Recombinant human prolactin for the treatment of lactation insufficiency.
ABSTRACT: CONTEXT:Lactation insufficiency has many aetiologies including complete or relative prolactin deficiency. Exogenous prolactin may increase breast milk volume in this subset. We hypothesized that recombinant human prolactin (r-hPRL) would increase milk volume in mothers with prolactin deficiency and mothers of preterm infants with lactation insufficiency. DESIGN:Study 1: R-hPRL was administered in an open-label trial to mothers with prolactin deficiency. Study 2: R-hPRL was administered in a randomized, double-blind, placebo-controlled trial to mothers with lactation insufficiency that developed while pumping breast milk for their preterm infants. PATIENTS:Study 1: Mothers with prolactin deficiency (n = 5). Study 2: Mothers of premature infants exclusively pumping breast milk (n = 11). DESIGN:Study 1: R-hPRL (60 ?g/kg) was administered subcutaneously every 12 h for 28 days. Study 2: Mothers of preterm infants were randomized to receive r-hPRL (60 ?g/kg), placebo or r-hPRL alternating with placebo every 12 h for 7 days. MEASUREMENTS:Change in milk volume. RESULTS:Study 1: Peak prolactin (27·9 ± 17·3 to 194·6 ± 19·5 ?g/l; P < 0·003) and milk volume (3·4 ± 1·6 to 66·1 ± 8·3 ml/day; P < 0·001) increased with r-hPRL administration. Study 2: Peak prolactin increased in mothers treated with r-hPRL every 12 h (n = 3; 79·3 ± 55·4 to 271·3 ± 36·7 ?g/l; P < 0·05) and daily (101·4 ± 61·5 vs 178·9 ± 45·9 ?g/l; P < 0·04), but milk volume increased only in the group treated with r-hPRL every 12 h (53·5 ± 48·5 to 235·0 ± 135·7 ml/day; P < 0·02). CONCLUSION:Twice daily r-hPRL increases milk volume in mothers with prolactin deficiency and in preterm mothers with lactation insufficiency.
Project description:The objective of this study was to determine the impact of recombinant human prolactin (r-hPRL) on the nutritional and immunologic composition of breast milk.We conducted 2 trials of r-hPRL treatment. In the first study, mothers with documented prolactin deficiency were given r-hPRL every 12 hours in a 28-day, open-label trial. In the second study, mothers with lactation insufficiency that developed while they were pumping breast milk for their preterm infants were given r-hPRL daily in a 7-day, double-blind, placebo-controlled trial. Breast milk characteristics were compared before and during 7 days of treatment.Among subjects treated with r-hPRL (N = 11), milk volumes (73 ± 36 to 146 ± 54 mL/day; P < .001) and milk lactose levels (155 ± 15 to 184 ± 8 mmol/L; P = .01) increased, whereas milk sodium levels decreased (12.1 ± 2.0 to 8.3 ± 0.5 mmol/L; P = .02). Milk calcium levels increased in subjects treated with r-hPRL twice daily (2.8 ± 0.6 to 5.0 ± 0.9 mmol/L; P = .03). Total neutral (1.5 ± 0.3 to 2.5 ± 0.4 g/L; P = .04) and acidic (33 ± 4 to 60 ± 6 mg/L; P = .02) oligosaccharide levels increased in r-hPRL-treated subjects, whereas total daily milk immunoglobulin A secretion was unchanged.r-hPRL treatment increased milk volume and induced changes in milk composition similar to those that occur during normal lactogenesis. r-hPRL also increased antimicrobially active oligosaccharide concentrations. These effects were achieved for women with both prolactin deficiency and lactation insufficiency.
Project description:We longitudinally compared fatty acids (FA) from human milk (HM) of mothers delivering term and preterm infants. HM was collected for 4 months postpartum at 12 time points for preterm and for 2 months postpartum at 8 time points for term group. Samples were collected from the first feed of the morning, and single breast was fully expressed. FA were analyzed by gas chromatography coupled with flame ionization detector. Oleic, palmitic and linoleic acids were the most abundant FA across lactation and in both groups. Preterm colostrum contained significantly (p < 0.05) higher 8:0, 10:0, 12:0, sum medium chain fatty acids (MCFA), 18:3 n-3 FA compared to term counterparts. Preterm mature milk contained significantly higher 12:0, 14:0, 18:2 n-6, sum saturated fatty acids (SFA), and sum MCFA. We did not observe any significant differences between the preterm and term groups for docosahexaenoic acid, arachidonic acid and eicosapentaenoic acid at any stage of lactation. Overall, preterm milk was higher for SFA with a major contribution from MCFA and higher in 18:2 n-6. These observational differences needs to be studied further for their implications on preterm developmental outcomes and on fortification strategies of either mothers' own milk or donor human milk.
Project description:Medications used to augment lactation increase prolactin secretion but can have intolerable side effects. We examined the biological activity of recombinant human prolactin (r-hPRL) as preliminary data for its use to augment lactation.Healthy, non-postpartum women (n = 21) with regular menstrual cycles underwent a seven day randomized, double-blind, placebo-controlled trial of r-hPRL. Expressible galactorrhea, markers of bone turnover, calcium homeostasis and gonadal function were measured and side effects recorded.Prolactin levels increased during r-hPRL administration (20.0 +/- 2.8 to 231.7 +/- 48.9 microg/L at 6 hours; p < 0.05). Five of nine participants who received r-hPRL developed expressible galactorrhea (p < 0.001). Urinary deoxypyridinoline decreased and bone specific alkaline phosphatase increased in r-hPRL and placebo groups. Menstrual cycle lengths were not altered and side effects were similar between r-hPRL and placebo groups.In summary, r-hPRL can cause expressible galactorrhea. Seven days of r-hPRL administration does not adversely affect bone turnover or menstrual cyclicity. Thus, r-hPRL may be a viable option for short-term lactation augmentation.Clinical Trials.gov NCT00438490.
Project description:Human milk is the gold standard of nutrition for infants, providing both protective and essential nutrients. Although much is known about milk from mothers giving birth to term infants, less is known about milk from mothers giving birth to premature infants. In addition, little is known about the composition and diversity of small molecules in these milks and how they change over the first month of lactation.The objective was to understand how milk metabolites vary over the first month of lactation in mothers giving birth to term and preterm infants.(1)H nuclear magnetic resonance (NMR) metabolomics was used to characterize metabolites that were present in micromolar to molar concentrations in colostrum (day 0-5 postpartum), transition milk (day 14), and mature milk (day 28) from mothers who delivered term (n = 15) and preterm (n = 13) infants. Principal components analysis, linear mixed-effects models (LMMs), and linear models (LMs) were used to explore the relation between infant maturity and the postpartum day of collection of milk samples.By using a standard NMR metabolite library, 69 metabolites were identified in the milks, including 15 sugars, 23 amino acids and derivatives, 11 energy-related metabolites, 10 fatty acid-associated metabolites, 3 nucleotides and derivatives, 2 vitamins, and 5 bacteria-associated metabolites. Many metabolite concentrations followed a similar progression over time in both term and preterm milks, with more biological variation in metabolite concentrations in preterm milk. However, although lacto-N-neotetraose (LMM, P = 4.0 × 10(-5)) and lysine (LM, P = 1.5 × 10(-4)) significantly decreased in concentration in term milk over time, they did not significantly change in preterm milk.Overall, the metabolic profile of human milk is dynamic throughout the first month of lactation, with more variability in preterm than in term milk and subtle differences in some metabolite concentrations. This trial was registered at clinicaltrials.gov as NCT01841268.
Project description:Human milk oligosaccharides (HMOs) are a major component of human milk, and play an important role in protecting the infant from infections. Preterm infants are particularly vulnerable, but have improved outcomes if fed with human milk. This study aimed to determine if the HMO composition of preterm milk differed from that of term milk at equivalent stage of lactation and equivalent postmenstrual age. In all, 22 HMOs were analyzed in 500 samples of milk from 25 mothers breastfeeding very preterm infants (< 32 weeks of gestational age, < 1500g of birthweight) and 28 mothers breastfeeding term infants. The concentrations of most HMOs were comparable at equivalent postpartum age. However, HMOs containing ?-1,2-linked fucose were reduced in concentration in preterm milk during the first month of lactation. The concentrations of a number of sialylated oligosaccharides were also different in preterm milk, in particular 3'-sialyllactose concentrations were elevated. At equivalent postmenstrual age, the concentrations of a number of HMOs were significantly different in preterm compared to term milk. The largest differences manifest around 40 weeks of postmenstrual age, when the milk of term infants contains the highest concentrations of HMOs. The observed differences warrant further investigation in view of their potential clinical impact.
Project description:Extremely preterm infants are highly susceptible to bacterial infections but breast milk provides some protection. It is unknown if leukocyte numbers and subsets in milk differ between term and preterm breast milk. This study serially characterised leukocyte populations in breast milk of mothers of preterm and term infants using multicolour flow cytometry methods for extended differential leukocyte counts in blood.Sixty mothers of extremely preterm (<28 weeks gestational age), very preterm (28-31 wk), and moderately preterm (32-36 wk), as well as term (37-41 wk) infants were recruited. Colostrum (d2-5), transitional (d8-12) and mature milk (d26-30) samples were collected, cells isolated, and leukocyte subsets analysed using flow cytometry.The major CD45+ leukocyte populations circulating in blood were also detectable in breast milk but at different frequencies. Progression of lactation was associated with decreasing CD45+ leukocyte concentration, as well as increases in the relative frequencies of neutrophils and immature granulocytes, and decreases in the relative frequencies of eosinophils, myeloid and B cell precursors, and CD16- monocytes. No differences were observed between preterm and term breast milk in leukocyte concentration, though minor differences between preterm groups in some leukocyte frequencies were observed.Flow cytometry is a useful tool to identify and quantify leukocyte subsets in breast milk. The stage of lactation is associated with major changes in milk leukocyte composition in this population. Fresh preterm breast milk is not deficient in leukocytes, but shorter gestation may be associated with minor differences in leukocyte subset frequencies in preterm compared to term breast milk.
Project description:The use of mother's own breast milk during initial hospitalization has a positive impact not only in reducing potential serious neonatal morbidities but also contribute to improvements in neurodevelopmental outcomes. Mothers of very preterm infants struggle to maintain a supply of breast milk during their infants' prolonged hospitalization. Galactogogues are medications that induce lactation by exerting its effects through oxytocin or prolactin enhancement. Domperidone is a potent dopamine D2 receptor antagonist which stimulates the release of prolactin. Small trials have established its ability in enhancing breast milk production. EMPOWER was designed to determine the safety and efficacy of domperidone in mothers experiencing an inadequate milk supply.EMPOWER is a multicenter, double masked, randomized controlled phase-II trial to evaluate the safety and effectiveness of domperidone in those mothers identified as having difficulty in breast milk production. Eligible mothers will be randomized to one of two allocated groups: Group A: domperidone 10 mg orally three times daily for 28 days; and Group B: identical placebo 10 mg orally three times daily for 14 days followed by domperidone 10 mg orally three times daily for 14 days. The primary outcome will be determined at the completion of the first 2-week period; the second 2-week period will facilitate answering the secondary questions regarding timing and duration of treatment. To detect an estimated 30% change between the two groups (from 40% to 28%, corresponding to an odds ratio of 0.6), a total sample size of 488 mothers would be required at 80% power and alpha=0.05. To account for a 15% dropout, this number is increased to 560 (280 per group). The duration of the trial is expected to be 36-40 months.The use of a galactogogue often becomes the measure of choice for mothers in the presence of insufficient breast milk production, particularly when the other techniques are unsuccessful. EMPOWER is designed to provide valuable information in guiding the practices for this high-risk group of infants and mothers. The results of this trial will also inform both mothers and clinicians about the choices available to increase and maintain sufficient breast milk.Clinical Trials.gov Identifier: NCT01512225.
Project description:Background:Neonates with severe conditions that cannot be breastfed should receive fresh or preserved expressed human milk in addition to parenteral nutrition. Objective:To identify the time during lactation when the macronutrients provide maximum energy and evaluate the effect of refrigeration and freezing. Methods:We analyzed the composition of fresh milk, refrigerated at +4°C and frozen at -20°C, expressed by mothers of 60 preterm and 30 term infants from a level III maternity, in colostrum, transitional, and mature milk. Results:In fresh milk, the protein level constantly decreases during lactation, with a significant difference after 3 weeks of lactation. Preterm milk of day 21 and day 30 had significantly lower protein than term milk (1.27 versus 1.43 g/dL, P=0.015 and 1.13 versus 1.28 g/dL, P=0.001). Refrigeration for 72 hours of term milk decreased protein content less than freezing. Preterm colostrum has significantly less protein after 48 hours of refrigeration or freezing. Preterm milk from day 60 lost carbohydrates if refrigerated 72 hours or frozen for 2 months. Lipids in preterm colostrum decrease after 8 weeks of freezing. Refrigeration for up to 72 hours did not change significantly the energy value of colostrum or transitional milk. Freezing preterm milk more than 2 weeks leads to significant loss of energy. Conclusions:Milk frozen for more than 2 weeks contains less protein and energy than milk refrigerated for up to 72 hours. In the absence of milk bank access, in common settings, short-term refrigeration is preferable to long-term freezing.
Project description:Hundreds of naturally occurring milk peptides are present in term human milk. Preterm milk is produced before complete maturation of the mammary gland, which could change milk synthesis and secretion processes within the mammary gland, leading to differences in protein expression and enzymatic activity, thereby resulting in an altered peptide profile.This study examined differences in peptides present between milk from women delivering at term and women delivering prematurely.Nano-LC tandem mass spectrometry was employed to identify naturally occurring peptides and compare their abundances between term and preterm human milk samples at multiple time points over lactation. Term milk samples were collected from 8 mothers and preterm milk was collected from 14 mothers. The 28 preterm and 32 term human milk samples were divided into 4 groups based on day of collection (<14, 14-28, 29-41, and 42-58 d).Preterm milk peptide counts, ion abundance, and concentration were significantly higher in preterm milk than term milk. Bioinformatic analysis of the cleavage sites for peptides identified suggested that plasmin was more active in preterm milk than term milk and that cytosol aminopeptidase and carboxypeptidase B2 likely contribute to extensive milk protein breakdown. Many identified milk peptides in both term and preterm milk overlapped with known functional peptides, including antihypertensive, antimicrobial, and immunomodulatory peptides.The high protein degradation by endogenous proteases in preterm milk might attenuate problems because of the preterm infant's immature digestive system. This trial was registered at clinicaltrials.gov as NCT01817127.
Project description:Most studies assessing the macronutrient content of human milk are published retrospectively using analyzers that fail to determine sodium content and do not take into account the role of volume in milk composition. We aimed to describe macronutrient content and sodium content in human milk over time, observe any associations between them, and determine the factors associated with the evolution of milk composition. A prospective, longitudinal, monocentric study was undertaken. Contents of protein, fat, and lactose of 102 milk samples from 40 mothers were determined using a human milk analyzer and that of sodium with a flame spectrophotometer. Milk volumes along with clinical data were recorded. Protein content in the fourth quartile of volume was significantly lower than that in the first three, suggesting the existence of a volume threshold for protein content at approximately 445 mL. After multivariate analysis, it was found that maternal age, average volume, and lactation period remained significantly associated with protein content, maternal age remained significantly associated with fat content, and only average volume with sodium content. In consideration of previous findings along with our data, we suggest that extra care should be taken with fortification for feeding preterm infants when the mother's milk volume is greater than 400-450 mL.