Neonatal outcomes and long-term neurodevelopmental evaluations of hospitalized early term infants: prospective case-control study

Abstract

BACKGROUNDS:

It was intended to compare early term babies to term babies by reviewing short-term issues and long-term neurodevelopmental evaluations.

METHODS:

It was planned as a prospective case-control study. Of the 4263 infants admitted to the neonatal intensive care unit, 109 infants born at early term by elective cesarean section and hospitalized within the first 10 postnatal days were included in the study. As the control group, 109 babies born at term were enrolled. Nutrition status of infants, reasons for hospitalization in the first postnatal week were recorded. When the babies were 18-24 months old, an appointment was made for neurodevelopmental evaluation.

RESULTS:

In the early term group, the time of breastfeeding was later than the control group, with a statistically significant difference. Similarly, breastfeeding difficulty, need for formula in the first week postpartum and hospitalization were found to be significantly higher in the early term group. Considering the short-term results; pathological weight loss, hyperbilirubinemia requiring phototherapy and feeding difficulties were statistically significantly higher in the early term group. Neurodevelopmental delay did not statistically differ across the groups, but the early term group’s MDI and PDI scores were found to be statistically lower than those of the term group.

CONCLUSION:

Early term infants are thought to be like term infants in many ways. Although these babies are similar to term babies, they are still physiologically immature. The short and long-term negative consequences of early term birth are obvious, non-medical elective early term births should be prevented.

Keywords

Birth breastfeeding early term neurodevolepmental term

Abbreviations

C/S

Cesarean section

ACOG

American Committee of Obstetrics and Gynecology

NICU

Neonatal Intensive Care Unit

MDI

Mental development index

PDI

Psychomotor development index

1 Introduction

While cesarean (C/S) birth rates should be 10–15% among all births, they have increased rapidly in recent years around the world, especially in middle and high-income countries. Between 1990 and 2014, the C/S birth rate increased from 22.3% to 32.3% in the United States, from 11.2% to 25% in Europe, and from 4% to 19.5% in Asia [1]. Similarly, C/S birth rates in Turkey increased from 7% to 48% between 1993 and 2014 [2]. Much of this increase is due to the increase in non-medically induced early term births [3]. Although the American Committee of Obstetrics and Gynecology (ACOG) does not recommend elective delivery before 39 weeks of gestation, most early term deliveries are due to preventable elective inductions [4].

Medical requirements for late preterm or early term delivery are defined as follows; preeclampsia, eclampsia, gestational hypertension, complicated chronic hypertension, oligohydramnios, uncontrolled gestational diabetes, previous cesarean section or myomectomy history, placental location anomaly, fetal growth retardation, premature rupture of membranes, gestational cholestasis, fetal congenital malformation [5]. Apart from these clinical indications, it has been stated that fetal lung maturation, suspected macrosomia, and well-controlled gestational diabetes alone are not an indication for early term delivery [4].

Both physicians, allied health staffes or families think that early term babies are like term babies in many respects. Although these babies are similar to term babies, they are still physiologically immature. It is known that late preterm babies should be monitored more closely in the postnatal period than term babies, and they experience problems such as pathological weight loss, jaundice and respiratory distress more frequently than term babies [6]. Early term babies have also not completed their maturity and have similar risks, and these babies should not be overlooked.

The aim of this study is to review the short-term problems, long-term neurodevelopmental evaluations of babies born with elective C/S at early term, and to compare the short and long-term outcomes with term babies born with elective C/S.

2 Material and methods

This study is a prospective case-control study that was performed in Dr. Behçet Uz Children’s Education and Research Hospital, clinic of neonatology. During the 1-year period during which the patient was admitted to the study, 4263 newborns (0-28 days) were admitted to the neonatal intensive care unit of our hospital. Since we are not a maternity hospital, some of these newborns were admitted to the outpatient clinic or emergency service, and some were accepted by referral from an external center. Babies born at 37-38 ^1/7 -6/7 weeks with elective C/S at early term and hospitalized within the first 10 postnatal days were included in the study. Similarly, babies born term (at 39-41^1/7 -6/7 weeks) with elective C/S and hospitalized within the first 10 postnatal days were included as the control group. Babies born at early term due to medical reasons (emergency obstetric indication, for example, preeclampsia (if this was the mandatory indication for delivery), eclampsia, ablasio placenta), had major congenital anomalies and had been small for gestational age were not included in the study. Moreover, babies who did not have family consent and who had deficiencies in the study form were excluded from the study. In the study, the week of gestation was defined based on the date of the last menstrual period. The C/S status of the mother due to medical or elective reasons was determined according to the obstetric indications of the obstetricians following the mother.

The infants included and excluded from the study are summarized in Fig. 1.

Fig. 1

Infants included and excluded from the study.

The selection of case and control groups were determined based on the fact that hospitalization was required as a result of hospital admissions between the dates range in which the study was carried out and that they met the criteria I mentioned above.

Ethics committee approval of the study was received from T.C. Ministry of Health Izmir Provincial Health Directorate H.S.U. Dr. Behçet Uz Children’s Education and Research Hospital Clinical Research Ethics Committee (Approval number 2019/248).

2.1 Procedure

Our hospital is a children’s hospital and not a maternity hospital, births do not take place in our hospital, therefore, early term and term infants born with elective C/S were admitted to our neonatal intansive care unit (NICU) either by referral from the hospital where the delivery was made or as a result of the evaluation made in the outpatient clinic or emergency service. Necessary respiratory support was given to babies with respiratory distress, and they were hospitalized in the NICU (2^nd or 3^rd Level) according to the needs of the baby.

2.2 Data collection

Week of gestation, parity, presence of problems in pregnancy (gestational diabetes/preeclampsia/hypothyroidism/infection), gender, birth weight, postpartum mother-baby discharge time, breastmilk/ breastfeeding/ formula support status in the first postnatal week, hospitalization reasons, discharge weight and rehospitalization status was recorded. Post-discharge follow-ups were performed in the risky baby follow-up clinic and when the babies were 18-24 months old, the families were contacted using the phone numbers registered in the hospital system and an appointment was made for neurodevelopmental evaluation.

2.3 Bayley-II ınfant and child development assessment scale

The Bayley Infant and Child Development Assessment Scale was developed by Nancy Bayley. In 1993, Bayley Infant and Child Development Assessment Scale-II version (Bayley-II) was published. Bayley-II evaluates the developmental status of the child in general terms, in accordance with the specific ages. The Bayley-II is used in the United States to assess children aged 1-42 months and monitor their development. It has been standardized in 1700 children and has been used in research and clinical practice for more than 40 years [7]. It is one of the best among the tests that evaluates child development. In a systematic review examining the effects of early interventions on motor development, it was once again emphasized that the Bayley scale is the most commonly used method to measure neuromotor and developmental outcomes [8].

Evaluation scales of Bayley and Bayley-II are mental development index (MDI) and psychomotor development index (PDI). In summary, MDI evaluates cognitive and language development, while PDI evaluates gross and fine motor development [9].

Long-term neurological and developmental outcomes were evaluated with Bayley-II at 18-24^th month. Bayley and neurologic examinations of the patients were performed by the same specialist at the Developmental and Behavioral Pediatrics Unit. Mental development index and PDI scores were recorded. Presence of neurodevelopmental retardation; was defined as cerebral palsy, bilateral hearing loss/blindness, or an MDI or PDI score below 70.

2.4 Sample size

The duration of the study was determined as 2 years (patient admission to the study was carried out for 1 year, the study lasted for 2 years, including neurological evaluations), and the infants included in the study were evaluated in terms of neurodevelopment between 18-24 months. Patient admission to the study was carried out between 2019-2020, neurological evaluation was performed between 2020-2021. Evaluating the number of patients hospitalized in our hospital in the previous years with similar characteristics and in a similar time period, 220 patients were planned to be included in the study based on these numbers.

2.5 Statistical analysis

Statistical data were evaluated with the SPSS 25 program (IBM Corporation, Armonk, New York, United States). During the statistical evaluation of the data, parametric methods were used in the analysis of the numeric data conforming to the normal distribution, and nonparametric methods were used in the analysis of the numeric data and categorical data that did not fit the normal distribution. Normalization evaluation was evaluated according to Kolmogorov-Smirnov analysis. Mean and standard deviation for parametric methods; median and minimum-maximum values were used for nonparametrics. Student-T test to evaluate whether the means of data belonging to two different groups differ from each other (Mann-Whitney U test if nonparametric), Fisher’s exact and Chi-square tests were used to evaluate the relationship between the proportions.

3 Results

A total of 218 infants were included in the study, 109 early term infants in the study group and 109 term infants in the control group. Gender distribution, maternal age and parity were similar between groups. 51.4% of all pregnants were primiparous. There was a statistically significant difference between the groups in terms of birth weights (birth weight, p = 0.02) (Table 1). In the early term group, the time of breastfeeding was 2.54±1.31 days later than the control group, with a statistically significant difference (p = 0.00). Similarly, breastfeeding difficulties, need for formula in the first week of postnatal period and hospitalization were found to be significantly higher in the early term group (p = 0.00, p = 0.01, p = 0.00, respectively) (Table 2). Considering the short-term results in the hospitalization process; pathological weight loss, hyperbilirubinemia requiring phototherapy and feeding difficulties were statistically significantly higher in the early term group (p = 0.04, p = 0.02, p = 0.00, respectively) (Table 3). There was no statistically significant difference between the groups in terms of respiratory support, surfactant requirement, neonatal transient tachypnea, sepsis, hypocalcemia and hypoglycemia (Table 3). No difference was found between the groups in terms of rehospitalization in the first 6 months postnatally. When the long-term neurological and developmental outcomes of the groups were compared with Bayley-II, there was no statistical difference between the groups in terms of neurodevelopmental delay. However, the MDI and PDI scores in the early term group were found to be lower than the term group, making a statistically significant difference (MDI, p = 0.05, PDI, p < 0.01) (Table 4).

Table 1
Demographic features

Early term Term p

(n:109) (n:109)

Gestation week* 37.73±0.44 39.64±0.68 <0.01

Birth weight (g)* 3214.16±423.84 3308.30±309.20 0.02

Gender (boy) 69 61 0.33

Maternal age* 27.02±4.36 27.31±4.64 0.32

Primiparity 50 62 0.13

Gestationel DM 13 5 0.08

Preeclampsia 5 2 0.24

Infection in last trimester 15 17 0.84

Mother-infant discharge (/days)* 1.62±1.07 1.59±0.84 0.77

	Early term	Term	p
Gestation week*	37.73±0.44	39.64±0.68	<0.01
Birth weight (g)*	3214.16±423.84	3308.30±309.20	0.02
Gender (boy)	69	61	0.33
Maternal age*	27.02±4.36	27.31±4.64	0.32
Primiparity	50	62	0.13
Gestationel DM	13	5	0.08
Preeclampsia	5	2	0.24
Infection in last trimester	15	17	0.84
Mother-infant discharge (/days)*	1.62±1.07	1.59±0.84	0.77

Abbreviations: *Mean±SD, DM: diabetes mellitus.

Table 2

Nutritional characteristics of early term and term infants and babies’ hospitalization status after the mother and baby discharge

	Early term	Term	p
	(n:109)	(n:109)
Time to breastfeed (/days)*	2.54±1.31	1.72±0.93	<0.01
Breastfeeding difficulties	52	29	<0.01
Formula support in the first week	63	41	0.01
PN 1^st-7^th day of hospitalization	99	68	<0.01

Abbreviations: *Mean±SD, PN: postnatal, Time to breastfeed(/days): the day when breastfeeding without formula or being able to be fed with expressed breast milk can be achieved, Breastfeeding difficulties: falling asleep while feeding, fatigue, need for resting while nutrition or orogastric tube requirement to complete feeding.

Table 3

Findings in the hospitalization process

	Early term	Term	p
	(n:109)	(n:109)
Hypernatremic dehydration	16	10	0.29
Pathological weight loss	30	17	0.04
Hyperbilirubinemia requiring treatment	92	74	0.02
Feeding difficulties	33	11	<0.01
Transition to t/o nutrition (days)*	4.43±3.28	4.18±1.66	0.74
Hypoglycemia	2	1	1.00
Early hypocalcemia	3	1	0.31
Late hypocalcemia	2	1	0.56
Culture (+) sepsis	7	9	0.79
Respiratory support	7	8	1.00
MV	4	1
Nasal ventilation	3	7	0.06
Surfactant requirement	3	1	0.31
Neonatal transient tachypnea	13	11	0.82
Pneumothorax	1	–	0.31
Length of hospitalization (/days)*	5.44±4.91	4.70±3.40	0.19

Abbreviations: *Mean±SD, t/o: total/oral, MV: mechanical ventilation, Hypernatremic dehydration: serum sodium value is ≥ 150 mEq/L, Pathological weight loss: ≥10% weight loss at postnatal 5^th day, Transition to t/o nutrition (days)*: day of transition to total oral feeding, Early hypocalcemia: <8 mg/dL, occurs in the first 3 days of life, Late hypocalcemia: <8 mg/dL, after the first 3 days of life [29].

Table 4

Long-term neurodevelopmental outcomes

	Early term	Term	p
	(n:109)	(n:109)
Rehospitalization (first 6 months
except 0-28 days)	10	6	0.43
Age at present (months)*	24.36±1.56	24.07±1.16	0.12
(n:60)**	(n:60)**
MDI/*	85.35±10.99	89.97±14.14	0.05
PDI/*	82.65±8.30	90.13±10.62	<0.01
NDI 1/**	9	6	0.40
MDI < 70**	6	6	1.00
PDI < 70**	4	1	0.13
Cerebral palsy**	–	–	–
Bilateral deafness**	–	–	–
Bilateral blindness**	–	–	–

Abbreviations: *Mean±SD **Data on 60 patients from early and term babies are available. MDI: mental developmental index, PDI: psychomotor developmental index, NDI¹: norodevelopmental retardation index: defined as the presence of 1 or more of the following; 1) Moderate to severe cerebral palsy with functional losses, 2) Bilateral hearing loss and blindness, 3) Bayley-II MDI or PDI score < 70.

4 Discussion

In the past years, ACOG and the Maternal Fetal Medicine Association have defened that delivery should be delayed until the 39^th week of pregnancy is complete, unless there is a medical necessity. However, despite all this, the rate of early term births continues to rise in the United States and around the world [10]. On the other hand, late preterm birth rates decreased to 8.8% [11].

In a study that included more than 40 million infants between 1995 and 2006, early term and term babies were compared and it was shown that neonatal, postnatal and infantile mortality rates in early term babies were higher than term babies [12]. ACOG stated that in 2013, the mortality rates of babies born at 37-38^1/7 -6/7 gestational weeks were 1.9 and 1.2 times higher, respectively, compared to term babies [13]. In another study, neonatal morbidity rates of babies born between 32-39 weeks of gestation were compared according to the weeks of birth and it was found that each 1-week growth in the gestational week provided a 23% reduction in neonatal morbidity [14, 15].

Nutritional problems are common in the transition to extrauterine life in early term babies [16]. This is potentially incomplete before the 38^th week of sucking-swallowing synchronization and may be due to the search-sucking reflex not fully developed until 36-38 weeks of gestation [17]. Breastfeeding success rates in early term infants are not well defined [18]. Escobar et al. reported that the most important factor leading to hospitalization due to dehydration in babies born between 36-39 weeks of gestation is insufficient breast milk in the early period [19]. This finding suggests that early term infants are less capable of suckling to meet their physiological needs [19]. In our study, similar to the literature, it was determined that the time to be fed with breast milk is later, breastfeeding difficulties are more common, formula use and hospitalization are higher in the first week postnatally in comparison to term babies. Early term infants are at increased risk of hospitalization due to breastfeeding failure compared to term infants.

In the study, it was determined that the rates of breastfeeding problems, pathological weight loss, and hyperbilirubinemia requiring treatment were higher in babies born early term compared to term babies. These findings of the study are consistent with the findings of Martinez et al., who showed that early term babies have a higher risk of hospitalization, feeding difficulties, hypoglycemia and hyperbilirubinemia [20]. Similarly, Sengupta et al. reported that the need for intravenous fluids, intravenous antibiotic treatment, and the risk of hospitalization and hypoglycemia were higher in early term infants [21]. In another population-based study conducted in Brazil recently, it was found that breastfeeding difficulties, hyperbilirubinemia requiring treatment, hypoglycemia, hospitalization and mortality rates were higher in early term babies than in term babies [22]. Early term births and associated morbidities place a significant economic burden on healthcare systems worldwide. Therefore, the benefits must be weighed against the risks when planning an elective delivery before 39 weeks of gestation.

In a meta-analysis a total of 327.272 babies born vaginally and 55.246 babies born with elective C/S were included in which 16 studies were examined in the literature, the risk of respiratory morbidity in newborns born with elective C/S was 95% higher than in newborns born vaginally. The overall risk ratio revealed a significant relationship between early term birth and delivery type; the risk of respiratory morbidity in early term newborns delivered by elective C/S was found to be 6.3 times higher than in early term newborns born vaginally [23]. In our study, no statistically significant difference was found in terms of respiratory morbidities between early term and term newborns. This may be due to the fact that only infants born with elective C/S were included in the study due to the homogeneity of the groups. In a study that will include more patients, subgroup analysis (such as 37 vs 39 gestation week) according to the weeks of gestation may cause a difference in respiratory morbidities between the groups.

Recent studies indicated that births before 39 weeks of gestation increase the risk of brain damage and long-term neurodevelopmental abnormalities [24]. The reason for this is, that approximately 50% of the cerebral cortical volume is occured between weeks of 34–40^th gestation and ıt has been shown to increase by 1.4% of gray matter volume between weeks of 36-40^th gestation [25, 26]. Neurological and developmental outcomes evaluated with Bayley-II at 18-24^th months, there was no statistical difference between the groups in terms of neurodevelopmental delay, however, MDI and PDI scores in the early term group were found to be lower than the term group, making a statistically significant difference. The increased risk of early hospitalization in early term infants alone may affect long-term neurodevelopmental outcomes [27]. Although the long-term results of preterm infants were evaluated only at 2 years of age in our study, in the literature; ıt has been stated that long-term childhood morbidities including school performance and behavior, increased hospitalization up to 5 years of age, asthma and wheezing rates are observed more frequently in early term infants [28].

To the best of our knowledge, this is the first prospective case-control study comparing the short- and long-term neurodevelopmental outcomes of early term infants with elective C/S, with term infants. On the other hand, our study has some limitations. First, since babies born by normal spontaneous vaginal delivery were not included in the study, the number of our patients may be insufficient to generalize. Second; due to the low number of patients, subgroup analysis was not performed between the study and control groups, and in studies with larger series where the number of patients will be increased, subgroup analyzes can be given priority according to the weeks of gestation. The third is; in the evaluation of long-term neurodevelopmental results, the comparison of the 18-24^th month results as well as the 5-year-old neurodevelopmental evaluations and school achievements can be planned as a second phase of the study.

5 Conclusion

Many pregnant women accept elective early term birth, unaware of the potential risks to their babies. However, the negative consequences of early term delivery are obvious, in this process, awareness of families and all healthcare professionals should be increased, families should be informed about possible risks and non-medical elective premature births should be prevented.

Footnotes

Acknowledgments

There are no contributors, either financial or material support.

Conflict of interest

The authors declare no conflict of interest.

Funding information

No funding was received for this project.

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