Almost But Not Quite Term: Special Risks for Late Preterm and Early

Term Infants

Sarah N. Taylor, M.D.Assistant Professor, Division of Neonatology

Medical University of South Carolina

February 4, 2012

What is a “Late Preterm Infant”?

• Near-term does not– “capture how immature and vulnerable”

Near termModerately preterm

Minimally preterm Marginally preterm

Late Preterm

NICHD workshop July 2005

Late Preterm Infant Definition

• NICHD: 34 0/7 to 36 6/7 weeks gestation– 34th week chosen secondary to obstetrical decision to not

give antenatal steroids at that gestation

• Other possibility: gestational age associated with “normal” birth weight (≥ 2500g) and can be admitted to normal newborn nursery (≥ 35 weeks)– 35 0/7 to 36 6/7 weeks gestation

37 0/7 - 37 6/7 weeks can also be “immature and vulnerable”

Escobar GJ et al Semin Perinatol 2006; Ramachandrappa A & Jain L et al Pediatr Clin North Am 2009; Raju TN et al Pediatr 2006

ACOG Has An Opinion

• Fetal pulmonary maturity should be confirmed before scheduled delivery at less than 39 weeks of gestation unless fetal maturity can be inferred from historic criteria (criteria suggesting 39 weeks of gestation)

ACOG Practice Bulletin No. 97 2008

New Definition: Early-Term Birth

• 37 0/7 to 38 6/7 weeks• Based on ACOG guidelines to delay elective

deliveries to 39 0/7– Supported by The March of Dimes, NICHD, Society

for Maternal-Fetal Medicine

Gyamfi-Bannerman C Semin Perinatol 2011; Clark SL et al Am J Obstet Gynecol 2009; Tita AT et al N Engl J Med 2009; Ashton DM Curr Opin Obstet Gynecol 2010; Spong CY et al Obstet & Gynecol 2011

How Many Late Preterm Infants Are There?

• 34-36 weeks gestation– 75% of preterm infants in U.S.

• 35-36 weeks gestation– 7% of all live births in U.S.– 58.3% of preterm births in U.S.

• Increasing population since 1990– <34 weeks, by 10%– 34-36 weeks, by 25%

Ramachandrappa A & Jain L Pediatr Clin North Am 2009; Sharpiro-Mendoza CK et al Pediatr 2008; Escobar GJ et al Semin Perinatol 2006

How Many Early Term Infants Born By Elective Repeat C/section?

• 24,077 at 19 centers 1999-2002• 13,258 elective• 35.8% before 39 completed weeks

– 6.3% at 37 weeks– 29.5% at 38 weeks– 49.1% at 39 weeks

• Increased respiratory disease, mechanical ventilation, newborn sepsis, hypoglycemia, admission to NICU, and hospital stay >5 days– 37 weeks, adjusted odds 1.8-4.2– 38 weeks, adjusted odds 1.3-2.1

Tita AT NEJM 2009

Despite the size and growth of this population,

minimal evidence-based practice and/or research available

Despite the size and growth of this population,

minimal evidence-based practice and/or research available

Therefore, this group is scary for both neonatologists and pediatricians

So, Why So Many Late Preterm Infants?

• Delivery at 34 weeks considered “safe”– Cut-off for antenatal steroids

• Increased fertility/multiples• Increased mothers with medical conditions

– Pregnancy and non-pregnancy-related

• Increased fetal monitoring• Babies are bigger

Verklan MT Crit Care Nurs Clin North Am 2009; Davidoff MJ et al Semin Perinatol 2006; Raju TN Clin Perinatol 2006Ramachandrappa A & Jain L Pediatr Clin North Am 2009; Shapiro-Mendoza CK et al Pediatr 2008; Escobar GJ et al Semin Perinatol 2006

So, Why So Many Late Preterm Infants?

• Delivery at 34 weeks considered “safe”– Cut-off for antenatal steroids

• Increased fertility/multiples• Increased mothers with medical conditions

– Pregnancy and non-pregnancy-related• Increased fetal monitoring• Babies are bigger• “I want this baby out”

Verklan MT Crit Care Nurs Clin North Am 2009; Davidoff MJ et al Semin Perinatol 2006; Raju TN Clin Perinatol 2006Ramachandrappa A & Jain L Pediatr Clin North Am 2009; Shapiro-Mendoza CK et al Pediatr 2008; Escobar GJ et al Semin Perinatol 2006

Higher Induction and Cesarean Section Rates

• Nearly 1 in 4 births born by induction• One in 3 births by cesarean section • Repeat c/section in 92% of women with primary

c/section

• Increases in inductions and c/sections are predominately in the late preterm and early term (34-39 weeks)

• Most frequent length of a singleton pregnancy is now 39 weeks instead of 40 weeks gestation

• Mean age of twin delivery: 35.3 weeks

Verklan MT Crit Care Nurs Clin North Am 2009; Lee YM et al Clin Perinatol 2006; Ramachandrappa A & Jain L Pediatr Clin North Am 2009; CDC 2005

Intermountain Healthcare System Had a Problem

• 9 hospitals involved in process improvement • Pre-test: 28% of elective deliveries were <39 weeks• Intervention: presentation of the morbidities associated

with delivery at <39 weeks– Rate of NICU admissions for normal pregnancies

• 37 weeks: 8.9%• 38 weeks: 4.5%• 39 weeks: 3.3%

– Rate of ventilator use for uncomplicated deliveries• 37 weeks: 1.4%• 38 weeks: 0.5%• 39 weeks: 0.3%

Oshiro BT, Henry E et al. Obstet & Gyn 2009

Results of Intervention

Percent of elective deliveries

Pre-intervention

6-months post 6-years post

Prior to 39 weeks

28 10 3

Oshiro BT, Henry E et al. Obstet & Gyn 2009

NICHD and Society for Maternal-Fetal Medicine Workshop 2/2011

• Timing of Indicated Late Preterm and Early Term Births

From Spong CY, Mercer BM, D’Alton M et al. Timing of indicated late-preterm and early-term birth. Obstetr and Gynecol 2011;118:323-33.

Definition of Indicated Late Preterm

• Multiple reasons– Indicated: Preterm labor, rupture of membranes,

pre-eclampsia, intrauterine growth restriction with abnormal testing, acute abruption,

– Debatable Indication: IUGR with reassuring testing, gestational hypertenstion, mild pre-eclampsia, oligohydramnios

Gyamfi-Bannerman C Semin Perinatol 2011; Zhang J et al Br J Obstet Gynaecol 2004; Holland MG et al Am J Ostet Gynecol 2009

Indicated Late Preterm Delivery• Placenta previa, accreta, increta, percreta• Prior classical cesarean• IUGR with abnormal studies• Twins: mono-mono, mono-di, fetal death, IUGR• Oligohydramnios• Chronic hypertension with difficult control• Severe preeclampsia• Diabetes- poorly controlled• Rupture of membranes• Progressive labor

Spong CY et al Obstetr & Gynecol 2011

Indicated Early Term Delivery

• Prior myomectomy necessitating cesarean• Singleton IUGR• Twins: di-di• Chronic hypertension-controlled• Mild preeclampsia• Diabetes- pregestational with vascular disease

Spong CY et al Obstetr & Gynecol 2011

If Delivering Late Preterm• Lung Maturity Testing

– Lung profile does not represent other organs– If delivery is necessary, then deliver despite maturity

• Antenatal Steroids– Recommended for preterm birth before 34 weeks– 1 RCT studied with elective C/section <39 weeks

• Less neonatal respiratory distress admissions • However, delaying delivery to 39 weeks was associated

with even less neonatal respiratory distress admissions

Spong CY et al Obstetr & Gynecol 2011; Stutchfield P et al BMJ 2005

What are the risks of late preterm delivery?

Results of Early Delivery

• Birth hospitalization– Median length of stay similar for “near-term” (35-

36 weeks) and full-term – However, wide variations in hospital stay for near-

term infants after both vaginal and cesarean deliveries

Wang ML & Dorer DJ Pediatr 2004

Hospitalization Following Elective Deliveries

• Elective delivery with no medical indication– Admission to special care nursery

• 17.8% at 37-38 weeks• 8% at 38-39 weeks• 4.6% ≥ 39 weeks

– Mean length of stay 4.5 days

Clark SL et al Am J Obstet Gynecol 2008

Rehospitalization

• Rates– 6.3% for 35-37 weeks; 3.4% for 38-40 weeks;

2.4% for >40 weeks (Oddie SJ et al Arch Dis Child 2005)

– 4.3% late preterm; 2.7% term (Tomashek KM et al Semin Perinatol 2006)

• Late rehospitalization (15-182 days post-discharge)– 9.1% for 34 wks; 6.8% for 35 wks; 7.3% of 36 wks;

5.6% for 37 wks, 4.4% for 38-40 wks, 3.6% for ≥40 wks (Escobar GJ et al Semin Perinatol 2006)

Why Are Infants Rehospitalized?

• Most common reasons– Jaundice, feeding difficulties, and/or dehydration

• Predictors of rehospitalization

Escobar GJ et al Semin Perinatol 2006; Oddie SJ et al Arch Dis Child 2005

Predictor Hazard Ratio 95% CI

36 weeks gestation 1.67 1.23-2.25

Male gender 1.24 1.08-1.42

Assisted ventilation as neonate

2.04 1.5-2.79

≥ 41 wks gestation 0.75 0.61-0.93

CI- confidence interval

Risk Factors for Rehospitalization

• Late preterm infants – 1.5 times more likely to require hospital-related

care– 1.8 times more likely to be admitted

Significant difference between breastfed late preterm and term infants

No significant difference between not breastfed late preterm and term infants

Tomashek KM et al Semin Perinatol 2006

Mortality Risk

• 2002 U.S. Mortality rate by gestational age

• For 34-36 weeks, mortality rate of 7.9% which is 3 times higher than the term infant rate

Gestational Age Rae per 1000 births

Term 2.5

35-36 weeks 6.9

30-34 weeks 18.5

<30 weeks 285.3

Escobar GJ et al Semin Perinatol 2006

Tomashek KM et al Semin Perinatol 2006; Tomashek KM et al J Pediatr 2007; Mathews TJ et al Natl Vital Stat Rep 2007

Mortality Risk for Early Term?

• Relative Risk of Mortality– At 37 weeks, 2.6-2.9 times the risk at 39 weeks– Also increased at 38 weeks compared to 39 weeks

Reddy UM et al Obsetrics Gynecol 2011

Neurodevelopment of the Late Preterm Infant

• Brain growth compare to 40 weeks gestation– Cerebral volume is only 53% – Weight is 66%– Cerebral cortex has less gyri/sulci and is smooth– Myelination and interneuronal connectivity is

incomplete

Kinney HC Semin Perinatol 2006; Ramachandrappa A & Jain L Pediatr Clin North Am 2009;Adams-Chapman I Clin Perinatol 2006; Verklan MT Crit Care Nurs Clin North Am 2009

Neurodevelopment Studies

• 20-year follow-up of late preterm infants with no congenital anomalies– Higher incidence of

• Cerebral palsy: Relative risk (RR) 2.7• Mental retardation: RR 1.6• Significantly increased psychological development

problems, behavioral and emotional disturbances, and other major disabilities

– More likely to receive disability allowance– Less likely to attain post-secondary degree

Lindstorm; Moster D et al NEJM 2008

In the United States

• Late preterm compared to term births through kindergarten– 36% higher risk for developmental delay or disability– 19% higher risk for suspension in kindergarten

• Repeat study controlling for neonatal complications– 35-36 week infants with admission to NICU had lower

neurocognitive scores– Late preterm without complications were similar to term

counterparts

Morse SB et al Pediatr 2009; Baron IS Early Hum Dev 2011

Early Years

• Within first 3 years, compared to term infants– Increased diagnosis of developmental delay– Increased referrals for special needs preschool

resources– Increased difficulties with school readiness

Inder TE et al Ann Neurol 1999; Verklan MT Crit Care Nurs Clin North Am 2009

So, experts are worried…

• NICHD and Association of Women’s Health, Obstetric, and Neonatal Nurses– Research agenda to better understand short- and

long-term medical complications that are associated with late preterm births

– Anticipation and management of potential morbidities

– Assistance with non-emergent obstetric intervention decisions

We need further evidence for late preterm infant management and

further medical support to extend pregnancies

Why do we do in the meantime?

Short-term Late Preterm Problems

• Feeding Difficulties• Dehydration• Breastfeeding

difficulties• Hypoglycemia• Hyperbilirubinemia

• Temperature Instability• Increased sepsis work-

ups

• Respiratory Failure• RDS• TTN

What is the Morbidity Risk?

• Newborn morbidity risk – Late preterm infant- 22%– Term infant-3%

Late preterm infants were 7 times more likely• Risk increases with decreasing gestational age• 38-41 wks: 3% 37 wks: 6% 34 wks: 52%• Compared to 40 weeks

– 35 week infants had 10X’s the risk– 36 week infants had 5X’s the risk

Shapiro-Mendoza CK et al Pediatr 2008

How Many Early Term Infants Born By Elective Repeat C/section?

• 24,077 at 19 centers 1999-2002• 13,258 elective• 35.8% before 39 completed weeks

– 6.3% at 37 weeks– 29.5% at 38 weeks– 49.1% at 39 weeks

• Increased respiratory disease, mechanical ventilation, newborn sepsis, hypoglycemia, admission to NICU, and hospital stay >5 days– 37 weeks, adjusted odds 1.8-4.2– 38 weeks, adjusted odds 1.3-2.1

Tita AT NEJM 2009

Outcomes After Lung Maturity Testing

• 36-38 6/7 weeks vs. 39-40 6/7 weeks– 6.1 vs. 2.5% for composite adverse neo outcome– Adjusted odds ratio

• RDS 7.6 (Confidence interval 2.2-26.6)• Treated hyperbilirubinemia 11.2 (CI 3.6-34)• Hypoglycemia 5.8 (2.4-14.3)

Bates E et al Obstet Gynecol 2010

What are the Newborn Morbidities?

• In the Shapiro-Mendoza et al study– Temperature instability– Hypoglycemia– Respiratory distress– Hyperbilirubinemia– Prolonged hospitalization

• In the Wang et al study– Temperature instability– Hypoglycemia– Respiratory distress– Jaundice

Shapiro-Mendoza CK et al Pediatr 2008; Wang ML & Dorer DJ Pediatr 2004

Neonatal Resuscitation

• Depends on gestational age AND mode of delivery

• Near-term and term infants– Comparable 1 and 5 minute Apgar scores

• Late preterm and term infants– 14% require more resuscitation interventions

when delivered by elective c/section

Wang ML & Dorer DJ Pediatr 2004; De Almelda MF et al J Perinatol 2007

Respiratory Distress

• For late preterm infants– Lungs are at the end of the terminal sac period of

lung development– Synchrony and control of breathing is improving– Changes in epithelial sodium channels with length

of gestation AND labor• Likely late preterm infant lung disease is a

combination of delayed fluid absorption and surfactant insufficiency

Jain L & Eaton DC Semin Perinatol 2006; Verklan MT Crit Care Nurs Clin North Am 2009

Respiratory Distress

• At delivery– 8% of 35-36 week infants required supplemental

oxygen for at least 1 hour (3X’s the term rate)• Any respiratory distress incidence

• 2004 study, late preterm have 9 times the odds of respiratory distress (28.9% vs. 4.2%)

Escobar GJ et al Semin Perinatol 2006; Italian study; Wang ML & Dorer DJ Pediatr 2004

Study 33-34 weeks 35-36 weeks 37-42 weeks

Italy 20.6% 7.3% 0.6%

Northern California 22.1% 8.3% 2.9%

Ventilation

• Compared to 38-40 weeks gestation, likelihood of ventilation– 37 weeks: 2X– 36 weeks: 5X– 35 weeks: 9X

• When delivered by c/section without labor,– 37 week infant had 5X the odds of severe

respiratory morbidity compared to a 39 week infant delivered vaginally

Escobar GJ et al Semin Perinatol 2006; Hansen AK et al BMJ 2008

Temperature Instability

• Late preterm infants have – Decreased

• Brown fat• Hormonal regulation of brown fat breakdown• Subcutaneous fat

– Increased• Body-surface area to body-weight ratio

Fanaroff and Martin 2006; Polin and Fox 2003

Hypothermia

• Primary reason for NICU admission for 5.2% of late preterm infants

• Hypothermia is associated with– Hypoglycemia– Respiratory distress/failure– Poor feeding– Sepsis evaluations

Vachharajani AJ & Dawson JG Clin Pediatr 2009

Hypoglycemia

• Newborn glucose control– Hepatic glycogenolysis and gluconeogenesis

• Late preterm infants– Immature hormonal control– Immature hepatic enzymes– Decreased hepatic glycogen stores– Immature ketogenic response increased risk for

neurologic sequelae– Increased risk for cold stress and feeding difficulties

Ramachandrappa A & Jain L Pediatr Clin North Am 2009; Verklan MT Crit Care Nurs Clin North Am 2009

Hypoglycemia in Late Preterm Infants

• Defined as <40 mg/dl in these studies• 8% of all neonates in the 1st 4 hours• Late preterm infants

– 3X’s more likely

• IV fluid support– 5% of term infants– 27% of 35-36 week infants

Wang ML & Dorer DJ Pediatr 2004; Garg M & Devaskar SU Clin Perinatol 2006

Sepsis Evaluations

• Likelihood of sepsis screen with gestational age• Rates of sepsis evaluations

– Late preterm infants 36.7% vs. 12.6% in term– 34 weeks 33% vs. 12% at 39 weeks

• Only 0.4% of screened infants had culture-proven sepsis• Screened late preterm infants were

– More likely to be treated with antibiotics– More likely to be treated longer

Wang ML & Dorer DJ Pediatr 2004; McIntire DD et al Obstet Gynecol 2008

Hyperbilirubinemia

• Prematurity is associated with– Reduced hepatic uptake– Decreased conjugation – Decreased GI function and motility

• Compounded by feeding difficulties

Ramachandrappa A & Jain L Pediatr Clin North Am 2009; Verklan MT Crit Care Nurs Clin North Am 2009

What’s the Risk?

• Odds for developing serum bilirubin >20 mg/dl– 4 times greater for infant born at 36 weeks

compared to infant born at 39-40 weeks

• Likelihood of hospital readmission for phototherapy compared to infants ≥ 40 weeks gestation– 35-36 weeks: 13.2%– 36-37 weeks: 7.7%– 37-38 weeks: 7.2%

Newman TB et al Pediatr 1999; Maisels MJ & Kring E Pediatr 1998

Also,

• Only one prospective study,– 35-37 week compared to 38-42 week infants were 2.4X

more likely to develop “significant hyperbilirubinemia” – Nearly 25% of 35-37 week infants required phototherapy

– Of concern, serum bilirubin was significantly higher for 35-37 week infants on Day 5 and Day 7

– For late preterm infants• Delayed bilirubin peak• Prolonged duration

Sarici SU et al Pediatr 2004

Feeding Issues• Related to all other morbidities

• Late preterm infants– Poor suck and swallow coordination

• Neuronal immaturity• Decreased oromotor tone• Decreased feeding cues (do not wake up when hungry)

• Have mentioned the need for IV fluids– 27% of 35-36 week infants– Also, 76% of 35-36 week infants with poor feeding

required prolonged hospital stay

Wang ML & Dorer DJ Pediatr 2004; Meier PP et al J Midwifery Womens Health 2007

Hospitalization for Feeding Difficulties

• For late preterm infants, feeding issues are the most common cause for increased length of stay

• At 35 weeks gestation– Nearly 7.3% admitted to NICU for feeding difficulties

• Rehospitalization– Late preterm infants are 2X as likely as term infants to be

rehospitalized with feeding difficulties

Vachharajani AJ & Dawson JG Clin Pediatr 2009; Adamkin DH Clin Perinatol 2006; Escobar GJ et al Arch Dis Child 2005

The Role of Breastfeeding

• Factors associated with prematurity– Preterm delivery– Diabetes, hypertension of pregnancy– C/section deliveryare also associated with delayed lactogenesis

• Add the decreased oral ability of preterm infants– Unable to completely empty breast– Decreased stimulation for mother’s milk production

• Add the likelihood of separation due to sepsis evaluations, IV infusions, and phototherapy

Henderson JJ et al. 2007; Hartmann P & Cregan M 2001; Rasmussen KM et al. 2004

Options to Promote Breastfeeding Success for the Late Preterm Infant

• Encourage skin-to-skin• PO ad lib but with minimum of 8 feeds in 24 hours• Monitor weight loss closely, if >3% in 1 day or >7% in 2-3

days, intervene• Thorough lactation evaluation

– If intake is worrisome,• Have mother pump and give by bottle or other mechanism• Consider nipple shield with expert support

• Monitor for special circumstances such as hypoglycemia, dehydration, hyperbilirubinemia, or maternal/infant separation

Academy of Breastfeeding Medicine Protocol

At Discharge

• Discharge should not occur prior to 48 hours• Temperature of 97.7°-99.3° F• Weight loss <7% of birth weight• Normal vital signs for 12 hours prior to discharge• Risk assess for hyperbilirubinemia with follow-up

arranged• Car seat safety test passed

Adamkin DH J Perinatol 2009; Ramachandrappa A & Jain L Pediatr Clin North Am 2009

Early and Frequent Outpatient Evaluations

• Feeding difficulties may present after birth hospitalization

• Hyperbilirubinemia is often delayed and prolonged– Reassess for jaundice within 72 hours of birth

• Weight loss is often evident week 2• Late preterm infant at risk for rehospitalization and

mortality

Realistic Risk with Opportunity for Great Improvement

• An improvement in care of late preterm infants effects the greatest population of preterm infants

• Large number of opportunities for prospective studies

• Opportunity to show cost effectiveness– Average cost for treating 25 week infant: $202,000– Average cost for treating 35 week infant:$4,200However, population costs– $38.9 million dollars for 25 week infant– $41.1 million dollars for 35 week infant

Gilbert WM et al Obstet Gynecol 2003

Pediatrician/Neonatologist Role

• Promote obstetrical intervention to optimize pregnancy until term gestation

• Respect the morbidity and mortality risk of the late preterm infant population

• Intensive clinic follow-up for the first postnatal weeks

taylorse@musc.edu