22 and 23 completed gestational weeks, respectively, compared to 11.1% and 10% at 24 and 25 completed gestational weeks, respectively. Only three (7.5%) infants at 23 completed gestational weeks survived without severe morbidity. In contrast, survival without severe morbidity was 39.6% and 63.6% at 24 and 25 completed gestational weeks, respectively.
We found a significant correlation between grade 3 and 4 IVH and gestational age (P<0.001), birth weight (P=0.020), completed course of antenatal corticosteroid treatment (P=0.002) and mode of delivery (P=0.003). Multivariate logistic regression analysis showed that every additional completed gestational week in this period of pregnancy was associated with a 2.2 times decrease in the incidence of grade 3 and 4 IVH (OR=2.2; 95% CI 1.170–4.046; P=0.014) and the completed course of antenatal corticosteroids with a 3.5 times decrease (OR=3.5; 95% CI 1.145–10.768; P=0.028). There was a correlation between moderate to severe BPD and gestational age (OR=3.738; 95% CI 1.832–7.628; P<0.001). However, moderate to severe BPD did not correlate with a completed course of antenatal corticosteroids (P=0.271). We found no other significant correlation between perinatal factors or interventions and other severe neonatal morbidities.
The survival without severe morbidity reached 40% in the studied population. It increased gradually from 23 to 25 completed gestational weeks, and no such case was recorded among infants born at 22 completed weeks of gestation. Of those who survived without major morbidity, the induction of lung maturity was initiated in 85% and completed in 48%, and delivery was by cesarean section in 74% of the cases.
Both mortality and the incidence of severe grades of IVH in extremely preterm infants are inversely associated with gestation age. The perinatal outcome can be significantly improved by a completed course of antenatal corticosteroids as a part of the active perinatal approach.
Therefore, the results of different perinatal centers vary significantly. They correlate well with the center-specific intention to actively manage the cases of threatened preterm labors during the periviable period, by obstetricians and neonatologists. In his recent study, Smith et al.  demonstrates that in 22–24 completed gestational weeks, the use of antenatal corticosteroids ranged from 28% to 100%; cesarean deliveries from 13% to 65%; and resuscitation from 30% to 100% among participating perinatal centers. In our center, the results over the same gestational weeks were 84%, 52% and 97%, respectively, which would rank our center among the most proactive.
Several studies reported national outcomes of infants born in the periviable period. Although the design and included population in a number of them is different from our study, some comparison can be made.
In our study, the proportion of patients that survived until discharge increased rapidly with gestational age. Compared to the study by Crane et al. , after excluding stillbirths, we found almost five times higher survival until discharge at 23 completed gestational weeks (11.4% vs. 52.5%). The cesarean section rate showed a similar trend (10.5% vs. 47.8%). Both studies included deliveries only in tertiary perinatal units. Better survival until discharge in our center probably can be attributed to a more active approach, which is apparent from the cesarean section rate. However, the rate of severe brain injury among the survivors is similar (44.0% vs. 42.5%) .
Compared to the results of the U.K. EPICure study from 2006, we recorded better survival until discharge in all gestational weeks. However, the EPICure study included newborns born and transferred from non-tertiary centers. This further favors the proactive approach and delivery in the tertiary center .
The EXPRESS study prospectively followed all extremely preterm infants born in Sweden from 2004 to 2007. After excluding stillbirths, the 1 year survival of the EXPRESS study population was comparable to survival until discharge of our population .
Data from five Taiwan perinatal centers reported a similar trend in survival until discharge . Our results were better for each gestational week. The survival until discharge in our population was comparable to the U.S. data . It was slightly worse at 22 and 23 weeks, but better at 24 and 25 completed gestational weeks.
The inborn subgroup of the Australian cohort of extremely preterm infants reported 1 year survival of 0%, 28%, 48% and 79% at 22, 23, 24 and 25 completed gestational weeks, respectively, and survival without major morbidity was similar to our study .
Many previous studies confirm that both mortality and morbidity of the infants born between 22 and 25 completed gestational weeks mostly depend on the gestational age at delivery , , , . Survival of extremely preterm delivered infants increases with every additional week. However, gestational age at delivery is not the only factor with a significant impact on the mortality and morbidity of an extremely preterm infant. Every 100 g increase in birth weight contributed to the survival of the infant. Naturally, birth weight and gestational age are interrelated; hence, the logistic regression analysis did not show any significance.
A completed course of antenatal corticosteroids was associated with significant improvement in survival until discharge and a lower incidence of grade 3 and 4 IVH regardless of the gestational age at delivery. Multivariate logistic regression analysis showed that the benefits from a completed course of corticosteroids is comparable to one additional gestational week. Other studies presenting beneficial effects of corticosteroids during the periviable period also appear , . Tyson  has suggested that the course of corticosteroids has an equivalent effect on the reduction in the death rate and profound impairment as an additional 1.23 gestational weeks. Therefore, the ability to delay delivery to a higher gestational age further enhances the benefits of a completed course of corticosteroids. This is in agreement with the results of Smith et al. , who concluded that antenatal corticosteroids given at 22–24 completed weeks reduce death rate, death or ROP, death or LOS, death or NEC and death or neuro-developmental impairment in infants born at 25–27 completed gestational weeks. We did not find any significant effect on the incidence of moderate and severe BPD, stage 3 or more ROP, or NEC.
The survival rate was higher in infants delivered by cesarean section. However, the multivariate logistic regression did not show a significant association to survival, nor to major morbidity. In our cohort, the better outcome of infants delivered by cesarean section can be attributed to the overall higher gestational age compared to those delivered vaginally. The mode of delivery remains a topic of discussion. There are studies that find a cesarean section beneficial for the infant , , whereas others do not . There is no proof that a cesarean section favors motor or mental childhood neuro-development . A cesarean section has to be considered carefully as it may have a negative impact on the mother’s health and subsequent pregnancies. On the other hand, the willingness of the obstetrician to perform a cesarean section to improve the prognosis of an extremely preterm infant is probably beneficial .
We found no significant correlation between the mortality rate and the markers of inflammation in the maternal serum, histopathological signs of placental inflammation or PPROM. Other studies suggest that prolonged exposure to inflammation affects fetal development. Not only does it increase the incidence of BPD and ROP, but it can also influence long-term neuro-development, as suggested by Lee et al.  and Korzeniewski et al. . In our study, the incidence of moderate to severe BPD and ROP stage 3 or more was not influenced by the presence of intra-amnial inflammation.
Ishii et al.  confirmed that an important factor in neonatal mortality in low gestational weeks is IVH, which is most common in the lowest gestational weeks and often affects decisions on the continuation of intensive care. In our study, IVH was the most common cause of death and the main reason for discontinuing intensive care. A higher incidence of IVH in lower gestational weeks can be attributed likely to hypoxic insult during the resuscitation and stabilization of these infants in the delivery room as intrapartum hypoxia was not common.
Intensive care for neonates born at the limits of viability is very challenging and neonatal morbidities were common among the neonates born in every studied gestational week. We found considerable survival without severe morbidity. There was a high rate of lung maturity induction and cesarean sections among these infants. In a few cases of those who survived without major morbidity, the induction of lung maturity started before 24 completed gestational weeks. These infants benefited from the early initiation of a proactive approach, which was similar to those in the study of Smith et al. . Morbidity rates for each completed gestational week were similar to those reported in other studies and survival without major morbidity was higher than for other studies , , .
Survival without severe neonatal morbidity in these extremely premature infants suggests a favorable long-term outcome, but it is not guaranteed. Extreme prematurity itself carries a risk of long-term neuro-developmental impairment and some morbidities, especially low-grade IVH, may increase the risk of long-term disability among extremely premature infants . Follow-up data are desirable for the further improvement of perinatal care strategies.
We are aware of other limitations of our study. First, the retrospective design did not allow us to detect and note every characteristic that may have a possible impact on the outcome or on the decision to choose the proactive approach, such as pregnancy-associated morbidities, the race or the socioeconomic status of the mother. On the other hand, the data came from a single unit and all recorded parameters were well defined, which added some credibility. Second, the limited number of cases did not allow us to come to more statistically significant conclusions.
The limit of viability remains a major issue with great impact on the biomedical ethics of care for these infants. A proactive approach in 23 completed gestational weeks is associated with the survival of half of these infants, but the incidence of severe neonatal morbidity remains high. Survival without severe morbidity rises from 24 completed gestational weeks, which is, therefore, officially recognized as the threshold of viability.
Our work confirms that the short-term outcome of pregnancy at the limits of viability is influenced by an active perinatal approach. The decision to start intensive care in cases of imminent delivery at the limits of viability should result from a mutual consensus among obstetricians, neonatologists and parents thoroughly informed about the outcome and the risks associated with intensive care for infants born at this gestational age. The most important factors associated with improved short-term outcome are gestational age and a completed course of antenatal corticosteroids. A completed course of corticosteroids improves the neonatal prognosis regardless of the gestational age. Infants may benefit from a cesarean section. However, the indication has to be considered carefully as it is associated with increased maternal morbidity, and represents risks for subsequent pregnancies.
The aforementioned factors also play a role in the incidence of severe grades of IVH, which is the most common cause of death and neuro-developmental impairment. When further intensive neonatal care is intended, the antenatal administration of corticosteroids, the prevention of intrauterine inflammation and the choice of appropriate mode of delivery are crucial. The benefit of this proactive perinatal management is apparent in cases where delivery is delayed to 24 completed gestational weeks, although some cases of survival without major morbidity were observed among infants born at 23 completed gestational weeks. Continuous evaluation of the resulting neonatal morbidity and the degrees of their severity is necessary. In cases that appear futile, discontinuation of intensive care needs to be reconsidered in close collaboration with the parents.
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About the article
Published Online: 2017-03-27
Published in Print: 2018-01-26
Conflict of interest: Authors state no conflict of interest.
Material and methods: Informed consent: Informed consent has been obtained from all individuals included in this study.
Ethical approval: The research related to human subject use has complied with all the relevant national regulations, and institutional policies, and is in accordance with the tenets of the Helsinki Declaration, and has been approved by the authors’ institutional review board or equivalent committee.