Effect of antenatal milk expression education on lactation outcomes in birthing people with pre-pregnancy body mass index ≥ 25: Protocol for a randomized, controlled trial

Background: Birthing people with pre-pregnancy body mass indices (BMIs) ≥ 25 kg/m2, particularly those without prior breastfeeding experience, are at increased risk for suboptimal lactation outcomes. Antenatal milk expression (AME) may be one way to counteract the negative effects of early infant formula supplementation common in this population. Methods: This ongoing, randomized controlled trial in the United States evaluates the efficacy of a telelactation-delivered AME education intervention versus an attention control condition on lactation outcomes to 1 year postpartum among 280 nulliparous-to-primiparous, non-diabetic birthing people with pre-pregnancy BMI ≥ 25 kg/m2. The assigned study treatment is delivered via four weekly online video consultations between gestational weeks 37-40. Participants assigned to AME meet with study personnel and a lactation consultant to learn and practice AME. Instructions are provided for home practice of AME between study visits. Control group participants view videos on infant care/development at study visits. Participants complete emailed surveys at enrollment (340/7-366/7 gestational weeks) and 2 weeks, 6 weeks, 12 weeks, 6 months, and 12 months postpartum. Surveys assess lactation and infant feeding practices; breastfeeding self-efficacy, attitudes, and satisfaction; perception of insufficient milk; onset of lactogenesis-II; lactation support and problems; and reasons for breastfeeding cessation. Surveys also assess factors associated with lactation outcomes, including demographic characteristics, health problems, birth trauma, racial discrimination, and weight stigma. Health information and infant feeding data are abstracted from the pregnancy and birth center electronic health record. Milk samples are collected from the intervention group at each study visit and from both groups at each postpartum follow-up for future analyses. Qualitative interviews are conducted at 6 weeks postpartum to understand AME experiences. Primary outcomes of interest are breastfeeding exclusivity and breastfeeding self-efficacy scores at 2 weeks postpartum. Outcomes will be examined longitudinally with generalized linear mixed-effects modeling. Discussion: This is the first adequately powered trial evaluating the effectiveness of AME among U.S. birthing people and within a non-diabetic population with pre-pregnancy BMI ≥ 25 kg/m2. This study will also provide the first evidence of acceptability and effectiveness of telelactation-delivered AME. Trial registration: ClinicalTrials.gov: NCT04258709

Study protocol for a stepped-wedge cluster (nested) randomized controlled trial of antenatal colostrum expression (ACE) instruction in first-time mothers: The ACE study

Background: Although many mothers initiate breastfeeding, supplementation with human-milk substitutes (formula) during the birth hospitalization is common and has been associated with early breastfeeding cessation. Colostrum hand expressed in the last few weeks before birth, known as antenatal colostrum expression (ACE), can be used instead of human-milk substitutes. However, evidence is lacking on the efficacy of ACE on breastfeeding outcomes and in non-diabetic mothers. Methods and Planned Analysis: This multicenter stepped-wedge cluster (nested) randomized controlled trial aims to recruit 945 nulliparous pregnant individuals. The trial is conducted in two phases. During Phase 1, control group participants are under standard care. During Phase 2, participants are randomized to ACE instruction via a pre-recorded online video or a one-on-one session with a midwife. Adjusted logistic regression analysis will be used to examine the relationship between ACE instruction and breastfeeding outcomes. Research Aims and Questions: Primary aim: (1) Does advising pregnant individuals to practice ACE and providing instruction improve exclusive breastfeeding rates at 4 months postpartum? Secondary research questions: (2) Do individuals who practice ACE have higher rates of exclusive breastfeeding during the initial hospital stay after birth? (3) Is teaching ACE via an online video non-inferior to one-on-one instruction from a midwife? (4) Does expressing colostrum in pregnancy influence time to secretory activation, or (5) result in any differences in the composition of postnatal colostrum? Discussion: Trial findings have important implications for maternity practice, with the online video providing an easily accessible opportunity for ACE education as part of standard antenatal care

Common genetic variants in the CLDN2 and PRSS1-PRSS2 loci alter risk for alcohol-related and sporadic pancreatitis

Pancreatitis is a complex, progressively destructive inflammatory disorder. Alcohol was long thought to be the primary causative agent, but genetic contributions have been of interest since the discovery that rare PRSS1, CFTR, and SPINK1 variants were associated with pancreatitis risk. We now report two significant genome-wide associations identified and replicated at PRSS1-PRSS2 (1×10-12) and x-linked CLDN2 (p < 1×10-21) through a two-stage genome-wide study (Stage 1, 676 cases and 4507 controls; Stage 2, 910 cases and 4170 controls). The PRSS1 variant affects susceptibility by altering expression of the primary trypsinogen gene. The CLDN2 risk allele is associated with atypical localization of claudin-2 in pancreatic acinar cells. The homozygous (or hemizygous male) CLDN2 genotype confers the greatest risk, and its alleles interact with alcohol consumption to amplify risk. These results could partially explain the high frequency of alcohol-related pancreatitis in men – male hemizygous frequency is 0.26, female homozygote is 0.07

A novel Alzheimer disease locus located near the gene encoding tau protein

This is the author accepted manuscript. The final version is available from the publisher via the DOI in this recordAPOE ε4, the most significant genetic risk factor for Alzheimer disease (AD), may mask effects of other loci. We re-analyzed genome-wide association study (GWAS) data from the International Genomics of Alzheimer's Project (IGAP) Consortium in APOE ε4+ (10 352 cases and 9207 controls) and APOE ε4- (7184 cases and 26 968 controls) subgroups as well as in the total sample testing for interaction between a single-nucleotide polymorphism (SNP) and APOE ε4 status. Suggestive associations (P<1 × 10-4) in stage 1 were evaluated in an independent sample (stage 2) containing 4203 subjects (APOE ε4+: 1250 cases and 536 controls; APOE ε4-: 718 cases and 1699 controls). Among APOE ε4- subjects, novel genome-wide significant (GWS) association was observed with 17 SNPs (all between KANSL1 and LRRC37A on chromosome 17 near MAPT) in a meta-analysis of the stage 1 and stage 2 data sets (best SNP, rs2732703, P=5·8 × 10-9). Conditional analysis revealed that rs2732703 accounted for association signals in the entire 100-kilobase region that includes MAPT. Except for previously identified AD loci showing stronger association in APOE ε4+ subjects (CR1 and CLU) or APOE ε4- subjects (MS4A6A/MS4A4A/MS4A6E), no other SNPs were significantly associated with AD in a specific APOE genotype subgroup. In addition, the finding in the stage 1 sample that AD risk is significantly influenced by the interaction of APOE with rs1595014 in TMEM106B (P=1·6 × 10-7) is noteworthy, because TMEM106B variants have previously been associated with risk of frontotemporal dementia. Expression quantitative trait locus analysis revealed that rs113986870, one of the GWS SNPs near rs2732703, is significantly associated with four KANSL1 probes that target transcription of the first translated exon and an untranslated exon in hippocampus (P≤1.3 × 10-8), frontal cortex (P≤1.3 × 10-9) and temporal cortex (P≤1.2 × 10-11). Rs113986870 is also strongly associated with a MAPT probe that targets transcription of alternatively spliced exon 3 in frontal cortex (P=9.2 × 10-6) and temporal cortex (P=2.6 × 10-6). Our APOE-stratified GWAS is the first to show GWS association for AD with SNPs in the chromosome 17q21.31 region. Replication of this finding in independent samples is needed to verify that SNPs in this region have significantly stronger effects on AD risk in persons lacking APOE ε4 compared with persons carrying this allele, and if this is found to hold, further examination of this region and studies aimed at deciphering the mechanism(s) are warranted

Relationship of Postpartum Levels of Cystatin and High-Sensitivity C-Reactive Protein and Duration of Lactation in Mothers with Previous Gestational Hypertension or Preeclampsia

Background: Women with hypertensive disorders of pregnancy are at increased risk of cardiovascular disease in later life. We sought to determine the association between lactation and markers of maternal cardiovascular health among postpartum women with and without hypertensive disorders of pregnancy via measures of inflammation (high-sensitivity C-reactive protein [hsCRP]) and renal function (cystatin C). Materials and Methods: This prospective cohort study enrolled primarily overweight and obese women during early pregnancy. At a postpartum study visit occurring 6-24 months after delivery, we collected data on lactation duration and measured hsCRP and cystatin C. We assessed associations between lactation duration and levels of hsCRP and cystatin C among normotensive women and women with preeclampsia or gestational hypertension using analysis of variance and chi-squared tests. Linear regression models adjusted for age, race, education, prepregnancy body mass index, current smoking, and time since delivery. Results: Of 425 women, 37 (9%) had preeclampsia and 48 (11%) had gestational hypertension during enrollment pregnancy. The postpartum visit occurred at a mean of 8.6 ± 4.4 months after delivery. Women with a history of preeclampsia had significantly higher levels of cystatin C (mean 0.86 versus 0.78 mg/L; p = 0.03) compared with normotensive women, but nonsignificant elevation in hsCRP (mean 8.39 versus 6.04 mg/L; p = 0.08). Women with gestational hypertension had no differences in mean hsCRP or cystatin C compared with normotensive women. Among the 237 women with any lactation, 78 (18%) lactated for at least 6 months. Lactation duration both in the overall sample and among women with gestational hypertension or preeclampsia was not associated with levels of hsCRP or cystatin C. Conclusions: Preeclampsia history was associated with elevated postpartum levels of cystatin C; however, duration of lactation was not associated with postpartum hsCRP or cystatin C, regardless of history of gestational hypertension or preeclampsia. Further research is needed on mechanisms through which lactation may affect maternal risk of cardiovascular disease

Breastfeeding and Later‐Life Cardiometabolic Health in Women With and Without Hypertensive Disorders of Pregnancy

Background Breastfeeding is associated with improved cardiometabolic profiles decades after pregnancy. Whether this association exists for women who experience hypertensive disorders of pregnancy (HDP) is unknown. The authors examined whether breastfeeding duration or exclusivity are associated with long‐term cardiometabolic health, and whether this relationship differs by HDP status. Methods and Results Participants (N=3598) were from the UK ALSPAC (Avon Longitudinal Study of Parents and Children) cohort. HDP status was assessed by medical record review. Breastfeeding behaviors were assessed by contemporaneous questionnaires. Breastfeeding duration was categorized as never, <1, 1 to <3, 3 to <6, 6 to <9, and 9+ months. Breastfeeding exclusivity was categorized as never, <1, 1 to <3, and 3 to 6 months. Measures of cardiometabolic health (body mass index, waist circumference, C‐reactive protein, insulin, proinsulin, glucose, lipids, blood pressure, mean arterial pressure, carotid intima‐media thickness, and arterial distensibility) were measured 18 years after pregnancy. Analyses were conducted using linear regression adjusting for relevant covariates. Breastfeeding was associated with improved cardiometabolic health (lower body mass index, waist circumference, C‐reactive protein, triglycerides, insulin, and proinsulin) in all women, but not for every breastfeeding duration. Interaction tests revealed additional benefits in women with a history of HDP, with the strongest benefit observed in the 6‐ to 9‐month breastfeeding category (diastolic blood pressure, −4.87 mm Hg [95% CI, −7.86 to −1.88], mean arterial pressure −4.61 [95% CI, −7.45 to −1.77], and low‐density lipoprotein cholesterol, −0.40 mmol/L [95% CI, −0.62 to −0.17 mmol/L]). Differences in C‐reactive protein and low‐density lipoprotein “survived” Bonferroni correction (P<0.001). Similar results were observed in the exclusive breastfeeding analyses. Conclusions Breastfeeding may be a mechanism to reduce the cardiovascular disease sequela associated with HDP; however, there is a need to establish whether associations reflect a causal effect