Preterm feeding recommendations are achievable in large-scale research studies

INTERGROWTH-21^st is a multi-country project to develop international, prescriptive standards for fetal growth, newborn size and preterm postnatal growth [1], to complement the existing WHO Child Growth Standards [2, 3]. Such standards describe how individuals should grow, as opposed to reference charts that describe how individuals have grown at particular times and locations [4]. The aim of the Postnatal Preterm Follow-up Study (PPFS), a component of the INTERGROWTH-21^st Project was to construct prescriptive standards to monitor the postnatal growth of preterm infants following our a priori conceptual framework [4]. Using a similar approach to the WHO Multicentre Growth Reference Study (MGRS) [2, 3], we studied a cohort of uncomplicated, preterm infants born to healthy, well-nourished women from geographically diverse populations, who received adequate antenatal care and were at low risk of adverse maternal and perinatal outcomes, and who were not exposed to any known non-microbiological contamination or toxic substances [5].

Preterm infants are a heterogeneous group, varying by gestational age at birth and the severity of their comorbidities, many of which are associated with being born at a very early gestational age and growth restricted [6]. Some of the comorbidities are also probably associated with immature gastrointestinal function, resulting in an imbalance between rapid growth, nutrient supply and the adequacy of the metabolic response, occurring during the unplanned transition from trans-placental nutrition to oral feeding [7, 8].

There is controversy, both conceptually and at a practical level, about how best to feed preterms; hence, feeding practices vary among and within countries [9]. Some practices have been proposed, which should support a tissue accretion rate matching that of normal intrauterine growth. This approach assumes that the growth rate of a fetus of a comparable gestational age is desirable for the postnatal growth, development and long-term health of a preterm. However, such a pattern is seldom attained in preterm neonates, who almost always show a postnatal cumulative nutritional deficit and so-called ‘extrauterine growth restriction’ [10]. Feeding guidelines for term infants are based on the substantial benefits of breast milk, e.g. decreased rates of infection and mortality, and better long-term outcomes, including improved neurocognitive and cardiovascular development. There is increasing evidence that there are also important benefits to be gained from giving the mother’s milk to sick and preterm infants in neonatal intensive care units [11]. However, their nutritional needs are different from those of term infants and should be evaluated carefully, especially bearing in mind the need to fortify human milk [11].

Therefore, in developing the preterm prescriptive growth standards, it was essential to ensure that the recommended feeding practices for optimal postnatal growth in preterms were implemented, including the provision of supplements and complementary foods when necessary. In this paper, we describe the breastfeeding and complementary feeding practices of the infants enrolled in PPFS.

In total, 224 preterms were born in FGLS. Of these, 201 (99 boys and 102 girls) were alive, free of congenital malformations and enrolled in PPFS. The distribution of the 201 preterm newborns across sites was: Brazil = 18 %; China = 9 %; India = 15 %; Italy = 12 %; Kenya = 15 %; Oman = 15 %; UK = 11 %, and USA = 5 %. We documented feeding practices of these infants during their first 8 months after birth.

Forty-seven percent of newborns were admitted to an intensive or special care unit after birth for respiratory support (10.1 %), surfactant treatment (2.4 %) or tube feeding/parenteral nutrition (34.3 %). The most common neonatal problems were hyperbilirubinemia (22.9 %), respiratory distress (10.4 %), lack of oral feeding for >24 h (11.9 %), and transient tachypnea (14.9 %). The median (IQR) length of stay at special care units was 4.0 (2–8) days; three (1.5 %) preterms stayed in hospital for ≥60 days (data not shown). As expected, most of the postnatal morbidities known to be related to severe prematurity (e.g. bronchopulmonary dysplasia, apnea of prematurity, retinopathy of prematurity) were observed in the very preterm infants (GA <32 weeks)

Within the first 72 h after birth, oral feeding was initiated in 94 % of the infants. The percentage of infants who received any breastfeeding was 81.8 % within 72 h of birth, 96.4 % at 2 weeks of age, 93.5 % at 8 weeks and 82 % at 4 months (Fig. 1). Exclusive breastfeeding increased from 51.1 % at 72 h after birth (Fig. 1) to 72.1 % by hospital discharge, (late preterms = 75.7 % and early preterms = 50.0 %, data not shown), with a further 16.9 % partially breastfed at hospital discharge (late preterms = 15.0 % and early preterms = 28.6 %, data not shown) (Fig. 2). The rate of exclusive breastfeeding continued to increase to 64.1 % at 2 weeks, and was sustained until 3 months of postnatal age in 55.5 % of the cohort (57.6 and 44.0 % of late and early preterms, respectively; data not shown). At 4 weeks, 31.1 % of infants were fed with breast milk and other milk/formula only, decreasing to 26.0 % at 8 weeks, 31.7 % at 3 months, 26.7 % at 4 months and 10.3 % at 6 months (Fig. 1). Exclusive breastfeeding gradually diminished between 5 and 8 months from 36.8 to 0.8 % and 41.7 to 4.6 %, in late and early preterms, respectively (data not shown), while the consumption of semi-solid and solid foods increased from 32.3 % at 5 months to 96.5 % at 8 months (37.2 to 97.5 %, and 4.17 to 90.9 %, in late and early preterms, respectively) (Fig. 2). High rates of any breastfeeding continued with 73.7 % still being breastfed at 6 months, and 70.4 % (early preterms = 70.8 % and late preterms = 68.2 %, data not shown) still receiving breast milk at 8 months of age (Fig. 2).

Grains, roots and tubers were consumed by 19.3 % of preterms at 5 months, 51.1 % at 6 months and 90.1 % at 8 months of age (Fig. 3). By 5 months, vitamin A-rich fruits and vegetables and other fruits and vegetables were being consumed by 12.4 and 16.8 %, respectively. These two food groups were not offered as frequently as grains, roots and tubers, but were given to 61.3 and 72.5 % of infants, respectively, by 8 months. Flesh foods, eggs, and legumes and nuts were offered to 36.8, 7.9, and 13.2 % of infants at 7 months of age, respectively. By 8 months, flesh foods were given to 51.4 % of preterms, while the consumption of eggs, and legumes and nuts remained low (14.1 and 19.7 %, respectively).

Iron supplements were routinely given to preterm infants at most sites in hospital and after discharge, except Oxford where, typically, only infants <35 weeks’ gestation received supplements. Most sites provided Vitamin D supplements for infants after discharge but in the participating Nairobi hospitals, vitamin D was only given to selected preterms, and the practice was not standard in Oman. Vitamin K was given at birth to preterm babies at all sites, and most gave multivitamins during and after the hospital stay. Participating hospitals in Brazil gave multivitamins to selected preterms only; standard practice in China was Vitamin A supplementation in hospital and after discharge.

The patterns of longitudinal growth in this cohort for length were very similar to those of the WHO Child Growth Standards for term neonates [2] during the first months of life, but weight and head circumference differed from the WHO standards until 64 weeks’ postmenstrual age [18].

One of the aims of the INTERGROWTH-21^st Project was to produce, for the first time, international standards for postnatal growth of preterm infants by gestational age, conforming to the prescriptive approach used in WHO MGRS. Healthy, well-nourished women with minimal constraints on fetal growth were studied prospectively, resulting in a relatively homogenous and ‘healthy’ population (according to gestational age) of preterm infants. To support the development of the standards, descriptive data were collected to document the degree to which feeding guidelines for adequate postnatal growth were followed.

The participating neonatal teams agreed to follow a set of recommended feeding practices based on the increasing evidence of the short- and long-term benefits of breastfeeding for preterm infants. This included guidelines on supplementation and the introduction of complementary foods.

In this cohort, nearly half the preterm infants were exclusively or predominantly breastfed until 4 months of age, and over two-thirds were still being breastfed at 8 months of age. The rates of exclusive or predominant breastfeeding were lower in this study than in WHO MGRS (MGRS – approximately 80 and 63 %; PPFS – 65.3 and 56.5 % at 4 weeks and 3 months, respectively) [19]. These results are not unexpected as breastfeeding rates are generally lower in preterm compared to term infants [9, 20–22], and establishing and maintaining breastfeeding in preterms requires considerable support. Factors that may impact upon the ability of preterms to breastfeed are clinical conditions related to prematurity, extended hospitalization, increased sleepiness and maternal illness. Other obstacles may include reduced muscular strength affecting latching, suckling and swallowing. The infant may also be discharged before lactation is fully established, so breastfeeding difficulties cannot be addressed by healthcare professionals. We emphasised these issues across the study sites, suggesting strategies to help mothers overcome these barriers. However, moving from the context of a research project to general practice will, realistically, be far more challenging.

It has been suggested that, wherever possible, preterm infants should be introduced to solid foods between 5 and 8 months of age to ensure that the appropriate transition period is not missed, and to encourage the development of feeding skills [23]. Healthy, late preterms, born ≥34 weeks’ gestation, may be introduced to solid foods using the same guidelines as term infants. The mean age at which complementary foods were introduced in PPFS was 6 months; not much later than reported for term infants (5.4 months) enrolled in a similar context, who achieved the recommended feeding criteria in WHO MGRS [24]. Of the complementary food groups, the grains, roots and tubers group was the most consistently offered, also similar to WHO MGRS.

Both the American Academy of Pediatrics and European Society of Paediatric Gastroenterology, Hepatology and Nutrition recommend preterm infants receive an iron supplement after hospital discharge [25, 26]. Unlike exclusively breastfed term infants, who can usually maintain their iron levels until approximately 6 months of age, breastfed preterm infants should receive regular iron supplementation, 2–4 mg/kg/day, from hospital discharge until approximately 6 to 12 months of age [25–27]. Such recommendations were fully implemented at all INTERGROWTH-21^st sites. There is some evidence to suggest that low birth weight infants and preterms <32 weeks’ gestation may benefit from multivitamins and vitamin D supplementation [14]; nearly all our sites provided these supplements after hospital discharge, and vitamin K was given as standard at birth.

PPFS was designed to construct prescriptive standards from a population of preterm infants with the best potential for healthy growth and development, if supported by adequate nutrition and clinical care. Exclusive breastfeeding was established in most PPFS infants by hospital discharge and breastfeeding remained an important source of nutrition for these infants throughout the study. This was consistent with the main goal of the INTERGROWTH-21^st Neonatal Group feeding guidelines [12], which were based on the most current evidence to promote optimal growth at the population level for uncomplicated preterm infants [14].

By 64 weeks’ postmenstrual age, the 50^th centiles of our cohort’s weights, lengths and head circumferences merged with those of the WHO Child Growth Standards [2], which indicates that preterm infants without severe postnatal complications, who are predominantly breastfed and receiving adequate postnatal care, progressively recuperate in early postnatal life [18].

There is little high-quality information available regarding the most appropriate patterns of postnatal growth for the optimal development and long-term health of preterm infants. Current evidence advocates breastfeeding with appropriate supplementation as the best way to support the growth and development of healthy preterm infants. When conducting postnatal growth research, it is essential to document feeding practices and the extent to which they adhered to the best available evidence.

Uncomplicated, preterm infants can follow evidence-based feeding recommendations centered on breastfeeding. When assessed against the WHO Child Growth Standards for 6 month old infants, adequate growth is achievable for babies born preterm with appropriate nutrition and clinical care.