Growth patterns of 11 to 29-month-old children consuming young child formula: secondary analysis of a randomized, controlled study.

INTRODUCTION: The impact of young child formula (YCF) consumption on children's growth, particularly under sub-optimal conditions, has scarcely been studied. In the current study, weight-for-age (WAZ), length-for-age (LAZ) and BMI-for-age (BAZ) z-score development was evaluated in children from five different countries (n = 668) who participated in a double-blind, randomized, controlled trial. METHODS: The children (1-3 years old) were randomized to one of two intervention YCFs (with presence or absence of prebiotics and n-3 LCPUFAs) during 52 weeks of intervention. Additional stratified analyses evaluated the growth patterns of underweight, overweight, or stunted children. RESULTS: No apparent differences in anthropometric measurements were observed between the intervention groups. In both YCF intervention groups, mean WAZ, LAZ and BAZ development was indicative for an adequate growth during the intervention period. Stratified analyses showed a stable WAZ and BAZ development among children with a healthy weight or overweight at baseline. Among underweight and stunted children normalization in mean weight (⁓1SD) and length (⁓0.8SD) gain, respectively, was observed. CONCLUSION: The current study suggests that consumption of YCF, either or not containing prebiotics and n-3 LCPUFAs, is associated with adequate growth among young children. This association may depend on the child's baseline nutritional status. Future studies to assess the potential role of YCF in supporting adequate weight/length gain among children at-risk for undernutrition are warranted.

Infant Milk Formula with Large, Milk Phospholipid-coated Lipid Droplets Enriched in Dairy Lipids Affects Body Mass Index Trajectories and Blood Pressure at School Age: Follow-up of a Randomized Controlled Trial.

BACKGROUND: Human milk comprises large fat globules enveloped by a native phospholipid membrane, whereas infant formulas contain small, protein-coated lipid droplets. Previous experimental studies indicated that mimicking the architecture of human milk lipid droplets in infant milk formula (IMF) alters lipid metabolism with lasting beneficial impact on later metabolic health. OBJECTIVES: To evaluate in a follow-up (FU) study of a randomized, controlled trial whether a Concept IMF with large, milk phospholipid-coated lipid droplets enriched with dairy lipids beneficially impacts long-term body mass index (BMI in kg/m2) trajectories and blood pressure at school age. METHODS: Fully formula-fed infants were randomly assigned to Concept IMF (n = 115) or Control IMF with conventional, small lipid droplets containing vegetable oils (n = 108) for the first 4 mo of age. A group of 88 breastfed infants served as a reference. During FU, anthropometrics were collected at 1, 3, 4, and 5 y of age, and blood pressure only at the last visit. RESULTS: Compared to Control, Concept group children had consistently lower mean BMI values during FU, with the most marked difference at 1 y of age (difference in means -0.71 kg/m2, 95% confidence interval (CI): -1.13, -0.29; P = 0.001); mean values were close to the breastfed group (P > 0.05). Contrary, the mean BMI values of the Control group were higher compared with the breastfed group during FU from 1 to 5 y of age (differences in means from 0.59 to 0.96 kg/m2, respectively; P < 0.02). At 5 y of age, the Concept group had a lower mean diastolic and arterial blood pressure compared with the Control group; -4.3mm Hg (95% CI: -7.3, -1.3; P = 0.005) and -3.7 mm Hg (95% CI: -6.5, -0.9; P = 0.01), respectively. CONCLUSIONS: Early life feeding of an innovative IMF with large, milk phospholipid-coated lipid droplets enriched with dairy lipids results in a BMI trajectory closer to breastfed infants and a lower blood pressure at school age. This trial was registered at the Dutch Trial Register as NTR3683 and NTR5538.

Infant formula containing large, milk phospholipid-coated lipid droplets and dairy lipids affects cognitive performance at school age.

Background: Breastfeeding has been positively associated with infant and child neurocognitive development and function. Contributing to this effect may be differences between human milk and infant formula in the milk lipid composition and milk fat globule structure. Objective: To evaluate the effects of an infant formula mimicking human milk lipid composition and milk fat globule structure on childhood cognitive performance. Methods: In a randomized, controlled trial, healthy term infants received until 4 months of age either a Standard infant formula (n = 108) or a Concept infant formula (n = 115) with large, milk phospholipid coated lipid droplets and containing dairy lipids. A breastfed reference group (n = 88) was included. Erythrocyte fatty acid composition was determined at 3 months of age. Neurocognitive function was assessed as exploratory follow-up outcome at 3, 4, and 5 years of age using the Flanker test, Dimensional Change Card Sort (DCCS) test and Picture Sequence Memory test from the National Institutes of Health Toolbox Cognition Battery. Mann-Whitney U test and Fisher exact test were used to compare groups. Results: Erythrocyte omega-6 to -3 long-chain polyunsaturated fatty acid ratio appeared to be lower in the Concept compared to the Standard group (P = 0.025). At age 5, only the Concept group was comparable to the Breastfed group in the highest reached levels on the Flanker test, and the DCCS computed score was higher in the Concept compared to the Standard group (P = 0.021). Conclusion: These outcomes suggest that exposure to an infant formula mimicking human milk lipid composition and milk fat globule structure positively affects child neurocognitive development. Underlying mechanisms may include a different omega-3 fatty acid status during the first months of life. Clinical trial registration: https://onderzoekmetmensen.nl/en/trial/28614, identifier NTR3683 and NTR5538.

An Infant Formula with Large, Milk Phospholipid-Coated Lipid Droplets Supports Adequate Growth and Is Well-Tolerated in Healthy, Term Asian Infants: A Randomized, Controlled Double-Blind Clinical Trial.

Lipids are essential for healthy infant growth and development. The structural complexity of lipids in human milk is not present in infant milk formula (IF). A concept IF was developed mimicking more closely the structure and composition of human milk fat globules. The current study evaluates whether a concept IF with large, milk phospholipid-coated lipid droplets (mode diameter 3 to 5 µm) is equivalent to standard IF with regard to growth adequacy and safety in healthy, term Asian infants. In this randomized, double-blind, controlled trial, infants were randomized after parents decided to introduce formula. Infants received a standard IF with (Control) or without the specific prebiotic mixture scGOS/lcFOS (9:1 ratio; Control w/o prebiotics), or a Concept IF with large, milk phospholipid-coated lipid droplets and the prebiotic mixture. A group of 67 breastfed infants served as a reference. As a priori defined, only those infants who were fully intervention formula-fed ≤28 days of age were included in the equivalence analysis (Control n = 29; Control w/o prebiotics n = 28; Concept n = 35, per-protocol population). Primary outcome was daily weight gain during the first four months of life, with the difference between the Concept and Control as the key comparison of interest. Additionally, adverse events, growth and tolerance parameters were evaluated. Equivalence of daily weight gain was demonstrated between the Concept and Control group after additional correction for ethnicity and birthweight (difference in estimated means of 0.1 g/d, 90%CI [-2.30, 2.47]; equivalence margin +/- 3 g/d). No clinically relevant group differences were observed in secondary growth outcomes, tolerance outcomes or number, severity or relatedness of adverse events. This study corroborates that an infant formula with large, milk phospholipid-coated lipid droplets supports adequate growth and is well tolerated and safe for use in healthy infants.

Efficacy and safety of the contraceptive vaginal ring (NuvaRing) compared with a combined oral contraceptive in Chinese women: a 1-year randomised trial.

OBJECTIVES: The aim of the study was to assess the efficacy and tolerability of the monthly vaginal ring (NuvaRing; 15 µg ethinylestradiol [EE] and 120 µg etonogestrel per day) compared with a monophasic (21/7) combined oral contraceptive (COC) containing 30 µg EE and 3 mg drospirenone in healthy Chinese women aged 18-40 years. METHODS: This was a phase III, open-label, randomised multicentre trial conducted in China. Participants received NuvaRing or COC for 13 cycles (3 weeks of ring/pill treatment followed by a 1-week ring-free/pill-free period). Contraceptive efficacy was assessed by in-treatment pregnancies and expressed by the Pearl Index (PI; number of pregnancies/100 woman-years of use). Cycle control was assessed by unscheduled (breakthrough) and absence of scheduled (withdrawal) bleeding events. Safety and tolerability were assessed throughout the study. RESULTS: Participants were randomised either to the NuvaRing (n = 732) or to the COC (n = 214); 588 (82.4%) and 182 (78.4%) participants, respectively, completed the study. There were 10 in-treatment pregnancies in the NuvaRing group (PI 1.92; 95% confidence interval [CI] 0.92, 3.53) and five in the COC group (PI 3.12; 95% CI 1.01, 7.29). Breakthrough bleeding/spotting ranged from 18.6% (Cycle 1) to 4.2% (Cycle 11) for NuvaRing and from 21.6% (Cycle 1) to 7.9% (Cycle 11) for COC. Absence of withdrawal bleeding ranged from 8.6% (Cycle 1) to 3.0% (Cycle 11) for NuvaRing and from 14.6% (Cycle 1) to 6.4% (Cycle 5) for COC. For NuvaRing and COC, respectively, 26.6% and 25.0% of participants had treatment-related adverse events, and 7.0% and 9.1% discontinued the study as a result. CONCLUSIONS: Once-monthly NuvaRing is efficacious and safe for use in Chinese women.

Women's perceptions and reasons for choosing the pill, patch, or ring in the CHOICE study: a cross-sectional survey of contraceptive method selection after counseling.

BACKGROUND: The European CHOICE study was a cross-sectional survey that evaluated women's combined hormonal contraceptive choices before and after contraceptive counseling in Austria, Belgium, Czech Republic and Slovakia, the Netherlands, Poland, Sweden, Switzerland, Israel, Russia, and Ukraine. The changes in method selection before and after counseling were reported previously. In this paper we present the reasons given by the 18,787 participating women for selecting their contraceptive method of choice, as well as their perceptions about the contraceptive pill, patch, and ring after counseling. METHODS: Women with an interest in a combined hormonal contraceptive method (pill, patch, or ring) were counseled using a standardized counseling leaflet. The women completed questionnaires, which included questions on why they had selected a particular method of contraception, and the extent to which they agreed with statements about the attributes of the pill, patch, and ring. The results for each country were compared with the percentages for all countries combined by using a binomial regression model. Multiple logistic regression models were used to investigate the extent to which the probability of choosing a method was related to prespecified aspects (i.e. perceptions) of each contraceptive method. RESULTS: 'Easy to use', 'convenience', and 'regular menstrual bleeding' were important selection criteria. 'Nondaily administration' was one of the main reasons women selected the patch or ring. 'Daily use' and 'will forget to take it' were the primary reasons for not selecting the pill, while the main reasons for not choosing the patch included 'not discrete, visible' and 'can fall off'. In a small number of instances, the ring was rejected because some women don't like to use a 'foreign body'. Women's perceptions influenced their contraceptive decisions: positive perceptions about a method increased the likelihood that a woman would select it. After counseling, many women associated the pill with forgetfulness, and many still did not know about the patch or ring's key attributes. Women's knowledge about a particular method was generally greater if they had chosen it. CONCLUSIONS: To support informed contraceptive decision-making, healthcare professionals should realize that a woman's view of a method's ease of use is more important than perceived efficacy, tolerability, health benefits, or risks.

Nexplanon, a radiopaque etonogestrel implant in combination with a next-generation applicator: 3-year results of a noncomparative multicenter trial.

OBJECTIVE: To investigate the efficacy, safety, removal characteristics, and x-ray visibility of Nexplanon, a radiopaque etonogestrel contraceptive implant combined with a next-generation applicator. STUDY DESIGN: A 3-year, nocomparative, multicenter study in women aged 18-40 years at 23 clinical sites. RESULTS: Of 301 women who had an implant inserted, none became pregnant while the implant was in situ. Serious adverse events were reported in 16 of 301 (5.3%) women; none were judged as drug related. Fibrosis around the implant was the most common removal complication (4.4%). The implant was visible on X-ray and palpable before removal with a mean removal time of 2 minutes. CONCLUSION: Nexplanon showed high contraceptive efficacy, palpability before removal, short removal times, and few removal complications. Nexplanon provides clinicians with a long-term hormonal contraceptive method with a safety and efficacy profile comparable to Implanon, radiopacity, and a new applicator.

The CHOICE study: effect of counselling on the selection of combined hormonal contraceptive methods in 11 countries.

OBJECTIVES: To encourage healthcare professionals to counsel women seeking combined hormonal contraceptives (CHCs) about alternative CHCs and to study the influence of counselling on women's selection of CHCs. METHODS: Women (15-40 years old) in 11 countries who consulted HCPs about CHCs were counselled about the pill, transdermal patch, and vaginal ring. Both the HCPs and the women completed questionnaires. RESULTS: Of women who were counselled (n = 18,787), 47% selected another CHC method than originally planned. One in four who intended to use the pill chose another method (16% chose the patch; 65% chose the ring). In total, patch use increased from 5% -8% (difference = 3.7% [97.5% CI: 3.3-4.2]; p < 0.0001). Ring use nearly quadrupled from 8% -30% (difference = 21.7% [97.5% CI: 21.0-22.5]; p < 0.0001). Nearly all women who were undecided prior to counselling selected a method after counselling. Selection of the pill increased most in Russia (+ 11%) and Sweden (+ 5%); patch selection was greatest in Russia (+ 7%) and Israel (+ 6%); ring use increased most in Ukraine and in the Czech Republic and Slovakia (+ 36%). CONCLUSIONS: Counselling increases use of alternative CHCs, such as the patch and the ring. Considerable differences between countries were noted.

Repeated ovarian stimulation with corifollitropin alfa in patients in a GnRH antagonist protocol: no concern for immunogenicity.

BACKGROUND: One injection of corifollitropin alfa replaces the first seven daily FSH injections in controlled ovarian stimulation (COS) cycles. Repeated treatment with therapeutic proteins may cause immune responses or hypersensitivity reactions. We assessed the immunogenicity and safety of corifollitropin alfa treatment in up to three COS cycles. METHODS: In this multicentre, phase III uncontrolled trial, patients (>60 kg) started treatment with one injection of 150 µg corifollitropin alfa on cycle Day 2 or 3 of menses and 0.25 mg ganielix on stimulation Day 5 or 6. Primary outcome measures were antibody formation against corifollitropin alfa (using highly sensitive radioimmunoprecipitation assay), hypersensitivity reactions, local tolerance and adverse events (AEs). RESULTS: First, second and third COS cycles were started by 682, 375 and 198 patients, respectively. No clinically relevant immunogenicity or drug-related hypersensitivity was observed. For 192 patients undergoing their third cycle a post-treatment blood sample was negative in the anti-corifollitropin antibody assay, resulting in an upper limit of the one-sided 95% confidence interval (CI) of 1.5%. Most frequent AEs were procedural pain (17.7%, 95% CI: 14.9-20.8%), headache (9.1%, 95% CI: 7.0-11.5%) and pelvic pain (7.6%, 95% CI: 5.7-9.9%). Cumulative ongoing pregnancy rate after three cycles, including frozen-thawed embryo transfer cycles and spontaneous pregnancies, was 61% (95% CI: 56-65%) after censoring for patients who discontinued. CONCLUSIONS: Treatment with corifollitropin alfa can safely and effectively initiate and sustain ovarian stimulation during the first 7 days of COS in normal responder patients undergoing up to three treatment cycles, without concerns of immunogenicity. The trial was registered under ClinicalTrials.gov identifier NCT00696878.

Comprehensive counseling about combined hormonal contraceptives changes the choice of contraceptive methods: results of the CHOICE program in Sweden.

OBJECTIVE: To study the influence of counseling on women's contraceptive decisions. DESIGN: A cross-sectional multicenter study. SETTING: Seventy Swedish family planning clinics. POPULATION: Women aged 15-40 years attending for a contraceptive consultation who expressed interest in a combined hormonal contraceptive (CHC) method. METHODS: Structured counseling about three CHCs and questionnaires completed after counseling from the healthcare professional. MAIN OUTCOME MEASURES: Method originally requested, perceptions of CHC attributes, method chosen and reasons for the choice. RESULTS: In all, 173 healthcare professionals and 1,944 women participated. The mean standard deviation (SD) age of the women was 22.6(6.1) years. After structured counseling, a majority of women (56.0%; n=1 069; 95% confidence interval (CI) 53.1-58.9) chose the daily pill, 6.2% (n=118; 95% CI 4.9-7.8) chose the weekly patch, and 22.5% (n=430; 95% CI 20.2-25.1) chose the monthly ring. The weekly patch was chosen more often after counseling (6.2 vs 2.4% before counseling; p<0.0001). The greatest change was in the proportion of women who chose the contraceptive ring after counseling (22.5% vs. 8.5% before counseling; p<0.0001). The proportion of undecided women after counseling was reduced considerably (3.9% vs. 27.8% before counseling). Among the 523 women who were undecided before counseling, 50.6% chose the pill, 10.2% the patch and 24.6% the ring, while 20.9% of women who initially requested the pill changed to another method. CONCLUSIONS: Structured counseling facilitated choice of contraceptive method for most women, leading to changes in women's selection of a CHC method.

The effects of Implanon on menstrual bleeding patterns.

OBJECTIVES: To evaluate an integrated analysis of bleeding patterns associated with use of the subdermal contraceptive implant Implanon (etonogestrel, Organon, part of Schering-Plough) and to provide physician guidance to optimize patient counselling. METHODS: Data from 11 clinical trials were reviewed (N = 923). Assessments included bleeding-spotting records, dysmenorrhoea, and patient-perceived reasons for discontinuation. Bleeding patterns were analysed via reference period (RP) analyses. RESULTS: Implanon use was associated with the following bleeding irregularities: amenorrhoea (22.2%) and infrequent (33.6%), frequent (6.7%), and/or prolonged bleeding (17.7%). In 75% of RPs, bleeding-spotting days were fewer than or comparable to those observed during the natural cycle, but they occurred at unpredictable intervals. The bleeding pattern experienced during the initial phase predicted future patterns for the majority of women. The group of women with favourable bleeding patterns during the first three months tended to continue with this pattern throughout the first two years of use, whereas the group with unfavourable initial patterns had at least a 50% chance that the pattern would improve. Only 11.3% of patients discontinued owing to bleeding irregularities, mainly because of prolonged flow and frequent irregular bleeding. Most women (77%) who had baseline dysmenorrhoea experienced complete resolution of symptoms. CONCLUSION: Implanon use is associated with an unpredictable bleeding pattern, which includes amenorrhoea and infrequent, frequent, and/or prolonged bleeding. The bleeding pattern experienced during the first three months is broadly predictive of future bleeding patterns for many women. Effective preinsertion counselling on the possible changes in bleeding patterns may improve continuation rates.

Tolerability and clinical safety of Implanon.

OBJECTIVES: To evaluate the tolerability and clinical safety of the subdermal, long-acting hormonal contraceptive Implanon. METHODS: This integrated safety analysis included 11 international studies concerning Implanon (68 mg etonogestrel) of which 10 had a duration of at least two years. Assessments included reports of adverse events (AEs), reasons and rates of discontinuation, insertion/removal complications, and the condition of the implant site. Metabolic and coagulation parameters are briefly discussed to fully describe the clinical safety profile. RESULTS: In total 942 women were exposed to Implanon for 24,679 cycles over the course of one to five years. The overall discontinuation rate was 32.7%; the most frequently reported reasons for discontinuation were adverse events (13.9%), bleeding irregularities (10.4%), and planning pregnancy (4.1%). The most commonly reported drug-related AE was headache (15.3%); however, headache was reported in only 1.6% of women as a reason for discontinuation. Insertion and removal times for Implanon were short with few complications, none of which were major. From earlier studies it is known that treatment with Implanon has little effect on metabolic and coagulation parameters. CONCLUSIONS: Implanon is a well-tolerated and safe method of long-acting hormonal contraception for women.