Preterm Delivery
June  2016

​A family is applying for life insurance for their nine-month-old infant. The applied for amount, while high, appears consistent with sibling's. The infant was born at 35 6/7 weeks, weight was 50th percentile for his gestation, was given surfactant at birth and stayed in the NICU for 10 days. He made all of his well child checks and received all of his immunizations on time.

His older sibling and his father have asthma. His weight and height at six months are at the 75th percentile, not correcting for prematurity. He was born in early fall and has had two episodes of bronchiolitis, both responsive to albuterol.

There was a 23-hour observation in the emergency room at two months of age with no oxygen given. Later that winter he was seen and released for a second episode of bronchiolitis. On both visits, the APS listed runny nose, cough and cold symptoms, some wheezing and no respiratory distress or retractions. He followed up with his pediatrician in the days following each presentation and was improving. He has met all of his developmental milestones, and no other concerns are listed in the APS.

What are the mortality concerns of a premature infant?
Let us first review some of the definitions of prematurity. Prematurity is defined as any birth before 37 weeks gestation, as calculated from the mother’s last menstrual period. Late preterm is defined as 34 weeks to 36 6/7 weeks gestation. Very preterm is a gestational age of less than 32 weeks, while extremely preterm is less than 28 weeks gestation.

Many authors use weight criteria when classifying more preterm infants. Low birth weight (LBW) is less than 2500 gm, very low birth weight (VLBW) is defined as less than 1500 gm, while extremely low birth weight (ELBW) is defined as less than 1000 gm.
Neonatal mortality rate is defined as death in the first 30 days of life, while infant mortality measures death in the first year of life.

According to the CDC, the premature birth rate in the US in 2014 was 9.6%. The rate has fluctuated a bit in recent years due to improvements in care, survival of ELBW infants which in the past would have perished and changes in obstetric practices involving scheduled Cesarean sections and induced deliveries. About one half of preterm births are the result of spontaneous preterm labor, the cause of which is unknown. Other factors precipitating early labor include but are not limited to pregnancy with multiples, infection, drug, alcohol or tobacco use, chronic health problems in the mother, pre-eclampsia, problems with the uterus or cervix and extremes in maternal age.

Most preterm infants do well (80% of late preterms survive without morbidity), but both mortality and morbidity increase with increasing prematurity. Even among term infants, mortality varies by increasing gestational age, early term infants have a higher mortality rate than late term infants (Figure 1).

Gestational Age (in weeks)Risk Ratios​95% Confidence Interval
​34​4.62​2.5 - 8.4
​353.91​2.3 - 6.5
​36​3.14​2.0 - 4.9
​37​1.81​1.2 - 2.8
​381.75​1.2 - 2.5
​39​1.02​0.7 - 1.5
​40​----​----
​41​1.130.6 - 2.1​
​42​3.42​1.1 - 10.4

Figure 1 – Mortality Risk Ratios for Death between Days 1-365 after Birth by Gestational Age (Excluding Known Birth Defects) Ref: Young et. al.

Associated long term morbidities can include, intellectual disabilities and behavior problems, cerebral palsy, respiratory problems, visual problems including retinopathy of prematurity, hearing loss and feeding and digestive issues. All of these issues are not necessarily a result of prematurity but are definitely associated with it. From a mortality standpoint, most of the mortality occurs in the first month, although there still is an increased mortality rate in the first year compared to term infants.

Research studies
In a study published in 2007, birth and death certificates of infants born in Utah between 1999 and 2004 were reviewed. Early neonatal (days 1-7), neonatal and infant mortality were calculated for each estimated gestational age (EGA) cohort.

Two separate calculations were performed, the first including all deaths and the second including infants whose listed cause of death was something other than birth defects. The term “birth defects” would encompass structural or biochemical abnormalities, including hereditary conditions such as chromosomal abnormalities, congenital heart disease, disorders of the central nervous system, etc.

The Risk Ratios for all-cause mortality during the first year of life for those without birth defects are detailed in Figure 1. Important information such as maternal age and health, birth weight and cause of early delivery were not included in this analysis.

An older study of births in Norway between the years 1967-88 also provides an estimate of the mortality associated with prematurity. The relative risk of mortality was adjusted for year of birth, maternal age, and maternal education (Figure 2). Congenital anomalies were not considered as a factor.

Gestational Age (in weeks)​Relative Mortality Risk (females)​95% Confidence Interval
​22 - 27​9.7​4.0 - 23.7
​28 - 32​1.8​0.93 - 3.5
​33 - 36​1.6​1.2 - 2.0
​37 - 42​1 (reference)​----
​> 42​1.2​0.32 - 1.6

Figure 2 – Relative Risk of Death between Ages 1-5.9 Years based on Gestational Age at Delivery Ref: Swamy et. al.

Late preterm infants are the fastest growing subset of neonates. In the US in 2006, late preterms (LP) accounted for approximately 74% of all preterm infants. There is a threefold higher infant mortality rate in LP compared to their term counterparts (7.7 vs. 2.5 per 1000 live births). Congenital anomalies account for some of this increased mortality (Figure 3). LP infants are twice as likely to have a congenital malformation as term infants, and they are four times more likely than term infants to die of them.

Contributing factors
Intrauterine growth retardation (IUGR), itself a cause of increased mortality, is more common among LPs. When accounting for SGA (small for gestational age) in LPs, there still is an increased mortality rate. Maternal placental and postnatal complications are also more common in LP vs. term infants. These are examples of causes of the prematurity, rather than the results of such.

Bronchiolitis is a very common illness typically caused by a viral infection that begins in the upper respiratory tract and involves the bronchiolar epithelial cells causing inflammation and mucus production. Usually managed in an outpatient setting, it is more prevalent during the winter months and can occur more than once in a single respiratory season.

Although essentially all children have antibody evidence of bronchiolitis by their third birthdays, this usually mild illness can become serious. Risk factors for severe disease include: prematurity, age less than 12 weeks, chronic pulmonary disease, congenital heart disease, immunodeficiency and neurologic disease. Severe disease would be manifested by respiratory distress, hypoxia and possibly respiratory failure.

EGA*​Birth DefectsImmaturityAsphyxiaInfections​Known causes**SIDSAccidents​All OthersTotal #
​34​70​5​10​0​2.5​2.5​0​10​40
​35​64​14​2​0​610​0​10​50​
​36​60​6.5​6.5​1.3​6.5​9.1​1.3​9.1​77
​37​57​3.4​2.3​4.5​9.1​11.4​5.7​6.8​88
​38​42​2.7​6​4.7​7.4​19.5​4.7​13.4​149
​39​43​2.1​7.7​7​4.9​21​5.6​8.4​143
​40​33​2.8​8.3​15.3​4.2​11.1​11.1​13.9​72
​41​48​4​0​12​4​16​8​8​25
​42​57​0​0​14.3​0​0​14.3​14.3​7

Figure 3 - Causes of Death for Each Gestational Age Cohort in the First Year by %
* EGA, Estimated Gestational Age, ** Endo/neuro/etc. Ref: Young et. al.

From 1915 to 2008, infant mortality rates went from 99.9 deaths to 6.6 deaths per 1000 live births. Similarly, neonatal mortality rates from 1950-2008 decreased from 20.5 deaths to 4.3 deaths per 1000 live births. Other countries’ rates have continued to decrease, but the US (and Canada) have essentially plateaued, leading to worse ranking.

Between 2000 and 2005, preterm births increased by 9% which accounted for a large portion of deaths. Low birthweight infants rose from 1983-2005, 6.8% to 8.2%. Canada saw a similar rise in ELBW infants. It appears that the lack of decline and/or slow improvement in infant and neonatal mortality rates has to do with the increasing number of live births of the very small and premature.

Returning to the case
This child is a late preterm infant who at nine months of age appears to be growing and developing normally. His weight is within the average range without correcting for prematurity. He received surfactant at birth, which is used as prevention or treatment of respiratory distress syndrome (policies regarding administration vary between institutions). He was discharged from his neonatal stay on no medications.

He did present on two separate occasions with symptoms of bronchiolitis including cough, runny nose and wheezing but no retractions or respiratory distress. Given that our proposed insured was a late preterm infant and only two months of age during his first episode, he was observed in the hospital to monitor his respiratory status. He ultimately was discharged home doing well and followed up the next day with his pediatrician. Although he was given albuterol and responded to it favorably, that is usually an indication of family history of asthma rather than severity of illness.

The majority of mortality with prematurity occurs in the first 30 days of life, often involves congenital malformations, low birth weight and respiratory distress of the newborn among other things. Conditions that would be concerning for possible increased mortality would include congenital heart disease, neurologic issues -- especially those including developmental delay, an oxygen requirement or feeding difficulties, especially if listed as failure to thrive.

Our youngster seems to be growing well and weathering the normal childhood illnesses without difficulties. The case was assessed at minimal to no excess mortality.

References
Kugelman, A, Colin, A “Late Preterm Infants: Near Term but Still in a Critical Development Period”. Pediatrics 2013:132 (4): 741-751.
Lau, C, et al “Extremely Low Birth Weight and Infant Mortality Rates in the United States”. Pediatrics 2013:131 (5): 855-860.
http://www.statisticbrain.com/premature-birth-statistics/ accessed 5/11/2016.
Young, P, et al “Mortality of Late Preterm (Near-Term) Newborns in Utah”. Pediatrics 2007:119 (3): 659-665.
Swamy K et al. “Association of Preterm Birth With Long-term Survival, Reproduction, and Next-Generation Preterm Birth”. JAMA. 2008;299(12):1429-1436.

UpToDateR last accessed 5/11/2016.