Normal Human Lactation: closing the gap

Normal Human Lactation: closing the gap | F1000Research "use strict";function _typeof(t){return(_typeof="function"==typeof Symbol&&"symbol"==typeof Symbol.iterator?function(t){return typeof t}:function(t){return t&&"function"==typeof Symbol&&t.constructor===Symbol&&t!==Symbol.prototype?"symbol":typeof t})(t)}!function(){var t=function(){var t,e,o=[],n=window,r=n;for(;r;){try{if(r.frames.__tcfapiLocator){t=r;break}}catch(t){}if(r===n.top)break;r=r.parent}t||(!function t(){var e=n.document,o=!!n.frames.__tcfapiLocator;if(!o)if(e.body){var r=e.createElement("iframe");r.style.cssText="display:none",r.name="__tcfapiLocator",e.body.appendChild(r)}else setTimeout(t,5);return!o}(),n.__tcfapi=function(){for(var t=arguments.length,n=new Array(t),r=0;r 3&&2===parseInt(n[1],10)&&"boolean"==typeof n[3]&&(e=n[3],"function"==typeof n[2]&&n[2]("set",!0)):"ping"===n[0]?"function"==typeof n[2]&&n[2]({gdprApplies:e,cmpLoaded:!1,cmpStatus:"stub"}):o.push(n)},n.addEventListener("message",(function(t){var e="string"==typeof t.data,o={};if(e)try{o=JSON.parse(t.data)}catch(t){}else o=t.data;var n="object"===_typeof(o)&&null!==o?o.__tcfapiCall:null;n&&window.__tcfapi(n.command,n.version,(function(o,r){var a={__tcfapiReturn:{returnValue:o,success:r,callId:n.callId}};t&&t.source&&t.source.postMessage&&t.source.postMessage(e?JSON.stringify(a):a,"*")}),n.parameter)}),!1))};"undefined"!=typeof module?module.exports=t:t()}(); dataLayer = dataLayer || []; // Standard GTM initialization - Google Consent Mode handles consent automatically (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start': new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0], j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src= 'https://www.googletagmanager.com/gtm.js?id='+i+dl+ '>m_auth=hzk0Vc3qFsQYhCrIoHz68A>m_preview=env-1>m_cookies_win=x';f.parentNode.insertBefore(j,f); })(window,document,'script','dataLayer','GTM-MWFK8L5J'); ;window.NREUM||(NREUM={});NREUM.init={distributed_tracing:{enabled:true},privacy:{cookies_enabled:true},ajax:{deny_list:["bam.nr-data.net"]}}; ;NREUM.loader_config={accountID:"438030",trustKey:"438030",agentID:"772317073",licenseKey:"97f8f67f26",applicationID:"772317073"} ;NREUM.info={beacon:"bam.nr-data.net",errorBeacon:"bam.nr-data.net",licenseKey:"97f8f67f26",applicationID:"772317073",sa:1} ;/*! For license information please see nr-loader-spa-1.236.0.min.js.LICENSE.txt */ (()=>{"use strict";var e,t,r={5763:(e,t,r)=>{r.d(t,{P_:()=>l,Mt:()=>g,C5:()=>s,DL:()=>v,OP:()=>T,lF:()=>D,Yu:()=>y,Dg:()=>h,CX:()=>c,GE:()=>b,sU:()=>_});var n=r(8632),i=r(9567);const o={beacon:n.ce.beacon,errorBeacon:n.ce.errorBeacon,licenseKey:void 0,applicationID:void 0,sa:void 0,queueTime:void 0,applicationTime:void 0,ttGuid:void 0,user:void 0,account:void 0,product:void 0,extra:void 0,jsAttributes:{},userAttributes:void 0,atts:void 0,transactionName:void 0,tNamePlain:void 0},a={};function s(e){if(!e)throw new Error("All info objects require an agent identifier!");if(!a[e])throw new Error("Info for ".concat(e," was never set"));return a[e]}function c(e,t){if(!e)throw new Error("All info objects require an agent identifier!");a[e]=(0,i.D)(t,o),(0,n.Qy)(e,a[e],"info")}var u=r(7056);const d=()=>{const e={blockSelector:"[data-nr-block]",maskInputOptions:{password:!0}};return{allow_bfcache:!0,privacy:{cookies_enabled:!0},ajax:{deny_list:void 0,enabled:!0,harvestTimeSeconds:10},distributed_tracing:{enabled:void 0,exclude_newrelic_header:void 0,cors_use_newrelic_header:void 0,cors_use_tracecontext_headers:void 0,allowed_origins:void 0},session:{domain:void 0,expiresMs:u.oD,inactiveMs:u.Hb},ssl:void 0,obfuscate:void 0,jserrors:{enabled:!0,harvestTimeSeconds:10},metrics:{enabled:!0},page_action:{enabled:!0,harvestTimeSeconds:30},page_view_event:{enabled:!0},page_view_timing:{enabled:!0,harvestTimeSeconds:30,long_task:!1},session_trace:{enabled:!0,harvestTimeSeconds:10},harvest:{tooManyRequestsDelay:60},session_replay:{enabled:!1,harvestTimeSeconds:60,sampleRate:.1,errorSampleRate:.1,maskTextSelector:"*",maskAllInputs:!0,get blockClass(){return"nr-block"},get ignoreClass(){return"nr-ignore"},get maskTextClass(){return"nr-mask"},get blockSelector(){return e.blockSelector},set blockSelector(t){e.blockSelector+=",".concat(t)},get maskInputOptions(){return e.maskInputOptions},set maskInputOptions(t){e.maskInputOptions={...t,password:!0}}},spa:{enabled:!0,harvestTimeSeconds:10}}},f={};function l(e){if(!e)throw new Error("All configuration objects require an agent identifier!");if(!f[e])throw new Error("Configuration for ".concat(e," was never set"));return f[e]}function h(e,t){if(!e)throw new Error("All configuration objects require an agent identifier!");f[e]=(0,i.D)(t,d()),(0,n.Qy)(e,f[e],"config")}function g(e,t){if(!e)throw new Error("All configuration objects require an agent identifier!");var r=l(e);if(r){for(var n=t.split("."),i=0;i {r.d(t,{D:()=>i});var n=r(50);function i(e,t){try{if(!e||"object"!=typeof e)return(0,n.Z)("Setting a Configurable requires an object as input");if(!t||"object"!=typeof t)return(0,n.Z)("Setting a Configurable requires a model to set its initial properties");const r=Object.create(Object.getPrototypeOf(t),Object.getOwnPropertyDescriptors(t)),o=0===Object.keys(r).length?e:r;for(let a in o)if(void 0!==e[a])try{"object"==typeof e[a]&&"object"==typeof t[a]?r[a]=i(e[a],t[a]):r[a]=e[a]}catch(e){(0,n.Z)("An error occurred while setting a property of a Configurable",e)}return r}catch(e){(0,n.Z)("An error occured while setting a Configurable",e)}}},6818:(e,t,r)=>{r.d(t,{Re:()=>i,gF:()=>o,q4:()=>n});const n="1.236.0",i="PROD",o="CDN"},385:(e,t,r)=>{r.d(t,{FN:()=>a,IF:()=>u,Nk:()=>f,Tt:()=>s,_A:()=>o,il:()=>n,pL:()=>c,v6:()=>i,w1:()=>d});const n="undefined"!=typeof window&&!!window.document,i="undefined"!=typeof WorkerGlobalScope&&("undefined"!=typeof self&&self instanceof WorkerGlobalScope&&self.navigator instanceof WorkerNavigator||"undefined"!=typeof globalThis&&globalThis instanceof WorkerGlobalScope&&globalThis.navigator instanceof WorkerNavigator),o=n?window:"undefined"!=typeof WorkerGlobalScope&&("undefined"!=typeof self&&self instanceof WorkerGlobalScope&&self||"undefined"!=typeof globalThis&&globalThis instanceof WorkerGlobalScope&&globalThis),a=""+o?.location,s=/iPad|iPhone|iPod/.test(navigator.userAgent),c=s&&"undefined"==typeof SharedWorker,u=(()=>{const e=navigator.userAgent.match(/Firefox[/\s](\d+\.\d+)/);return Array.isArray(e)&&e.length>=2?+e[1]:0})(),d=Boolean(n&&window.document.documentMode),f=!!navigator.sendBeacon},1117:(e,t,r)=>{r.d(t,{w:()=>o});var n=r(50);const i={agentIdentifier:"",ee:void 0};class o{constructor(e){try{if("object"!=typeof e)return(0,n.Z)("shared context requires an object as input");this.sharedContext={},Object.assign(this.sharedContext,i),Object.entries(e).forEach((e=>{let[t,r]=e;Object.keys(i).includes(t)&&(this.sharedContext[t]=r)}))}catch(e){(0,n.Z)("An error occured while setting SharedContext",e)}}}},8e3:(e,t,r)=>{r.d(t,{L:()=>d,R:()=>c});var n=r(2177),i=r(1284),o=r(4322),a=r(3325);const s={};function c(e,t){const r={staged:!1,priority:a.p[t]||0};u(e),s[e].get(t)||s[e].set(t,r)}function u(e){e&&(s[e]||(s[e]=new Map))}function d(){let e=arguments.length>0&&void 0!==arguments[0]?arguments[0]:"",t=arguments.length>1&&void 0!==arguments[1]?arguments[1]:"feature";if(u(e),!e||!s[e].get(t))return a(t);s[e].get(t).staged=!0;const r=[...s[e]];function a(t){const r=e?n.ee.get(e):n.ee,a=o.X.handlers;if(r.backlog&&a){var s=r.backlog[t],c=a[t];if(c){for(var u=0;s&&u {let[t,r]=e;return r.staged}))&&(r.sort(((e,t)=>e[1].priority-t[1].priority)),r.forEach((e=>{let[t]=e;a(t)})))}function f(e,t){var r=e[1];(0,i.D)(t[r],(function(t,r){var n=e[0];if(r[0]===n){var i=r[1],o=e[3],a=e[2];i.apply(o,a)}}))}},2177:(e,t,r)=>{r.d(t,{c:()=>f,ee:()=>u});var n=r(8632),i=r(2210),o=r(1284),a=r(5763),s="nr@context";let c=(0,n.fP)();var u;function d(){}function f(e){return(0,i.X)(e,s,l)}function l(){return new d}function h(){u.aborted=!0,u.backlog={}}c.ee?u=c.ee:(u=function e(t,r){var n={},c={},f={},g=!1;try{g=16===r.length&&(0,a.OP)(r).isolatedBacklog}catch(e){}var p={on:b,addEventListener:b,removeEventListener:y,emit:v,get:x,listeners:w,context:m,buffer:A,abort:h,aborted:!1,isBuffering:E,debugId:r,backlog:g?{}:t&&"object"==typeof t.backlog?t.backlog:{}};return p;function m(e){return e&&e instanceof d?e:e?(0,i.X)(e,s,l):l()}function v(e,r,n,i,o){if(!1!==o&&(o=!0),!u.aborted||i){t&&o&&t.emit(e,r,n);for(var a=m(n),s=w(e),d=s.length,f=0;fn,p:()=>i});var n=r(2177).ee.get("handle");function i(e,t,r,i,o){o?(o.buffer([e],i),o.emit(e,t,r)):(n.buffer([e],i),n.emit(e,t,r))}},4322:(e,t,r)=>{r.d(t,{X:()=>o});var n=r(5546);o.on=a;var i=o.handlers={};function o(e,t,r,o){a(o||n.E,i,e,t,r)}function a(e,t,r,i,o){o||(o="feature"),e||(e=n.E);var a=t[o]=t[o]||{};(a[r]=a[r]||[]).push([e,i])}},3239:(e,t,r)=>{r.d(t,{bP:()=>s,iz:()=>c,m$:()=>a});var n=r(385);let i=!1,o=!1;try{const e={get passive(){return i=!0,!1},get signal(){return o=!0,!1}};n._A.addEventListener("test",null,e),n._A.removeEventListener("test",null,e)}catch(e){}function a(e,t){return i||o?{capture:!!e,passive:i,signal:t}:!!e}function s(e,t){let r=arguments.length>2&&void 0!==arguments[2]&&arguments[2],n=arguments.length>3?arguments[3]:void 0;window.addEventListener(e,t,a(r,n))}function c(e,t){let r=arguments.length>2&&void 0!==arguments[2]&&arguments[2],n=arguments.length>3?arguments[3]:void 0;document.addEventListener(e,t,a(r,n))}},4402:(e,t,r)=>{r.d(t,{Ht:()=>u,M:()=>c,Rl:()=>a,ky:()=>s});var n=r(385);const i="xxxxxxxx-xxxx-4xxx-yxxx-xxxxxxxxxxxx";function o(e,t){return e?15&e[t]:16*Math.random()|0}function a(){const e=n._A?.crypto||n._A?.msCrypto;let t,r=0;return e&&e.getRandomValues&&(t=e.getRandomValues(new Uint8Array(31))),i.split("").map((e=>"x"===e?o(t,++r).toString(16):"y"===e?(3&o()|8).toString(16):e)).join("")}function s(e){const t=n._A?.crypto||n._A?.msCrypto;let r,i=0;t&&t.getRandomValues&&(r=t.getRandomValues(new Uint8Array(31)));const a=[];for(var s=0;s {r.d(t,{Bq:()=>n,Hb:()=>o,oD:()=>i});const n="NRBA",i=144e5,o=18e5},7894:(e,t,r)=>{function n(){return Math.round(performance.now())}r.d(t,{z:()=>n})},7243:(e,t,r)=>{r.d(t,{e:()=>o});var n=r(385),i={};function o(e){if(e in i)return i[e];if(0===(e||"").indexOf("data:"))return{protocol:"data"};let t;var r=n._A?.location,o={};if(n.il)t=document.createElement("a"),t.href=e;else try{t=new URL(e,r.href)}catch(e){return o}o.port=t.port;var a=t.href.split("://");!o.port&&a[1]&&(o.port=a[1].split("/")[0].split("@").pop().split(":")[1]),o.port&&"0"!==o.port||(o.port="https"===a[0]?"443":"80"),o.hostname=t.hostname||r.hostname,o.pathname=t.pathname,o.protocol=a[0],"/"!==o.pathname.charAt(0)&&(o.pathname="/"+o.pathname);var s=!t.protocol||":"===t.protocol||t.protocol===r.protocol,c=t.hostname===r.hostname&&t.port===r.port;return o.sameOrigin=s&&(!t.hostname||c),"/"===o.pathname&&(i[e]=o),o}},50:(e,t,r)=>{function n(e,t){"function"==typeof console.warn&&(console.warn("New Relic: ".concat(e)),t&&console.warn(t))}r.d(t,{Z:()=>n})},2587:(e,t,r)=>{r.d(t,{N:()=>c,T:()=>u});var n=r(2177),i=r(5546),o=r(8e3),a=r(3325);const s={stn:[a.D.sessionTrace],err:[a.D.jserrors,a.D.metrics],ins:[a.D.pageAction],spa:[a.D.spa],sr:[a.D.sessionReplay,a.D.sessionTrace]};function c(e,t){const r=n.ee.get(t);e&&"object"==typeof e&&(Object.entries(e).forEach((e=>{let[t,n]=e;void 0===u[t]&&(s[t]?s[t].forEach((e=>{n?(0,i.p)("feat-"+t,[],void 0,e,r):(0,i.p)("block-"+t,[],void 0,e,r),(0,i.p)("rumresp-"+t,[Boolean(n)],void 0,e,r)})):n&&(0,i.p)("feat-"+t,[],void 0,void 0,r),u[t]=Boolean(n))})),Object.keys(s).forEach((e=>{void 0===u[e]&&(s[e]?.forEach((t=>(0,i.p)("rumresp-"+e,[!1],void 0,t,r))),u[e]=!1)})),(0,o.L)(t,a.D.pageViewEvent))}const u={}},2210:(e,t,r)=>{r.d(t,{X:()=>i});var n=Object.prototype.hasOwnProperty;function i(e,t,r){if(n.call(e,t))return e[t];var i=r();if(Object.defineProperty&&Object.keys)try{return Object.defineProperty(e,t,{value:i,writable:!0,enumerable:!1}),i}catch(e){}return e[t]=i,i}},1284:(e,t,r)=>{r.d(t,{D:()=>n});const n=(e,t)=>Object.entries(e||{}).map((e=>{let[r,n]=e;return t(r,n)}))},4351:(e,t,r)=>{r.d(t,{P:()=>o});var n=r(2177);const i=()=>{const e=new WeakSet;return(t,r)=>{if("object"==typeof r&&null!==r){if(e.has(r))return;e.add(r)}return r}};function o(e){try{return JSON.stringify(e,i())}catch(e){try{n.ee.emit("internal-error",[e])}catch(e){}}}},3960:(e,t,r)=>{r.d(t,{K:()=>a,b:()=>o});var n=r(3239);function i(){return"undefined"==typeof document||"complete"===document.readyState}function o(e,t){if(i())return e();(0,n.bP)("load",e,t)}function a(e){if(i())return e();(0,n.iz)("DOMContentLoaded",e)}},8632:(e,t,r)=>{r.d(t,{EZ:()=>u,Qy:()=>c,ce:()=>o,fP:()=>a,gG:()=>d,mF:()=>s});var n=r(7894),i=r(385);const o={beacon:"bam.nr-data.net",errorBeacon:"bam.nr-data.net"};function a(){return i._A.NREUM||(i._A.NREUM={}),void 0===i._A.newrelic&&(i._A.newrelic=i._A.NREUM),i._A.NREUM}function s(){let e=a();return e.o||(e.o={ST:i._A.setTimeout,SI:i._A.setImmediate,CT:i._A.clearTimeout,XHR:i._A.XMLHttpRequest,REQ:i._A.Request,EV:i._A.Event,PR:i._A.Promise,MO:i._A.MutationObserver,FETCH:i._A.fetch}),e}function c(e,t,r){let i=a();const o=i.initializedAgents||{},s=o[e]||{};return Object.keys(s).length||(s.initializedAt={ms:(0,n.z)(),date:new Date}),i.initializedAgents={...o,[e]:{...s,[r]:t}},i}function u(e,t){a()[e]=t}function d(){return function(){let e=a();const t=e.info||{};e.info={beacon:o.beacon,errorBeacon:o.errorBeacon,...t}}(),function(){let e=a();const t=e.init||{};e.init={...t}}(),s(),function(){let e=a();const t=e.loader_config||{};e.loader_config={...t}}(),a()}},7956:(e,t,r)=>{r.d(t,{N:()=>i});var n=r(3239);function i(e){let t=arguments.length>1&&void 0!==arguments[1]&&arguments[1],r=arguments.length>2?arguments[2]:void 0,i=arguments.length>3?arguments[3]:void 0;return void(0,n.iz)("visibilitychange",(function(){if(t)return void("hidden"==document.visibilityState&&e());e(document.visibilityState)}),r,i)}},1214:(e,t,r)=>{r.d(t,{em:()=>v,u5:()=>N,QU:()=>S,_L:()=>I,Gm:()=>L,Lg:()=>M,gy:()=>U,BV:()=>Q,Kf:()=>ee});var n=r(2177);const i="nr@original";var o=Object.prototype.hasOwnProperty,a=!1;function s(e,t){return e||(e=n.ee),r.inPlace=function(e,t,n,i,o){n||(n="");var a,s,c,u="-"===n.charAt(0);for(c=0;c 2?n-2:0),o=2;o {r(A[T],e,w),r(E[T],e,w)})),r(l._A,"fetch",y),t.on(y+"end",(function(e,r){var n=this;if(r){var i=r.headers.get("content-length");null!==i&&(n.rxSize=i),t.emit(y+"done",[null,r],n)}else t.emit(y+"done",[e],n)})),t}const O={},j=["pushState","replaceState"];function S(e){const t=function(e){return(e||n.ee).get("history")}(e);return!l.il||O[t.debugId]++||(O[t.debugId]=1,s(t).inPlace(window.history,j,"-")),t}var P=r(3239);const C={},R=["appendChild","insertBefore","replaceChild"];function I(e){const t=function(e){return(e||n.ee).get("jsonp")}(e);if(!l.il||C[t.debugId])return t;C[t.debugId]=!0;var r=s(t),i=/[?&](?:callback|cb)=([^&#]+)/,o=/(.*)\.([^.]+)/,a=/^(\w+)(\.|$)(.*)$/;function c(e,t){var r=e.match(a),n=r[1],i=r[3];return i?c(i,t[n]):t[n]}return r.inPlace(Node.prototype,R,"dom-"),t.on("dom-start",(function(e){!function(e){if(!e||"string"!=typeof e.nodeName||"script"!==e.nodeName.toLowerCase())return;if("function"!=typeof e.addEventListener)return;var n=(a=e.src,s=a.match(i),s?s[1]:null);var a,s;if(!n)return;var u=function(e){var t=e.match(o);if(t&&t.length>=3)return{key:t[2],parent:c(t[1],window)};return{key:e,parent:window}}(n);if("function"!=typeof u.parent[u.key])return;var d={};function f(){t.emit("jsonp-end",[],d),e.removeEventListener("load",f,(0,P.m$)(!1)),e.removeEventListener("error",l,(0,P.m$)(!1))}function l(){t.emit("jsonp-error",[],d),t.emit("jsonp-end",[],d),e.removeEventListener("load",f,(0,P.m$)(!1)),e.removeEventListener("error",l,(0,P.m$)(!1))}r.inPlace(u.parent,[u.key],"cb-",d),e.addEventListener("load",f,(0,P.m$)(!1)),e.addEventListener("error",l,(0,P.m$)(!1)),t.emit("new-jsonp",[e.src],d)}(e[0])})),t}var k=r(5763);const H={};function L(e){const t=function(e){return(e||n.ee).get("mutation")}(e);if(!l.il||H[t.debugId])return t;H[t.debugId]=!0;var r=s(t),i=k.Yu.MO;return i&&(window.MutationObserver=function(e){return this instanceof i?new i(r(e,"fn-")):i.apply(this,arguments)},MutationObserver.prototype=i.prototype),t}const z={};function M(e){const t=function(e){return(e||n.ee).get("promise")}(e);if(z[t.debugId])return t;z[t.debugId]=!0;var r=n.c,o=s(t),a=k.Yu.PR;return a&&function(){function e(r){var n=t.context(),i=o(r,"executor-",n,null,!1);const s=Reflect.construct(a,[i],e);return t.context(s).getCtx=function(){return n},s}l._A.Promise=e,Object.defineProperty(e,"name",{value:"Promise"}),e.toString=function(){return a.toString()},Object.setPrototypeOf(e,a),["all","race"].forEach((function(r){const n=a[r];e[r]=function(e){let i=!1;[...e||[]].forEach((e=>{this.resolve(e).then(a("all"===r),a(!1))}));const o=n.apply(this,arguments);return o;function a(e){return function(){t.emit("propagate",[null,!i],o,!1,!1),i=i||!e}}}})),["resolve","reject"].forEach((function(r){const n=a[r];e[r]=function(e){const r=n.apply(this,arguments);return e!==r&&t.emit("propagate",[e,!0],r,!1,!1),r}})),e.prototype=a.prototype;const n=a.prototype.then;a.prototype.then=function(){var e=this,i=r(e);i.promise=e;for(var a=arguments.length,s=new Array(a),c=0;c e())),t};function m(e,t){i.inPlace(t,["onreadystatechange"],"fn-",E)}function b(){var e=this,t=r.context(e);e.readyState>3&&!t.resolved&&(t.resolved=!0,r.emit("xhr-resolved",[],e)),i.inPlace(e,f,"fn-",E)}if(function(e,t){for(var r in e)t[r]=e[r]}(o,p),p.prototype=o.prototype,i.inPlace(p.prototype,J,"-xhr-",E),r.on("send-xhr-start",(function(e,t){m(e,t),function(e){h.push(e),a&&(y?y.then(A):u?u(A):(w=-w,x.data=w))}(t)})),r.on("open-xhr-start",m),a){var y=c&&c.resolve();if(!u&&!c){var w=1,x=document.createTextNode(w);new a(A).observe(x,{characterData:!0})}}else t.on("fn-end",(function(e){e[0]&&e[0].type===d||A()}));function A(){for(var e=0;e {r.d(t,{t:()=>n});const n=r(3325).D.ajax},6660:(e,t,r)=>{r.d(t,{A:()=>i,t:()=>n});const n=r(3325).D.jserrors,i="nr@seenError"},3081:(e,t,r)=>{r.d(t,{gF:()=>o,mY:()=>i,t9:()=>n,vz:()=>s,xS:()=>a});const n=r(3325).D.metrics,i="sm",o="cm",a="storeSupportabilityMetrics",s="storeEventMetrics"},4649:(e,t,r)=>{r.d(t,{t:()=>n});const n=r(3325).D.pageAction},7633:(e,t,r)=>{r.d(t,{Dz:()=>i,OJ:()=>a,qw:()=>o,t9:()=>n});const n=r(3325).D.pageViewEvent,i="firstbyte",o="domcontent",a="windowload"},9251:(e,t,r)=>{r.d(t,{t:()=>n});const n=r(3325).D.pageViewTiming},3614:(e,t,r)=>{r.d(t,{BST_RESOURCE:()=>i,END:()=>s,FEATURE_NAME:()=>n,FN_END:()=>u,FN_START:()=>c,PUSH_STATE:()=>d,RESOURCE:()=>o,START:()=>a});const n=r(3325).D.sessionTrace,i="bstResource",o="resource",a="-start",s="-end",c="fn"+a,u="fn"+s,d="pushState"},7836:(e,t,r)=>{r.d(t,{BODY:()=>A,CB_END:()=>E,CB_START:()=>u,END:()=>x,FEATURE_NAME:()=>i,FETCH:()=>_,FETCH_BODY:()=>v,FETCH_DONE:()=>m,FETCH_START:()=>p,FN_END:()=>c,FN_START:()=>s,INTERACTION:()=>l,INTERACTION_API:()=>d,INTERACTION_EVENTS:()=>o,JSONP_END:()=>b,JSONP_NODE:()=>g,JS_TIME:()=>T,MAX_TIMER_BUDGET:()=>a,REMAINING:()=>f,SPA_NODE:()=>h,START:()=>w,originalSetTimeout:()=>y});var n=r(5763);const i=r(3325).D.spa,o=["click","submit","keypress","keydown","keyup","change"],a=999,s="fn-start",c="fn-end",u="cb-start",d="api-ixn-",f="remaining",l="interaction",h="spaNode",g="jsonpNode",p="fetch-start",m="fetch-done",v="fetch-body-",b="jsonp-end",y=n.Yu.ST,w="-start",x="-end",A="-body",E="cb"+x,T="jsTime",_="fetch"},5938:(e,t,r)=>{r.d(t,{W:()=>o});var n=r(5763),i=r(2177);class o{constructor(e,t,r){this.agentIdentifier=e,this.aggregator=t,this.ee=i.ee.get(e,(0,n.OP)(this.agentIdentifier).isolatedBacklog),this.featureName=r,this.blocked=!1}}},9144:(e,t,r)=>{r.d(t,{j:()=>m});var n=r(3325),i=r(5763),o=r(5546),a=r(2177),s=r(7894),c=r(8e3),u=r(3960),d=r(385),f=r(50),l=r(3081),h=r(8632);function g(){const e=(0,h.gG)();["setErrorHandler","finished","addToTrace","inlineHit","addRelease","addPageAction","setCurrentRouteName","setPageViewName","setCustomAttribute","interaction","noticeError","setUserId"].forEach((t=>{e[t]=function(){for(var r=arguments.length,n=new Array(r),i=0;i 1?r-1:0),i=1;i {e.exposed&&e.api[t]&&o.push(e.api[t](...n))})),o.length>1?o:o[0]}(t,...n)}}))}var p=r(2587);function m(e){let t=arguments.length>1&&void 0!==arguments[1]?arguments[1]:{},m=arguments.length>2?arguments[2]:void 0,v=arguments.length>3?arguments[3]:void 0,{init:b,info:y,loader_config:w,runtime:x={loaderType:m},exposed:A=!0}=t;const E=(0,h.gG)();y||(b=E.init,y=E.info,w=E.loader_config),(0,i.Dg)(e,b||{}),(0,i.GE)(e,w||{}),(0,i.sU)(e,x),y.jsAttributes??={},d.v6&&(y.jsAttributes.isWorker=!0),(0,i.CX)(e,y),g();const T=function(e,t){t||(0,c.R)(e,"api");const h={};var g=a.ee.get(e),p=g.get("tracer"),m="api-",v=m+"ixn-";function b(t,r,n,o){const a=(0,i.C5)(e);return null===r?delete a.jsAttributes[t]:(0,i.CX)(e,{...a,jsAttributes:{...a.jsAttributes,[t]:r}}),x(m,n,!0,o||null===r?"session":void 0)(t,r)}function y(){}["setErrorHandler","finished","addToTrace","inlineHit","addRelease"].forEach((e=>h[e]=x(m,e,!0,"api"))),h.addPageAction=x(m,"addPageAction",!0,n.D.pageAction),h.setCurrentRouteName=x(m,"routeName",!0,n.D.spa),h.setPageViewName=function(t,r){if("string"==typeof t)return"/"!==t.charAt(0)&&(t="/"+t),(0,i.OP)(e).customTransaction=(r||"http://custom.transaction")+t,x(m,"setPageViewName",!0)()},h.setCustomAttribute=function(e,t){let r=arguments.length>2&&void 0!==arguments[2]&&arguments[2];if("string"==typeof e){if(["string","number"].includes(typeof t)||null===t)return b(e,t,"setCustomAttribute",r);(0,f.Z)("Failed to execute setCustomAttribute.\nNon-null value must be a string or number type, but a type of was provided."))}else(0,f.Z)("Failed to execute setCustomAttribute.\nName must be a string type, but a type of was provided."))},h.setUserId=function(e){if("string"==typeof e||null===e)return b("enduser.id",e,"setUserId",!0);(0,f.Z)("Failed to execute setUserId.\nNon-null value must be a string type, but a type of was provided."))},h.interaction=function(){return(new y).get()};var w=y.prototype={createTracer:function(e,t){var r={},i=this,a="function"==typeof t;return(0,o.p)(v+"tracer",[(0,s.z)(),e,r],i,n.D.spa,g),function(){if(p.emit((a?"":"no-")+"fn-start",[(0,s.z)(),i,a],r),a)try{return t.apply(this,arguments)}catch(e){throw p.emit("fn-err",[arguments,this,"string"==typeof e?new Error(e):e],r),e}finally{p.emit("fn-end",[(0,s.z)()],r)}}}};function x(e,t,r,i){return function(){return(0,o.p)(l.xS,["API/"+t+"/called"],void 0,n.D.metrics,g),i&&(0,o.p)(e+t,[(0,s.z)(),...arguments],r?null:this,i,g),r?void 0:this}}function A(){r.e(439).then(r.bind(r,7438)).then((t=>{let{setAPI:r}=t;r(e),(0,c.L)(e,"api")})).catch((()=>(0,f.Z)("Downloading runtime APIs failed...")))}return["actionText","setName","setAttribute","save","ignore","onEnd","getContext","end","get"].forEach((e=>{w[e]=x(v,e,void 0,n.D.spa)})),h.noticeError=function(e,t){"string"==typeof e&&(e=new Error(e)),(0,o.p)(l.xS,["API/noticeError/called"],void 0,n.D.metrics,g),(0,o.p)("err",[e,(0,s.z)(),!1,t],void 0,n.D.jserrors,g)},d.il?(0,u.b)((()=>A()),!0):A(),h}(e,v);return(0,h.Qy)(e,T,"api"),(0,h.Qy)(e,A,"exposed"),(0,h.EZ)("activatedFeatures",p.T),T}},3325:(e,t,r)=>{r.d(t,{D:()=>n,p:()=>i});const n={ajax:"ajax",jserrors:"jserrors",metrics:"metrics",pageAction:"page_action",pageViewEvent:"page_view_event",pageViewTiming:"page_view_timing",sessionReplay:"session_replay",sessionTrace:"session_trace",spa:"spa"},i={[n.pageViewEvent]:1,[n.pageViewTiming]:2,[n.metrics]:3,[n.jserrors]:4,[n.ajax]:5,[n.sessionTrace]:6,[n.pageAction]:7,[n.spa]:8,[n.sessionReplay]:9}}},n={};function i(e){var t=n[e];if(void 0!==t)return t.exports;var o=n[e]={exports:{}};return r[e](o,o.exports,i),o.exports}i.m=r,i.d=(e,t)=>{for(var r in t)i.o(t,r)&&!i.o(e,r)&&Object.defineProperty(e,r,{enumerable:!0,get:t[r]})},i.f={},i.e=e=>Promise.all(Object.keys(i.f).reduce(((t,r)=>(i.f[r](e,t),t)),[])),i.u=e=>(({78:"page_action-aggregate",147:"metrics-aggregate",242:"session-manager",317:"jserrors-aggregate",348:"page_view_timing-aggregate",412:"lazy-feature-loader",439:"async-api",538:"recorder",590:"session_replay-aggregate",675:"compressor",733:"session_trace-aggregate",786:"page_view_event-aggregate",873:"spa-aggregate",898:"ajax-aggregate"}[e]||e)+"."+{78:"ac76d497",147:"3dc53903",148:"1a20d5fe",242:"2a64278a",317:"49e41428",348:"bd6de33a",412:"2f55ce66",439:"30bd804e",538:"1b18459f",590:"cf0efb30",675:"ae9f91a8",733:"83105561",786:"06482edd",860:"03a8b7a5",873:"e6b09d52",898:"998ef92b"}[e]+"-1.236.0.min.js"),i.o=(e,t)=>Object.prototype.hasOwnProperty.call(e,t),e={},t="NRBA:",i.l=(r,n,o,a)=>{if(e[r])e[r].push(n);else{var s,c;if(void 0!==o)for(var u=document.getElementsByTagName("script"),d=0;d {s.onerror=s.onload=null,clearTimeout(h);var i=e[r];if(delete e[r],s.parentNode&&s.parentNode.removeChild(s),i&&i.forEach((e=>e(n))),t)return t(n)},h=setTimeout(l.bind(null,void 0,{type:"timeout",target:s}),12e4);s.onerror=l.bind(null,s.onerror),s.onload=l.bind(null,s.onload),c&&document.head.appendChild(s)}},i.r=e=>{"undefined"!=typeof Symbol&&Symbol.toStringTag&&Object.defineProperty(e,Symbol.toStringTag,{value:"Module"}),Object.defineProperty(e,"__esModule",{value:!0})},i.j=364,i.p="https://js-agent.newrelic.com/",(()=>{var e={364:0,953:0};i.f.j=(t,r)=>{var n=i.o(e,t)?e[t]:void 0;if(0!==n)if(n)r.push(n[2]);else{var o=new Promise(((r,i)=>n=e[t]=[r,i]));r.push(n[2]=o);var a=i.p+i.u(t),s=new Error;i.l(a,(r=>{if(i.o(e,t)&&(0!==(n=e[t])&&(e[t]=void 0),n)){var o=r&&("load"===r.type?"missing":r.type),a=r&&r.target&&r.target.src;s.message="Loading chunk "+t+" failed.\n("+o+": "+a+")",s.name="ChunkLoadError",s.type=o,s.request=a,n[1](s)}}),"chunk-"+t,t)}};var t=(t,r)=>{var n,o,[a,s,c]=r,u=0;if(a.some((t=>0!==e[t]))){for(n in s)i.o(s,n)&&(i.m[n]=s[n]);if(c)c(i)}for(t&&t(r);u {i.r(o);var e=i(3325),t=i(5763);const r=Object.values(e.D);function n(e){const n={};return r.forEach((r=>{n[r]=function(e,r){return!1!==(0,t.Mt)(r,"".concat(e,".enabled"))}(r,e)})),n}var a=i(9144);var s=i(5546),c=i(385),u=i(8e3),d=i(5938),f=i(3960),l=i(50);class h extends d.W{constructor(e,t,r){let n=!(arguments.length>3&&void 0!==arguments[3])||arguments[3];super(e,t,r),this.auto=n,this.abortHandler,this.featAggregate,this.onAggregateImported,n&&(0,u.R)(e,r)}importAggregator(){let e=arguments.length>0&&void 0!==arguments[0]?arguments[0]:{};if(this.featAggregate||!this.auto)return;const r=c.il&&!0===(0,t.Mt)(this.agentIdentifier,"privacy.cookies_enabled");let n;this.onAggregateImported=new Promise((e=>{n=e}));const o=async()=>{let t;try{if(r){const{setupAgentSession:e}=await Promise.all([i.e(860),i.e(242)]).then(i.bind(i,3228));t=e(this.agentIdentifier)}}catch(e){(0,l.Z)("A problem occurred when starting up session manager. This page will not start or extend any session.",e)}try{if(!this.shouldImportAgg(this.featureName,t))return void(0,u.L)(this.agentIdentifier,this.featureName);const{lazyFeatureLoader:r}=await i.e(412).then(i.bind(i,8582)),{Aggregate:o}=await r(this.featureName,"aggregate");this.featAggregate=new o(this.agentIdentifier,this.aggregator,e),n(!0)}catch(e){(0,l.Z)("Downloading and initializing ".concat(this.featureName," failed..."),e),this.abortHandler?.(),n(!1)}};c.il?(0,f.b)((()=>o()),!0):o()}shouldImportAgg(r,n){return r!==e.D.sessionReplay||!1!==(0,t.Mt)(this.agentIdentifier,"session_trace.enabled")&&(!!n?.isNew||!!n?.state.sessionReplay)}}var g=i(7633),p=i(7894);class m extends h{static featureName=g.t9;constructor(r,n){let i=!(arguments.length>2&&void 0!==arguments[2])||arguments[2];if(super(r,n,g.t9,i),("undefined"==typeof PerformanceNavigationTiming||c.Tt)&&"undefined"!=typeof PerformanceTiming){const n=(0,t.OP)(r);n[g.Dz]=Math.max(Date.now()-n.offset,0),(0,f.K)((()=>n[g.qw]=Math.max((0,p.z)()-n[g.Dz],0))),(0,f.b)((()=>{const t=(0,p.z)();n[g.OJ]=Math.max(t-n[g.Dz],0),(0,s.p)("timing",["load",t],void 0,e.D.pageViewTiming,this.ee)}))}this.importAggregator()}}var v=i(1117),b=i(1284);class y extends v.w{constructor(e){super(e),this.aggregatedData={}}store(e,t,r,n,i){var o=this.getBucket(e,t,r,i);return o.metrics=function(e,t){t||(t={count:0});return t.count+=1,(0,b.D)(e,(function(e,r){t[e]=w(r,t[e])})),t}(n,o.metrics),o}merge(e,t,r,n,i){var o=this.getBucket(e,t,n,i);if(o.metrics){var a=o.metrics;a.count+=r.count,(0,b.D)(r,(function(e,t){if("count"!==e){var n=a[e],i=r[e];i&&!i.c?a[e]=w(i.t,n):a[e]=function(e,t){if(!t)return e;t.c||(t=x(t.t));return t.min=Math.min(e.min,t.min),t.max=Math.max(e.max,t.max),t.t+=e.t,t.sos+=e.sos,t.c+=e.c,t}(i,a[e])}}))}else o.metrics=r}storeMetric(e,t,r,n){var i=this.getBucket(e,t,r);return i.stats=w(n,i.stats),i}getBucket(e,t,r,n){this.aggregatedData[e]||(this.aggregatedData[e]={});var i=this.aggregatedData[e][t];return i||(i=this.aggregatedData[e][t]={params:r||{}},n&&(i.custom=n)),i}get(e,t){return t?this.aggregatedData[e]&&this.aggregatedData[e][t]:this.aggregatedData[e]}take(e){for(var t={},r="",n=!1,i=0;i t.max&&(t.max=e),e 2&&void 0!==arguments[2])||arguments[2];super(e,r,j.t,n),c.il&&((0,t.OP)(e).initHidden=Boolean("hidden"===document.visibilityState),(0,N.N)((()=>(0,s.p)("docHidden",[(0,p.z)()],void 0,j.t,this.ee)),!0),(0,O.bP)("pagehide",(()=>(0,s.p)("winPagehide",[(0,p.z)()],void 0,j.t,this.ee))),this.importAggregator())}}var P=i(3081);class C extends h{static featureName=P.t9;constructor(e,t){let r=!(arguments.length>2&&void 0!==arguments[2])||arguments[2];super(e,t,P.t9,r),this.importAggregator()}}var R,I=i(2210),k=i(1214),H=i(2177),L={};try{R=localStorage.getItem("__nr_flags").split(","),console&&"function"==typeof console.log&&(L.console=!0,-1!==R.indexOf("dev")&&(L.dev=!0),-1!==R.indexOf("nr_dev")&&(L.nrDev=!0))}catch(e){}function z(e){try{L.console&&z(e)}catch(e){}}L.nrDev&&H.ee.on("internal-error",(function(e){z(e.stack)})),L.dev&&H.ee.on("fn-err",(function(e,t,r){z(r.stack)})),L.dev&&(z("NR AGENT IN DEVELOPMENT MODE"),z("flags: "+(0,b.D)(L,(function(e,t){return e})).join(", ")));var M=i(6660);class B extends h{static featureName=M.t;constructor(r,n){let i=!(arguments.length>2&&void 0!==arguments[2])||arguments[2];super(r,n,M.t,i),this.skipNext=0;try{this.removeOnAbort=new AbortController}catch(e){}const o=this;o.ee.on("fn-start",(function(e,t,r){o.abortHandler&&(o.skipNext+=1)})),o.ee.on("fn-err",(function(t,r,n){o.abortHandler&&!n[M.A]&&((0,I.X)(n,M.A,(function(){return!0})),this.thrown=!0,(0,s.p)("err",[n,(0,p.z)()],void 0,e.D.jserrors,o.ee))})),o.ee.on("fn-end",(function(){o.abortHandler&&!this.thrown&&o.skipNext>0&&(o.skipNext-=1)})),o.ee.on("internal-error",(function(t){(0,s.p)("ierr",[t,(0,p.z)(),!0],void 0,e.D.jserrors,o.ee)})),this.origOnerror=c._A.onerror,c._A.onerror=this.onerrorHandler.bind(this),c._A.addEventListener("unhandledrejection",(t=>{const r=function(e){let t="Unhandled Promise Rejection: ";if(e instanceof Error)try{return e.message=t+e.message,e}catch(t){return e}if(void 0===e)return new Error(t);try{return new Error(t+(0,D.P)(e))}catch(e){return new Error(t)}}(t.reason);(0,s.p)("err",[r,(0,p.z)(),!1,{unhandledPromiseRejection:1}],void 0,e.D.jserrors,this.ee)}),(0,O.m$)(!1,this.removeOnAbort?.signal)),(0,k.gy)(this.ee),(0,k.BV)(this.ee),(0,k.em)(this.ee),(0,t.OP)(r).xhrWrappable&&(0,k.Kf)(this.ee),this.abortHandler=this.#e,this.importAggregator()}#e(){this.removeOnAbort?.abort(),this.abortHandler=void 0}onerrorHandler(t,r,n,i,o){"function"==typeof this.origOnerror&&this.origOnerror(...arguments);try{this.skipNext?this.skipNext-=1:(0,s.p)("err",[o||new F(t,r,n),(0,p.z)()],void 0,e.D.jserrors,this.ee)}catch(t){try{(0,s.p)("ierr",[t,(0,p.z)(),!0],void 0,e.D.jserrors,this.ee)}catch(e){}}return!1}}function F(e,t,r){this.message=e||"Uncaught error with no additional information",this.sourceURL=t,this.line=r}let U=1;const q="nr@id";function G(e){const t=typeof e;return!e||"object"!==t&&"function"!==t?-1:e===c._A?0:(0,I.X)(e,q,(function(){return U++}))}function V(e){if("string"==typeof e&&e.length)return e.length;if("object"==typeof e){if("undefined"!=typeof ArrayBuffer&&e instanceof ArrayBuffer&&e.byteLength)return e.byteLength;if("undefined"!=typeof Blob&&e instanceof Blob&&e.size)return e.size;if(!("undefined"!=typeof FormData&&e instanceof FormData))try{return(0,D.P)(e).length}catch(e){return}}}var X=i(7243);class W{constructor(e){this.agentIdentifier=e,this.generateTracePayload=this.generateTracePayload.bind(this),this.shouldGenerateTrace=this.shouldGenerateTrace.bind(this)}generateTracePayload(e){if(!this.shouldGenerateTrace(e))return null;var r=(0,t.DL)(this.agentIdentifier);if(!r)return null;var n=(r.accountID||"").toString()||null,i=(r.agentID||"").toString()||null,o=(r.trustKey||"").toString()||null;if(!n||!i)return null;var a=(0,_.M)(),s=(0,_.Ht)(),c=Date.now(),u={spanId:a,traceId:s,timestamp:c};return(e.sameOrigin||this.isAllowedOrigin(e)&&this.useTraceContextHeadersForCors())&&(u.traceContextParentHeader=this.generateTraceContextParentHeader(a,s),u.traceContextStateHeader=this.generateTraceContextStateHeader(a,c,n,i,o)),(e.sameOrigin&&!this.excludeNewrelicHeader()||!e.sameOrigin&&this.isAllowedOrigin(e)&&this.useNewrelicHeaderForCors())&&(u.newrelicHeader=this.generateTraceHeader(a,s,c,n,i,o)),u}generateTraceContextParentHeader(e,t){return"00-"+t+"-"+e+"-01"}generateTraceContextStateHeader(e,t,r,n,i){return i+"@nr=0-1-"+r+"-"+n+"-"+e+"----"+t}generateTraceHeader(e,t,r,n,i,o){if(!("function"==typeof c._A?.btoa))return null;var a={v:[0,1],d:{ty:"Browser",ac:n,ap:i,id:e,tr:t,ti:r}};return o&&n!==o&&(a.d.tk=o),btoa((0,D.P)(a))}shouldGenerateTrace(e){return this.isDtEnabled()&&this.isAllowedOrigin(e)}isAllowedOrigin(e){var r=!1,n={};if((0,t.Mt)(this.agentIdentifier,"distributed_tracing")&&(n=(0,t.P_)(this.agentIdentifier).distributed_tracing),e.sameOrigin)r=!0;else if(n.allowed_origins instanceof Array)for(var i=0;i 2&&void 0!==arguments[2])||arguments[2];super(r,n,Z.t,i),(0,t.OP)(r).xhrWrappable&&(this.dt=new W(r),this.handler=(e,t,r,n)=>(0,s.p)(e,t,r,n,this.ee),(0,k.u5)(this.ee),(0,k.Kf)(this.ee),function(r,n,i,o){function a(e){var t=this;t.totalCbs=0,t.called=0,t.cbTime=0,t.end=E,t.ended=!1,t.xhrGuids={},t.lastSize=null,t.loadCaptureCalled=!1,t.params=this.params||{},t.metrics=this.metrics||{},e.addEventListener("load",(function(r){_(t,e)}),(0,O.m$)(!1)),c.IF||e.addEventListener("progress",(function(e){t.lastSize=e.loaded}),(0,O.m$)(!1))}function s(e){this.params={method:e[0]},T(this,e[1]),this.metrics={}}function u(e,n){var i=(0,t.DL)(r);i.xpid&&this.sameOrigin&&n.setRequestHeader("X-NewRelic-ID",i.xpid);var a=o.generateTracePayload(this.parsedOrigin);if(a){var s=!1;a.newrelicHeader&&(n.setRequestHeader("newrelic",a.newrelicHeader),s=!0),a.traceContextParentHeader&&(n.setRequestHeader("traceparent",a.traceContextParentHeader),a.traceContextStateHeader&&n.setRequestHeader("tracestate",a.traceContextStateHeader),s=!0),s&&(this.dt=a)}}function d(e,t){var r=this.metrics,i=e[0],o=this;if(r&&i){var a=V(i);a&&(r.txSize=a)}this.startTime=(0,p.z)(),this.listener=function(e){try{"abort"!==e.type||o.loadCaptureCalled||(o.params.aborted=!0),("load"!==e.type||o.called===o.totalCbs&&(o.onloadCalled||"function"!=typeof t.onload)&&"function"==typeof o.end)&&o.end(t)}catch(e){try{n.emit("internal-error",[e])}catch(e){}}};for(var s=0;s 1?e[1]=i:e.push(i)}else e[0]&&e[0].headers&&s(e[0].headers,n)&&(this.dt=n);function s(e,t){var r=!1;return t.newrelicHeader&&(e.set("newrelic",t.newrelicHeader),r=!0),t.traceContextParentHeader&&(e.set("traceparent",t.traceContextParentHeader),t.traceContextStateHeader&&e.set("tracestate",t.traceContextStateHeader),r=!0),r}}function x(e,t){this.params={},this.metrics={},this.startTime=(0,p.z)(),this.dt=t,e.length>=1&&(this.target=e[0]),e.length>=2&&(this.opts=e[1]);var r,n=this.opts||{},i=this.target;"string"==typeof i?r=i:"object"==typeof i&&i instanceof Y?r=i.url:c._A?.URL&&"object"==typeof i&&i instanceof URL&&(r=i.href),T(this,r);var o=(""+(i&&i instanceof Y&&i.method||n.method||"GET")).toUpperCase();this.params.method=o,this.txSize=V(n.body)||0}function A(t,r){var n;this.endTime=(0,p.z)(),this.params||(this.params={}),this.params.status=r?r.status:0,"string"==typeof this.rxSize&&this.rxSize.length>0&&(n=+this.rxSize);var o={txSize:this.txSize,rxSize:n,duration:(0,p.z)()-this.startTime};i("xhr",[this.params,o,this.startTime,this.endTime,"fetch"],this,e.D.ajax)}function E(t){var r=this.params,n=this.metrics;if(!this.ended){this.ended=!0;for(var o=0;o 2&&void 0!==arguments[2])||arguments[2];super(e,t,we.t,r),this.importAggregator()}}new class{constructor(e){let t=arguments.length>1&&void 0!==arguments[1]?arguments[1]:(0,_.ky)(16);c._A?(this.agentIdentifier=t,this.sharedAggregator=new y({agentIdentifier:this.agentIdentifier}),this.features={},this.desiredFeatures=new Set(e.features||[]),this.desiredFeatures.add(m),Object.assign(this,(0,a.j)(this.agentIdentifier,e,e.loaderType||"agent")),this.start()):(0,l.Z)("Failed to initial the agent. Could not determine the runtime environment.")}get config(){return{info:(0,t.C5)(this.agentIdentifier),init:(0,t.P_)(this.agentIdentifier),loader_config:(0,t.DL)(this.agentIdentifier),runtime:(0,t.OP)(this.agentIdentifier)}}start(){const t="features";try{const r=n(this.agentIdentifier),i=[...this.desiredFeatures];i.sort(((t,r)=>e.p[t.featureName]-e.p[r.featureName])),i.forEach((t=>{if(r[t.featureName]||t.featureName===e.D.pageViewEvent){const n=function(t){switch(t){case e.D.ajax:return[e.D.jserrors];case e.D.sessionTrace:return[e.D.ajax,e.D.pageViewEvent];case e.D.sessionReplay:return[e.D.sessionTrace];case e.D.pageViewTiming:return[e.D.pageViewEvent];default:return[]}}(t.featureName);n.every((e=>r[e]))||(0,l.Z)("".concat(t.featureName," is enabled but one or more dependent features has been disabled (").concat((0,D.P)(n),"). This may cause unintended consequences or missing data...")),this.features[t.featureName]=new t(this.agentIdentifier,this.sharedAggregator)}})),(0,T.Qy)(this.agentIdentifier,this.features,t)}catch(e){(0,l.Z)("Failed to initialize all enabled instrument classes (agent aborted) -",e);for(const e in this.features)this.features[e].abortHandler?.();const r=(0,T.fP)();return delete r.initializedAgents[this.agentIdentifier]?.api,delete r.initializedAgents[this.agentIdentifier]?.[t],delete this.sharedAggregator,r.ee?.abort(),delete r.ee?.get(this.agentIdentifier),!1}}}({features:[J,m,S,class extends h{static featureName=oe;constructor(t,r){if(super(t,r,oe,!(arguments.length>2&&void 0!==arguments[2])||arguments[2]),!c.il)return;const n=this.ee;let i;(0,k.QU)(n),this.eventsEE=(0,k.em)(n),this.eventsEE.on(se,(function(e,t){this.bstStart=(0,p.z)()})),this.eventsEE.on(ae,(function(t,r){(0,s.p)("bst",[t[0],r,this.bstStart,(0,p.z)()],void 0,e.D.sessionTrace,n)})),n.on(ce+ne,(function(e){this.time=(0,p.z)(),this.startPath=location.pathname+location.hash})),n.on(ce+ie,(function(t){(0,s.p)("bstHist",[location.pathname+location.hash,this.startPath,this.time],void 0,e.D.sessionTrace,n)}));try{i=new PerformanceObserver((t=>{const r=t.getEntries();(0,s.p)(te,[r],void 0,e.D.sessionTrace,n)})),i.observe({type:re,buffered:!0})}catch(e){}this.importAggregator({resourceObserver:i})}},C,xe,B,class extends h{static featureName=de;constructor(e,r){if(super(e,r,de,!(arguments.length>2&&void 0!==arguments[2])||arguments[2]),!c.il)return;if(!(0,t.OP)(e).xhrWrappable)return;try{this.removeOnAbort=new AbortController}catch(e){}let n,i=0;const o=this.ee.get("tracer"),a=(0,k._L)(this.ee),s=(0,k.Lg)(this.ee),u=(0,k.BV)(this.ee),d=(0,k.Kf)(this.ee),f=this.ee.get("events"),l=(0,k.u5)(this.ee),h=(0,k.QU)(this.ee),g=(0,k.Gm)(this.ee);function m(e,t){h.emit("newURL",[""+window.location,t])}function v(){i++,n=window.location.hash,this[ve]=(0,p.z)()}function b(){i--,window.location.hash!==n&&m(0,!0);var e=(0,p.z)();this[pe]=~~this[pe]+e-this[ve],this[ye]=e}function y(e,t){e.on(t,(function(){this[t]=(0,p.z)()}))}this.ee.on(ve,v),s.on(be,v),a.on(be,v),this.ee.on(ye,b),s.on(ge,b),a.on(ge,b),this.ee.buffer([ve,ye,"xhr-resolved"],this.featureName),f.buffer([ve],this.featureName),u.buffer(["setTimeout"+le,"clearTimeout"+fe,ve],this.featureName),d.buffer([ve,"new-xhr","send-xhr"+fe],this.featureName),l.buffer([me+fe,me+"-done",me+he+fe,me+he+le],this.featureName),h.buffer(["newURL"],this.featureName),g.buffer([ve],this.featureName),s.buffer(["propagate",be,ge,"executor-err","resolve"+fe],this.featureName),o.buffer([ve,"no-"+ve],this.featureName),a.buffer(["new-jsonp","cb-start","jsonp-error","jsonp-end"],this.featureName),y(l,me+fe),y(l,me+"-done"),y(a,"new-jsonp"),y(a,"jsonp-end"),y(a,"cb-start"),h.on("pushState-end",m),h.on("replaceState-end",m),window.addEventListener("hashchange",m,(0,O.m$)(!0,this.removeOnAbort?.signal)),window.addEventListener("load",m,(0,O.m$)(!0,this.removeOnAbort?.signal)),window.addEventListener("popstate",(function(){m(0,i>1)}),(0,O.m$)(!0,this.removeOnAbort?.signal)),this.abortHandler=this.#e,this.importAggregator()}#e(){this.removeOnAbort?.abort(),this.abortHandler=void 0}}],loaderType:"spa"})})(),window.NRBA=o})(); window.jQuery || document.write(' ') CKEDITOR_BASEPATH='https://f1000research.com/js/vendor/ckeditor/' window.reactTheme = 'research'; window.MathJax = { CommonHTML: { linebreaks: { automatic: true } }, 'HTML-CSS': { linebreaks: { automatic: true } }, SVG: { linebreaks: { automatic: true } }, AuthorInit: function() { MathJax.Hub.Register.MessageHook('End Process', function () { let timeout = false; // holder for timeout id const delay = 250; // delay after event is "complete" to run callback const reflowMath = function() { const dispFormulas = document.querySelectorAll('.disp-formula.panel'); if (!dispFormulas) { return; } for (const dispFormula of dispFormulas) { const child = dispFormula.querySelector('.MathJax_Preview').nextSibling.firstChild; const isMultiline = MathJax.Hub.getAllJax(dispFormula)[0].root.isMultiline; if (dispFormula.offsetWidth < child.offsetWidth || isMultiline) { MathJax.Hub.Queue(['Rerender', MathJax.Hub, dispFormula]); } } }; window.addEventListener('resize', function() { clearTimeout(timeout); // clear the timeout timeout = setTimeout(reflowMath, delay); // start timing for event "completion" }); }); }, }; if (window.location.hash == '#_=_'){ window.location = window.location.href.split('#')[0] } !function(f,b,e,v,n,t,s){if(f.fbq)return;n=f.fbq=function() {n.callMethod? n.callMethod.apply(n,arguments):n.queue.push(arguments)} ;if(!f._fbq)f._fbq=n; n.push=n;n.loaded=!0;n.version='2.0';n.queue=[];t=b.createElement(e);t.async=!0; t.src=v;s=b.getElementsByTagName(e)[0];s.parentNode.insertBefore(t,s)}(window, document,'script','https://connect.facebook.net/en_US/fbevents.js'); fbq('init', '1641728616063202'); fbq('track', "PixelInitialized", {}); (function(h,o,t,j,a,r){ h.hj=h.hj||function(){(h.hj.q=h.hj.q||[]).push(arguments)}; h._hjSettings={hjid:2318163,hjsv:6}; a=o.getElementsByTagName('head')[0]; r=o.createElement('script');r.async=1; r.src=t+h._hjSettings.hjid+j+h._hjSettings.hjsv; a.appendChild(r); })(window,document,'https://static.hotjar.com/c/hotjar-','.js?sv='); search file_upload Submit your research search menu close search Browse Gateways & Collections How to Publish Submit your Research My Submissions Article Guidelines Article Guidelines (New Versions) Open Data, Software and Code Guidelines Open Data and Accessible Source Materials Guidelines (HSS) Open Data, Software and Code Guidelines (PSE) Prepublication Checks Production Process Posters and Slides Guidelines Document Guidelines Article Processing Charges Peer Review Finding Article Reviewers About How it Works For Reviewers Our Advisors Policies Glossary FAQs For Developers Newsroom Contact My Research Submissions Content and Tracking Alerts My Details Sign In file_upload Submit your research { "@context": "https://schema.org", "@type": "ScholarlyArticle", "mainEntityOfPage": { "@type": "WebPage", "@id": "https://f1000research.com/articles/7-801" }, "headline": "Normal Human Lactation: closing the gap", "datePublished": "2018-06-20T10:26:55", "dateModified": "2018-06-20T10:26:55", "author": [ { "@type": "Person", "name": "Melinda Boss" }, { "@type": "Person", "name": "Hazel Gardner" }, { "@type": "Person", "name": "Peter Hartmann" } ], "publisher": { "@type": "Organization", "name": "F1000Research", "logo": { "@type": "ImageObject", "url": "https://f1000research.com/img/AMP/F1000Research_image.png", "height": 480, "width": 60 } }, "image": { "@type": "ImageObject", "url": "https://f1000research.com/img/AMP/F1000Research_image.png", "height": 1200, "width": 150 }, "description": "With the exception of infant growth, there are no well-defined parameters describing normal human lactation. This represents a major gap in the continuum of care that does not exist for other major organs. Biological normality occurs naturally and is characterized by well-integrated function. We have proposed a definition that highlights four key elements that describe parameters for biological normality: comfort, milk supply, infant health, and maternal health. Notwithstanding the current limitations, published data have been collated to provide preliminary markers for the initiation of lactation and to describe objective tests once lactation is established. Reference limits have been calculated for maternal markers of secretory activation, including progesterone in maternal blood and total protein, lactose, sodium, and citrate in maternal milk. Objective measurements for established lactation, including 3-hourly pumping and 24-hour milk production, together with pre-feed to post-feed milk fat changes (a useful indicator of the available milk removed by the infant) have been outlined. Considered together with the parameters describing normal function, this information provides a preliminary objective framework for the assessment of human lactation." } { "@context": "http://schema.org", "@type": "BreadcrumbList", "itemListElement": [ { "@type": "ListItem", "position": "1", "item": { "@id": "https://f1000research.com/", "name": "Home" } }, { "@type": "ListItem", "position": "2", "item": { "@id": "https://f1000research.com/browse/articles", "name": "Browse" } }, { "@type": "ListItem", "position": "3", "item": { "@id": "https://f1000research.com/articles/7-801", "name": "Normal Human Lactation: closing the gap" } } ] } Home Browse Normal Human Lactation: closing the gap ALL Metrics - Views Downloads Get PDF Get XML Cite How to cite this article Boss M, Gardner H and Hartmann P. Normal Human Lactation: closing the gap [version 1; peer review: 4 approved] . F1000Research 2018, 7 (F1000 Faculty Rev):801 ( https://doi.org/10.12688/f1000research.14452.1 ) NOTE: If applicable, it is important to ensure the information in square brackets after the title is included in all citations of this article. Close Copy Citation Details Export Export Citation Sciwheel EndNote Ref. Manager Bibtex ProCite Sente EXPORT Select a format first Track Share ▬ ✚ Review Normal Human Lactation: closing the gap [version 1; peer review: 4 approved] Melinda Boss https://orcid.org/0000-0003-3024-9651 1 , Hazel Gardner 2 , Peter Hartmann https://orcid.org/0000-0002-7709-0740 2 Melinda Boss https://orcid.org/0000-0003-3024-9651 1 , Hazel Gardner 2 , Peter Hartmann https://orcid.org/0000-0002-7709-0740 2 PUBLISHED 20 Jun 2018 Author details Author details 1 M315 School of Allied Health, Faculty of Health and Medical Sciences, University of Western Australia, Crawley, Australia 2 M313 School of Molecular Sciences, Faculty of Science, University of Western Australia, Crawley, Australia Melinda Boss Roles: Conceptualization, Writing – Original Draft Preparation, Writing – Review & Editing Hazel Gardner Roles: Data Curation, Formal Analysis, Visualization Peter Hartmann Roles: Conceptualization, Supervision, Writing – Review & Editing OPEN PEER REVIEW DETAILS REVIEWER STATUS Abstract With the exception of infant growth, there are no well-defined parameters describing normal human lactation. This represents a major gap in the continuum of care that does not exist for other major organs. Biological normality occurs naturally and is characterized by well-integrated function. We have proposed a definition that highlights four key elements that describe parameters for biological normality: comfort, milk supply, infant health, and maternal health. Notwithstanding the current limitations, published data have been collated to provide preliminary markers for the initiation of lactation and to describe objective tests once lactation is established. Reference limits have been calculated for maternal markers of secretory activation, including progesterone in maternal blood and total protein, lactose, sodium, and citrate in maternal milk. Objective measurements for established lactation, including 3-hourly pumping and 24-hour milk production, together with pre-feed to post-feed milk fat changes (a useful indicator of the available milk removed by the infant) have been outlined. Considered together with the parameters describing normal function, this information provides a preliminary objective framework for the assessment of human lactation. READ ALL READ LESS Keywords Lactation, Breastfeeding, Reference ranges, Reference limits, Normal function, Maternal, Breastmilk Corresponding Author(s) Melinda Boss ( [email protected] ) Close Corresponding author: Melinda Boss Competing interests: No competing interests were disclosed. Grant information: The authors declare that no grants were involved in supporting this work. Melinda Boss gratefully acknowledges research funding from the Family Larsson-Rosenquist Foundation (PG 52000600). Hazel Gardner is supported by an unrestricted research grant from Medela AG, Switzerland (PG52085000). Peter Hartmann holds an emeritus professorial position and declares that no grants were involved in supporting his contribution to this work. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Copyright: © 2018 Boss M et al . This is an open access article distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. How to cite: Boss M, Gardner H and Hartmann P. Normal Human Lactation: closing the gap [version 1; peer review: 4 approved] . F1000Research 2018, 7 (F1000 Faculty Rev):801 ( https://doi.org/10.12688/f1000research.14452.1 ) First published: 20 Jun 2018, 7 (F1000 Faculty Rev):801 ( https://doi.org/10.12688/f1000research.14452.1 ) Latest published: 20 Jun 2018, 7 (F1000 Faculty Rev):801 ( https://doi.org/10.12688/f1000research.14452.1 ) Introduction The rationale for writing a review is usually based on bringing together recent major advances and published discussion in a particular area of research. Unfortunately, basic research into the physiology and biochemistry of the lactating human mammary gland is limited, and there have been no major advances toward the assessment of its normal function in recent times. As a result, the lactating mammary gland is a poor cousin when compared with other major organs such as the heart, brain, liver, lungs, and kidneys. These all have an array of objective tests available to assess function. This review examines the evidence available toward the development of methods for the objective assessment of lactation. Discussion will be limited to the maternal aspects of lactation physiology and biochemistry during the period of exclusive breastfeeding of the infant (that is, the period of time from birth and during the period of exclusive breastfeeding). The mean milk production of lactating women by 8 days postpartum ( Figure 1 ) is 650 mL/24 hours, and from 1 to 6 months of lactation the mean range for exclusively breastfed infants is between 750 and 800 mL/24 hours 1 . Therefore, for mothers exclusively breastfeeding their babies, it can be calculated that the energy output in human milk accounts for about 20% to 30% of the maternal resting energy requirement 2 . This large energy commitment clearly demonstrates the evolutionary importance of lactation for human survival. The World Health Organization (WHO) recommends exclusive breastfeeding for the first 6 months of an infant’s life followed by the addition of nutritionally adequate and safe complementary foods while breastfeeding continues for up to 2 years of age or beyond 3 . In Australia, there is a high rate of lactation initiation (96%). However, these figures decline rapidly after birth, and only 15.4% of infants are exclusively breastfed at 5 months of age 4 . Thus, in Australia, as in many other high-income countries, almost all mothers elect to breastfeed, but many encounter difficulties that affect their ability to continue. Figure 1. Daily values for milk production in the first 8 days postpartum. Figure shows weighted means and standard deviations collated from published values. Data sources: 5 – 14 . Vital to the assessment of function of major organs is the objective measurement of various aspects of their physiology and biochemistry and the comparison of these values with reference ranges. An objective measurement of normal function can then form the scientific basis for identification of potential abnormality (function falling outside the normal range), diagnosis of disease, and the evaluation of treatments. Unfortunately, there are no routine clinical tests available for the assessment of normal function for lactation. Normal human lactation In order to identify objective measurements for normal lactation function, it is first necessary to define normal lactation. Here, “normality” is considered in the biological sense, namely that normal function occurs naturally and not as a result of any disease, treatment, or genetic abnormality. Normal function does not require medical intervention or support. Thus, the following definition for lactation during the first 6 months after a term birth is proposed. Normal human lactation is comfortable for both the mother and infant provides adequate milk for the infant’s optimal growth and development requires coordinated maternal and infant adaptation that is facilitated by good maternal and infant health. Reference ranges and reference limits In the context of biological function, a reference range describes a range of values for a physiological measurement in a healthy person. A reference range for a particular measurement is the interval between which 95% of values for a reference group taken from the general population fall. Values outside the upper and lower limits of a reference range are not necessarily abnormal but can be considered to be indicators of possible pathology. A reference range is derived from a normal curve based on measurements for at least 120 healthy individuals. A reference limit describes cases where only one side of the range is of interest 15 . The above definition of normal human lactation defines the inclusive and exclusive parameters for studies aimed at determining reference ranges or reference limits (or both) for the assessment of human lactation. With the exception of the growth rate of breastfed infants (WHO growth charts 16 ), there are no studies that meet these criteria. Most substrates, metabolites, and hormones associated with human lactation change markedly according to the period of lactation, time of day, time of breastfeeding, duration of the breastfeed, and the degree of fullness of the breast. Thus, these factors need to be standardized for the development of normal ranges across the course of lactation. These deficiencies notwithstanding, it is nevertheless important to review the literature and construct approximate objective parameters for human lactation. This review concentrates on areas where even roughly defined reference ranges could greatly assist in the understanding of lactation function (and consequently dysfunction). In this context, maternal parameters associated with secretory activation 17 and established lactation will be highlighted. In addition to this restriction to a consideration of maternal factors in the first instance, a pragmatic approach was taken to emphasize methods that could be implemented now (for example, blood progesterone and milk sodium) and then methods that could be readily developed in the future for clinical use (for example, milk lactose and milk production). There are many other factors that potentially could be used to assist clinical diagnosis, including certain proteins (α-lactalbumin), carbohydrates (oligosaccharides), lipids (medium-chain fatty acids), and enzymes (aurora kinase-A), but there is not enough evidence in human lactation to provide potential diagnosis and treatment protocols. Lactation cycle The breast reaches a mature functional state only during lactation 18 . The lactation cycle begins with conception. Pregnancy induces ductal proliferation and subsequent lobular alveolar development in the mammary gland. Alveolar development leads to secretory differentiation 17 with the maturation of lactocytes and the production of unique milk components. Delivery of the placenta triggers secretory activation and the transition to copious milk secretion. Sustained milk synthesis requires the continuation of efficient and regular milk removal by the infant in the context of normal function or by breast pump or hand expression if required. The lactation cycle is completed when the breast returns to quiescence following weaning of the infant. Secretory differentiation and secretory activation Lactation is established in two phases. First, secretory differentiation is observed as the breast develops the capacity to synthesize unique milk products in colostrum, including lactose, casein, α-lactalbumin, and lactoferrin. The second phase, secretory activation, begins around 60 hours (range of 24–72 hours) after birth and is triggered by delivery of the placenta 19 , 20 . Secretory differentiation There is little information on variation in breast growth and function during pregnancy. Breast volume generally increases after conception, but there is considerable variation between mothers 21 . Importantly, this variation does not appear to influence the potential for milk synthesis postpartum 5 , 19 , 22 . Secretory differentiation occurs from about 20 weeks of pregnancy and requires the action of a lactogenic complex of hormones. The increasing concentration of prolactin in maternal blood is related to the increased excretion of lactose in urine, and the increase in the concentration of human placental lactogen is related to breast growth. During this phase, the tight junctions between lactocytes are leaky, allowing milk constituents to pass into the blood. Lactose cannot be metabolized once it enters the blood vascular system and is excreted in the urine. Therefore, the 24-hour output of lactose in urine provides a measure of the synthesis of lactose in the mammary glands. Coupling the 24-hour output of lactose in urine with the measurement of lactose in colostrum provides an estimate of the rate of synthesis of colostrum during pregnancy. These measurements confirm that the rate of colostrum synthesis at this time is low (about 30 mL/24 hours) 17 , 23 . Secretory activation Secretory activation is a process manifest by the initiation of copious milk secretion ( Figure 1 ). The increase in milk secretion is accompanied by many metabolic changes. The most documented of these changes are decreases in blood progesterone ( Figure 2 ), milk protein, and sodium ( Figure 3 ) and increases in milk lactose and citrate ( Figure 4 ). Figure 2. Daily concentrations of serum progesterone and prolactin in the first 8 days postpartum. Figure shows weighted means and standard deviations collated from published values. Data sources: 24 – 31 . Figure 3. Serum prolactin levels 90 minutes post-feed and 45 minutes after beginning of feed at 1 month postpartum. Data source: 32 . Figure 4. Daily breastmilk concentrations of total protein and sodium in the first 8 days postpartum. Figure shows weighted means and standard deviations collated from published values. Data sources: 7 , 36 – 50 . Colostrum and the first 3 days Colostrum is available to the infant for the first 60 hours (range of 24–72 hours) after birth 19 , 20 . The volume ingested by healthy newborns in the first 24 hours of life is small and mirrors synthesis (29 mL ± 24, mean ± standard deviation [SD]) ( Figure 1 ). Research interest in colostrum is limited for two reasons: first, from the generalized lack of research into human lactation (see above) and, second, by its appearance and small volume. More than 300 years ago, Cadogan observed that, “When a child is first born, there seems to be no provision at all made for it: for mother’s milk seldom comes in ’till the third day: so that according to nature, a child would be left a day and a half or two days, without food; to me a very sufficient proof that it wants none” 33 . Furthermore, Dettwyler reported that, “In historical times, and even today, babies in some societies are denied colostrum, with all its beneficial properties, in the belief that it is a poisonous substance dangerous for the newborn” 34 . In contrast to historical beliefs, evidence is now emerging that the first 3 days postpartum are critically important for the establishment of lactation. In a study of pump-dependent mothers who had delivered preterm, Meier et al . compared milk expression by using the standard suction pattern on a breast pump with using a pattern that mimicked the infant sucking 35 . The pattern was applied from birth to 3 days postpartum and then a standard pump was used up to 14 days postpartum. This treatment resulted in a 60% increase in milk synthesis from 6 to 14 days postpartum compared with the standard pumping pattern. Morton et al . studied pump-dependent mothers who had delivered preterm and combined hand massage with electric pumping in the immediate postpartum period and found that this intervention increased milk synthesis at 2 weeks compared with the use of a standard breast pump from birth 51 . Additionally, a study in the Democratic Republic of the Congo reported that 14% of mothers provided with standard care and 16% provided with the Ten Steps to Successful Breastfeeding program were exclusively breastfeeding at 6 months postpartum but that 45% of mothers provided with only steps 1 to 9 were exclusively breastfeeding at 6 months 52 , 53 . These findings show that subtle interventions in the early postpartum period can induce profound outcomes during established lactation. Progesterone withdrawal Kuhn first demonstrated that the withdrawal of progesterone was related to the ovary switching from progesterone to 20αOH-progesterone synthesis 54 . The resulting fall in progesterone was shown to be the “lactogenic trigger” in the rat 54 . Subsequently, in all mammals studied, progesterone withdrawal has been found to be the trigger for secretory activation. In women, progesterone is synthesized in the placenta and falls precipitously by more than an order of magnitude after the delivery of the placenta ( Figure 2 ). Consequently, colostrum synthesis continues until about 24 to 72 hours after birth when the process of secretory activation initiates the transition of colostrum into mature breastmilk. Thus, if viable fragments of placenta are retained after delivery, secretory activation will be either fully or partly inhibited. Assays for progesterone concentration in blood are readily available. In addition, laboratory assays for progesterone concentrations in milk are available, and an in-home assay for urinary metabolites of progesterone has been developed 55 . Despite the availability of these assays, progesterone is never measured when assessing the initiation of lactation in women who are at risk of or appear to have impaired secretory activation. Given what is known about progesterone withdrawal triggering secretory activation, it can be hypothesized that elevated blood progesterone is a sensitive indicator of retained viable placental fragments. Furthermore, it is possible that the inhibitory effects of elevated blood progesterone on secretory activation are reduced by the administration of mifepristone (RU486), a progesterone antagonist. However, more research is required before these possibilities can be adopted clinically. Prolactin At secretory activation, elevated concentrations of prolactin are observed during the period of progesterone withdrawal ( Figure 2 ). Plasma prolactin is high early in lactation and progressively decreases, but levels at 6 months of lactation are still higher than those reported for non-lactating women 32 . The role of prolactin during the initiation of lactation is complex 18 . The concentrations reported for prolactin during the early postpartum period are highly variable and difficult to interpret. This can be attributed to the secretion of prolactin varying in response to the suckling stimulus, and peak values are observed about 45 minutes after the infant latches to the breast ( Figure 3 ). Levels then decrease to about half the peak levels by the next breastfeed. Prolactin also shows a circadian variation 56 and increases at mealtimes. No studies have monitored prolactin levels in relation to the timing of breastfeeds, meals, and time of day, and this probably accounts for the large variation in reported concentrations of prolactin during secretory activation. Prolactin is present as different isoforms and undergoes considerable post-translational modifications, including glycosylation, phosphorylation, proteolytic cleavage, and polymerization. These modifications influence the function of this complex hormone. It is clear that prolactin is required for successful secretory activation 57 , but it probably does not play a rate-limiting role. The threshold concentration of prolactin (reference limit for normality) needed for normal secretory activation is unknown. This information is urgently required to ensure that mothers with normal concentrations of prolactin are not subjected to unwarranted medication with peripherally selective dopamine D 2 receptor antagonist activity to treat low milk supply. Closure of tight junctions and the effect on milk composition Closure of the tight junctions between lactocytes is related to the withdrawal of progesterone. At this time, the concentration of sodium in the mammary secretion rapidly decreases ( Figure 5 ) as milk production increases ( Figure 1 ) and provides a simple objective assessment of the progress of secretory activation ( Figure 4 ) 58 . Indeed, sodium-sensitive electrodes that permit the measurement of sodium using only a few drops of breastmilk are available (Na + LAQUA twin electrode, Horiba Scientific, Kyoto, Japan). Figure 5. Daily breastmilk concentrations of lactose to day 8 and citrate to day 6 and citrate in the first 8 days postpartum. Figure shows weighted means and standard deviations collated from published values. Data sources: 7 , 39 , 42 , 43 , 45 , 47 – 49 , 65 – 70 . Milk volume and the concentrations of sodium, lactose, citrate, and total protein all appear to reach stable levels by 8 days postpartum ( Figure 1 , Figure 4 , and Figure 5 ). Decreases in sodium and total protein and increases in lactose and citrate in the mammary secretion can be used to monitor secretory activation 5 , 59 ( Figure 4 and Figure 5 ). Collation of the published values for the changes in progesterone, sodium, total protein, lactose, and citrate enables the calculation of weighted daily means. From these means and SDs, it is possible to calculate reference limits for normality ( Table 1 ). It follows that the mean plus two SDs for progesterone in maternal blood and sodium and total protein in milk as well as the mean minus two SDs for lactose and citrate in milk provide reference limits that could be considered normal. Reference limits for days 3 and 6 are presented in Table 1 . However, it must be recognized that these are tentative values because very few studies have determined the changes in blood progesterone and milk composition in the same mothers and, more importantly, most studies do not provide an objective assessment of the success of the mothers in establishing normal lactation. Table 1. Reference limits at 3 and 6 days postpartum * . 3 days postpartum 6 days postpartum Maternal serum Maternal serum Progesterone, μg/L <7.1 <2.2 Milk Milk Total protein, g/L <34.1 <24.3 Sodium, g/L <0.81 43.4 >53.6 Citrate, g/L >0.24 >0.92 *Expressed as weighted means ± two standard deviations from the mean for maternal serum concentrations for progesterone and milk concentrations for sodium, total protein, lactose, and citrate As stated, milk sodium can be measured to track the progress of secretory activation. In the future, timed urinary lactose measurements after birth would also be useful. High levels of urinary lactose combined with low levels of milk sodium would indicate that lactose synthesis (milk synthesis) is occurring but the milk is not being removed from the mammary gland; that is, there is a “baby” problem rather than a “mother” problem. Citrate has been claimed to be the harbinger of lactation 60 , but the metabolic stimulus driving the increase of this metabolite is not known. Citrate still provides a very good marker for secretory activation ( Figure 5 ). It is not measured routinely in clinical pathology laboratories and therefore is not available at this time for the assessment of secretory activation. Milk synthesis and milk production It is important to define the difference between milk synthesis and milk production measurements. Whereas milk synthesis is a measure of the maternal capacity to synthesize milk, milk production is a measure of the infant’s ability to remove milk from the mother’s breasts ( Figure 1 ). Daily progressive measurements of both of these parameters would be very useful in the assessment of lactation 6 , 7 . Twenty-four-hour measurements of milk production by weighing the infant immediately before and after each breastfeed to determine the milk intake is extremely difficult to carry out in the immediate postpartum period. Milk synthesis cannot currently be measured directly; however, the increase in milk citrate appears to be closely related to the mother’s ability to synthesize milk. A greater knowledge of the metabolic factors related to the increase in citrate in early postpartum milk secretion is required to confirm this possibility. Established lactation Once lactation is established from about 2 weeks postpartum, milk production remains relatively constant up to 6 months of lactation for infants that are exclusively breastfed 1 . Milk synthesis is not limited by the capacity of the mother to synthesize milk but rather by the infant’s appetite 67 . Thus, milk production in breastfeeding mothers is not a measure of the mother’s capacity to synthesize breastmilk but rather a measurement of the infant’s appetite. Furthermore, the variation in milk production reported between infants is large, ranging from about 500 to 1,000 mL/24 hours with a mean of 750–800 mL/24 hours 1 . The WHO Child Growth Standards provide reference values for breastfed infants; however, nearly all studies of normal intake of exclusively breastfeeding infants precede their release. Therefore, reference values for breastmilk production require further investigation. Nevertheless, measurement of milk production is currently the best objective method available to measure normal breast function during established lactation. Measurement of milk production The most clinically feasible measure of breastmilk transfer to the infant is to weigh the infant immediately before and after each breastfeed over a 24-hour period 67 . From a nutritional standpoint, a longer period would be desirable; however, this method is quite demanding of mother and infant and the quality of the data degrades as the collection period is extended. Alternatively, each breast can be expressed for 10 minutes every hour for three consecutive hours in a calm environment. The volume of milk expressed at the third expression multiplied by 24 also provides an estimate of 24-hour milk synthesis 67 . It is possible to use this method in a clinical setting, but further validation is required. Total breastmilk transfer from both breasts over a period of 14 days can be measured by using the deuterium oxide dose-to-mother technique. This is an excellent technique for nutritional studies for determining macro- and micro-nutrient intake. However, this method is based on the dilution of the isotope over a period of 14 days and requires stable milk production over this period. Measurement of milk production is a good starting point for assessment of breast function, particularly when there are concerns that supply is inadequate. Milk fat Fat is the most variable component of human milk, and around 70% of this variation is due to the extent of breast fullness 68 . As the breast empties, the fat content increases 68 . This provides one of the few objective tests available to determine the proportion of available milk removed by the infant during a breastfeed. Mature milk from a full breast appears bluish-white because of the low fat content pre-feed. Post-feed, the milk changes in color to creamy white as the breast is drained and the fat content increases. This response is more obvious if the milk is allowed to settle. If there is not much change in the color of the milk between the pre-feed and post-feed samples, the baby has not removed much milk. Furthermore, if the pre-feed milk is bluish-white, the breast is full of milk, and if the pre-feed milk is creamy white, the breast is drained of milk. Because visual assessments of a breastfeed are very unreliable, observations of the color of the milk can provide only limited objectivity in the clinical assessment of a breastfeed. A more objective measure of breastmilk transfer was discussed previously. The change in fat content can be measured objectively with a creamatocrit centrifuge (Medela AG, Baar, Switzerland) ( Table 2 ) 69 . Table 2. Concentrations of fat in mature human milk 1 , 19 . Fat Amount, g/L Standard deviation, g/L Average 41.1 ± 7.8 Pre-feed 30.3 ± 17.5 Post-feed 57.8 ± 24.0 Milk ejection Milk ejection occurs because of a neuro-hormonal reflex triggered by stimulation of the nipple areolar area, which results in the contraction of myoepithelial cells surrounding the alveoli and subsequent expulsion of milk. It is a conditioned reflex and is responsive to environmental inputs. Each woman has multiple milk ejections during a breastfeed, but most mothers sense only the first. Milk ejection can be readily measured by ultrasound imaging of the non-suckled breast 70 . In mothers who do not sense milk ejection, measurement of an increase in duct diameter during a breastfeed can be used to confirm milk ejection. Conclusions In a whole of body comparison, the lactating human breast rivals the brain in its energy requirements and has the highest energy requirement of the organs in the reproductive cycle. Evidence-based reference ranges or limits for normal function (or both) provide a foundation for clinical diagnosis and treatment of problems encountered. Despite its metabolic importance, there is an enormous gap in our understanding of these parameters for the biochemistry and physiology of lactation. This review has shown that only approximate reference ranges can be calculated. Nevertheless, they provide a starting point. There have been many successful health programs aimed at encouraging women to breastfeed their babies, but there is little ability to adequately monitor and support lactation initiation and establishment with objective tests. Under these conditions, it is not surprising that in high-income countries, even when most women choose to breastfeed, the rate of sustained lactation rapidly declines after birth. It seems obvious that to effectively “close the gap” more scientific evidence must be integrated with psychological and practical support for all women who want to breastfeed their infants. Author contributions Melinda Boss contributed conceptualization, preparation of the original draft, and review and editing of the manuscript. Hazel Gardner contributed data curation, formal analysis, and visualization. Peter Hartmann contributed conceptualization, supervision, and review and editing of the manuscript. Competing interests No competing interests were disclosed. Grant information The authors declare that no grants were involved in supporting this work. Melinda Boss gratefully acknowledges research funding from the Family Larsson-Rosenquist Foundation (PG 52000600). Hazel Gardner is supported by an unrestricted research grant from Medela AG, Switzerland (PG52085000). Peter Hartmann holds an emeritus professorial position and declares that no grants were involved in supporting his contribution to this work. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Faculty Opinions recommended References 1. Kent JC, Mitoulas LR, Cregan MD, et al. : Volume and frequency of breastfeedings and fat content of breast milk throughout the day. Pediatrics. 2006; 117 (3): e387–95. PubMed Abstract | Publisher Full Text 2. Butte NF, King JC: Energy requirements during pregnancy and lactation. Public Health Nutr. 2005; 8 (7A): 1010–27. PubMed Abstract | Publisher Full Text | Faculty Opinions Recommendation 3. UNICEF, WHO: Infant and Young Child Nutrition: Global Strategy on Infant and Young Child Feeding. Geneva: World Health Organisation; 2002. Reference Source 4. Australian Institute of Health and Welfare: Australian National Infant Feeding Survey: indicator results. Canberra: AIHW; Contract No.: Cat. no. PHE 156. 2010. Reference Source 5. Arthur PG, Smith M, Hartmann PE: Milk lactose, citrate, and glucose as markers of lactogenesis in normal and diabetic women. J Pediatr Gastroenterol Nutr. 1989; 9 (4): 488–96. PubMed Abstract | Publisher Full Text 6. Neville MC, Keller R, Seacat J, et al. : Studies in human lactation: milk volumes in lactating women during the onset of lactation and full lactation. Am J Clin Nutr. 1988; 48 (6): 1375–86. PubMed Abstract | Publisher Full Text 7. Saint L, Smith M, Hartmann PE: The yield and nutrient content of colostrum and milk of women from giving birth to 1 month post-partum. Br J Nutr. 1984; 52 (1): 87–95. PubMed Abstract | Publisher Full Text 8. Casey CE, Hambidge KM, Neville MC: Studies in human lactation: zinc, copper, manganese and chromium in human milk in the first month of lactation. Am J Clin Nutr. 1985; 41 (6): 1193–200. PubMed Abstract | Publisher Full Text 9. Casey CE, Neifert MR, Seacat JM, et al. : Nutrient intake by breast-fed infants during the first five days after birth. Am J Dis Child. 1986; 140 (9): 933–6. PubMed Abstract | Publisher Full Text 10. Dollberg S, Lahav S, Mimouni FB: A comparison of intakes of breast-fed and bottle-fed infants during the first two days of life. J Am Coll Nutr. 2001; 20 (3): 209–11. PubMed Abstract | Publisher Full Text 11. Evans KC, Evans RG, Royal R, et al. : Effect of caesarean section on breast milk transfer to the normal term newborn over the first week of life. Arch Dis Child Fetal Neonatal Ed. 2003; 88 (5): F380–2. PubMed Abstract | Publisher Full Text | Free Full Text 12. Hester SN, Hustead DS, Mackey AD, et al. : Is the macronutrient intake of formula-fed infants greater than breast-fed infants in early infancy? J Nutr Metab. 2012; 2012 : 891201. PubMed Abstract | Publisher Full Text | Free Full Text | Faculty Opinions Recommendation 13. Roderuck C, Williams HH, Macy IG: Metabolism of women during the reproductive cycle; the utilization of thiamine during lactation. J Nutr. 1946; 32 (3): 249–65. PubMed Abstract | Publisher Full Text 14. Yamauchi Y, Yamanouchi I: Breast-feeding frequency during the first 24 hours after birth in full-term neonates. Pediatrics. 1990; 86 (2): 171–5. PubMed Abstract 15. Katayev A, Balciza C, Seccombe DW: Establishing reference intervals for clinical laboratory test results: is there a better way? Am J Clin Pathol. 2010; 133 (2): 180–6. PubMed Abstract | Publisher Full Text 16. WHO Multicentre Growth Reference Study Group: WHO Child Growth Standards based on length/height, weight and age. Acta Paediatr Suppl. 2006; 450 : 76–85. PubMed Abstract | Faculty Opinions Recommendation 17. Pang WW, Hartmann PE: Initiation of human lactation: secretory differentiation and secretory activation. J Mammary Gland Biol Neoplasia. 2007; 12 (4): 211–21. PubMed Abstract | Publisher Full Text 18. Hassiotou F, Geddes D: Anatomy of the human mammary gland: Current status of knowledge. Clin Anat. 2013; 26 (1): 29–48. PubMed Abstract | Publisher Full Text | Faculty Opinions Recommendation 19. Kent JC: How breastfeeding works. J Midwifery Womens Health. 2007; 52 (6): 564–70. PubMed Abstract | Publisher Full Text | Faculty Opinions Recommendation 20. Dewey KG, Nommsen-Rivers LA, Heinig MJ, et al. : Risk factors for suboptimal infant breastfeeding behavior, delayed onset of lactation, and excess neonatal weight loss. Pediatrics. 2003; 112 (3 Pt 1): 607–19. PubMed Abstract | Publisher Full Text | Faculty Opinions Recommendation 21. Daly SE, Kent JC, Huynh DQ, et al. : The determination of short-term breast volume changes and the rate of synthesis of human milk using computerized breast measurement. Exp Physiol. 1992; 77 (1): 79–87. PubMed Abstract | Publisher Full Text 22. Kulski JK, Hartmann PE: Changes in human milk composition during the initiation of lactation. Aust J Exp Biol Med Sci. 1981; 59 (1): 101–14. PubMed Abstract | Publisher Full Text 23. Cox DB, Kent JC, Casey TM, et al. : Breast growth and the urinary excretion of lactose during human pregnancy and early lactation: endocrine relationships. Exp Physiol. 1999; 84 (2): 421–34. PubMed Abstract | Publisher Full Text 24. Heidrich A, Schleyer M, Spingler H, et al. : Postpartum blues: relationship between not-protein bound steroid hormones in plasma and postpartum mood changes. J Affect Disord. 1994; 30 (2): 93–8. PubMed Abstract | Publisher Full Text 25. Klier CM, Muzik M, Dervic K, et al. : The role of estrogen and progesterone in depression after birth. J Psychiatr Res. 2007; 41 (3–4): 273–9. PubMed Abstract | Publisher Full Text 26. Nott PN, Franklin M, Armitage C, et al. : Hormonal changes and mood in the puerperium. Br J Psychiatry. 1976; 128 : 379–83. PubMed Abstract | Publisher Full Text 27. O'Hara MW, Schlechte JA, Lewis DA, et al. : Controlled prospective study of postpartum mood disorders: psychological, environmental, and hormonal variables. J Abnorm Psychol. 1991; 100 (1): 63–73. PubMed Abstract | Publisher Full Text 28. Abou-Saleh MT, Ghubash R, Karim L, et al. : Hormonal aspects of postpartum depression. Psychoneuroendocrinology. 1998; 23 (5): 465–75. PubMed Abstract | Publisher Full Text 29. Turnbull AC, Patten PT, Flint AP, et al. : Significant fall in progesterone and rise in oestradiol levels in human peripheral plasma before onset of labour. Lancet. 1974; 1 (7848): 101–3. PubMed Abstract 30. Aono T, Shioji T, Shoda T, et al. : The initiation of human lactation and prolactin response to suckling. J Clin Endocrinol Metab. 1977; 44 (6): 1101–6. PubMed Abstract | Publisher Full Text 31. Rasmussen KM, Kjolhede CL: Prepregnant overweight and obesity diminish the prolactin response to suckling in the first week postpartum. Pediatrics. 2004; 113 (5): e465–71. PubMed Abstract | Publisher Full Text 32. Cox DB, Owens RA, Hartmann PE: Blood and milk prolactin and the rate of milk synthesis in women. Exp Physiol. 1996; 81 (6): 1007–20. PubMed Abstract | Publisher Full Text 33. Cadogan W: An Essay Upon Nursing, and the Management of Children: From Their Birth to Three Years of Age. London: J. Roberts; 1748; 34. Reference Source 34. Dettwyler KA: A time to wean: the hominid blueprint for the natural age of weaning in modern human populations. In: Stuart-Macadam P, Dettwyler K, editors. Breastfeeding: biocultural perspectives . New York: Aldine de Gruyter; 1995; 39–73. Reference Source 35. Meier PP, Engstrom JL, Janes JE, et al. : Breast pump suction patterns that mimic the human infant during breastfeeding: greater milk output in less time spent pumping for breast pump-dependent mothers with premature infants. J Perinatol. 2012; 32 (2): 103–10. PubMed Abstract | Publisher Full Text | Free Full Text | Faculty Opinions Recommendation 36. Gross SJ, David RJ, Bauman L, et al. : Nutritional composition of milk produced by mothers delivering preterm. J Pediatr. 1980; 96 (4): 641–4. PubMed Abstract | Publisher Full Text 37. Hazebroek A, Hofman A: Sodium content of breast milk in the first six months after delivery. Acta Paediatr Scand. 1983; 72 (3): 459–60. PubMed Abstract | Publisher Full Text 38. Koo WW, Gupta JM: Breast milk sodium. Arch Dis Child. 1982; 57 (7): 500–2. PubMed Abstract | Publisher Full Text | Free Full Text 39. Lemons JA, Moye L, Hall D, et al. : Differences in the composition of preterm and term human milk during early lactation. Pediatr Res. 1982; 16 (2): 113–7. PubMed Abstract | Publisher Full Text 40. Manganaro R, Marseglia L, Mamì C, et al. : Breast milk sodium concentration, sodium intake and weight loss in breast-feeding newborn infants. Br J Nutr. 2007; 97 (2): 344–8. PubMed Abstract | Publisher Full Text 41. Mastroeni SS, Okada IA, Rondó PH, et al. : Concentrations of Fe, K, Na, Ca, P, Zn and Mg in maternal colostrum and mature milk. J Trop Pediatr. 2006; 52 (4): 272–5. PubMed Abstract | Publisher Full Text 42. Morriss FH Jr, Brewer ED, Spedale SB, et al. : Relationship of human milk pH during course of lactation to concentrations of citrate and fatty acids. Pediatrics. 1986; 78 (3): 458–64. PubMed Abstract 43. Neville MC, Allen JC, Archer PC, et al. : Studies in human lactation: milk volume and nutrient composition during weaning and lactogenesis. Am J Clin Nutr. 1991; 54 (1): 81–92. PubMed Abstract | Publisher Full Text 44. Bashir S, Rashid Z, Shaheen H: Correlation of Mother Milk Sodium Levels in Term Mothers with Neonatal Hyperbilirubinemia. Pakistan Journal of Medical & Health Sciences. 2015; 9 (2): 611–3. Reference Source 45. Hibberd CM, Brooke OG, Carter ND, et al. : Variation in the composition of breast milk during the first 5 weeks of lactation: implications for the feeding of preterm infants. Arch Dis Child. 1982; 57 (9): 658–62. PubMed Abstract | Publisher Full Text | Free Full Text 46. Anderson DM, Williams FH, Merkatz RB, et al. : Length of gestation and nutritional composition of human milk. Am J Clin Nutr. 1983; 37 (5): 810–4. PubMed Abstract | Publisher Full Text 47. Cregan MD, de Mello TR, Kershaw D, et al. : Initiation of lactation in women after preterm delivery. Acta Obstet Gynecol Scand. 2002; 81 (9): 870–7. PubMed Abstract | Publisher Full Text 48. Healy DL, Rattigan S, Hartmann PE, et al. : Prolactin in human milk: correlation with lactose, total protein, and alpha-lactalbumin levels. Am J Physiol. 1980; 238 (1): E83–6. PubMed Abstract | Publisher Full Text 49. Narang AP, Bains HS, Kansal S, et al. : Serial composition of human milk in preterm and term mothers. Indian J Clin Biochem. 2006; 21 (1): 89–94. PubMed Abstract | Publisher Full Text | Free Full Text 50. Ronayne de Ferrer PA, Baroni A, Sambucetti ME, et al. : Lactoferrin levels in term and preterm milk. J Am Coll Nutr. 2000; 19 (3): 370–3. PubMed Abstract | Publisher Full Text 51. Morton J, Hall JY, Wong RJ, et al. : Combining hand techniques with electric pumping increases milk production in mothers of preterm infants. J Perinatol. 2009; 29 (11): 757–64. PubMed Abstract | Publisher Full Text | Faculty Opinions Recommendation 52. Yotebieng M, Labbok M, Soeters HM, et al. : Ten Steps to Successful Breastfeeding programme to promote early initiation and exclusive breastfeeding in DR Congo: a cluster-randomised controlled trial. Lancet Glob Health. 2015; 3 (9): e546–55. PubMed Abstract | Publisher Full Text | Faculty Opinions Recommendation 53. UNICEF: The baby-friendly hospital initiative. UNICEF; 1991. Reference Source 54. Kuhn NJ: Progesterone withdrawal as the lactogenic trigger in the rat. J Endocrinol. 1969; 44 (1): 39–54. PubMed Abstract | Publisher Full Text 55. Brown JB, Blackwell LF, Cox RI, et al. : Chemical and homogeneous enzyme immunoassay methods for the measurement of estrogens and pregnanediol and their glucuronides in urine. Prog Clin Biol Res. 1988; 285 : 119–38. PubMed Abstract 56. Maningat PD, Sen P, Rijnkels M, et al. : Gene expression in the human mammary epithelium during lactation: the milk fat globule transcriptome. Physiol Genomics. 2009; 37 (1): 12–22. PubMed Abstract | Publisher Full Text | Free Full Text | Faculty Opinions Recommendation 57. Hartmann PE, Kulski JK: Changes in the composition of the mammary secretion of women after abrupt termination of breast feeding. J Physiol (Lond). 1978; 275 : 1–11. PubMed Abstract | Publisher Full Text | Free Full Text 58. Nguyen DA, Neville MC: Tight junction regulation in the mammary gland. J Mammary Gland Biol Neoplasia. 1998; 3 (3): 233–46. PubMed Abstract | Publisher Full Text 59. Kulski JK, Hartmann PE: Milk insulin, GH and TSH: relationship to changes in milk lactose, glucose and protein during lactogenesis in women. Endocrinol Exp. 1983; 17 (3–4): 317–26. PubMed Abstract 60. Peaker M, Linzell JL: Citrate in milk: a harbinger of lactogenesis. Nature. 1975; 253 (5491): 464. PubMed Abstract | Publisher Full Text 61. Coppa GV, Gabrielli O, Pierani P, et al. : Changes in carbohydrate composition in human milk over 4 months of lactation. Pediatrics. 1993; 91 (3): 637–41. PubMed Abstract 62. Kent JC, Arthur PG, Retallack RW, et al. : Calcium, phosphate and citrate in human milk at initiation of lactation. J Dairy Res. 1992; 59 (2): 161–7. PubMed Abstract | Publisher Full Text 63. Neubauer SH, Ferris AM, Chase CG, et al. : Delayed lactogenesis in women with insulin-dependent diabetes mellitus. Am J Clin Nutr. 1993; 58 (1): 54–60. PubMed Abstract | Publisher Full Text 64. Viverge D, Grimmonprez L, Cassanas G, et al. : Variations in oligosaccharides and lactose in human milk during the first week of lactation. J Pediatr Gastroenterol Nutr. 1990; 11 (3): 361–4. PubMed Abstract | Publisher Full Text 65. Kent JC: The roles of citrate and casein in determining the calcium concentration of the milk of women and sows. Perth, Western Australia: University of Western Australia; 2000. 66. Dangat K, Upadhyay D, Kilari A, et al. : Altered breast milk components in preeclampsia; An in-vitro proton NMR spectroscopy study. Clin Chim Acta. 2016; 463 : 75–83. PubMed Abstract | Publisher Full Text 67. Family Larsson-Rosenquist Foundation: Breastfeeding and Breast Milk - from Biochemistry to Impact. A Multidisciplinary Introduction. Stuttgart: George Thieme Verlag KG; 2018. 68. Daly SE, Di Rosso A, Owens RA, et al. : Degree of breast emptying explains changes in the fat content, but not fatty acid composition, of human milk. Exp Physiol. 1993; 78 (6): 741–55. PubMed Abstract | Publisher Full Text 69. Fleet I, Linzell J: Rapid method of estimating fat in very small quantities of milk. Journal of Physiology, London. 1964; 175 (1): P15–&. 70. Ramsay DT, Kent JC, Owens RA, et al. : Ultrasound imaging of milk ejection in the breast of lactating women. Pediatrics. 2004; 113 (2): 361–7. PubMed Abstract | Publisher Full Text Comments on this article Comments (2) Version 1 VERSION 1 PUBLISHED 20 Jun 2018 Reviewer Response 12 Jul 2018 Laurie Nommsen-Rivers , University of Cincinnati, USA 12 Jul 2018 Reviewer Response Normal Human Lactation: Closing the Gap , is groundbreaking and sure to spark healthy debate on the development of globally relevant parameters for defining normal lactation. Laurie A. Nommsen-Rivers, Associate Professor ... Continue reading Normal Human Lactation: Closing the Gap , is groundbreaking and sure to spark healthy debate on the development of globally relevant parameters for defining normal lactation. Laurie A. Nommsen-Rivers, Associate Professor and Ruth Rosevear Chair of Maternal and Child Nutrition, University of Cincinnati, Cincinnati, Ohio Icie Gertrude Macy was a pioneer in the field of milk biochemistry; she published the first comprehensive collection of known research on the composition of human milk in 1953 (1). Thirty years later a new generation of visionaries organized a conference specifically focused on human lactation methodologies in Winter Park, Colorado (2). From this conference, the classic text, Human Lactation: Milk Components and Methodologies , was published in 1985 and endures as a resource for investigators in human lactation. The Winter Park conference also served as fertilizer for what became the International Society for Research in Human Milk and Lactation (ISRHML). Here we are more than 30 years since Winter Park and lacking an update specific to the components and methodologies of human lactation. After so many years, Normal Human Lactation: Closing the Gap, authored by Boss, Gardner, and Hartmann, is a groundbreaking contribution to human lactation research by an outstanding research team. Like any trailblazing undertaking, the devil is in the details. I applaud Boss, et al ., for publishing their critical review in an open forum. It is in this spirit that I respectfully posit that the greatest benefit in publishing Normal Human Lactation: Closing the Gap, is its potential to generate a consensus document by the current generation of lactation scientists on the parameters of “normal lactation.” My commentary focuses on three themes that exemplify the need for further input by a committee of lactation experts: 1) the parameters that define “normal” human lactation, 2) the selection of diagnostic indicators we use to evaluate abnormal lactation, and 3) in setting diagnostic values for normal lactation, consideration of human lactation reference values versus human lactation standards (a.k.a. global reference values). Addressing the first theme, the authors eloquently make a case for establishing a clinical definition of normal function for lactation: An objective measurement of normal function can then form the scientific basis for identification of potential abnormality (function falling outside of normal range), diagnosis of disease and the evaluation of treatments. Unfortunately, there are no tests available for the assessment of normal function for lactation. However, defining “normal” poses many challenges. For example, the first criterion listed by Boss, et al . for normal lactation is “comfortable for both mother and infant.” Is this statement perhaps conflating “normal lactation” with “normal breastfeeding?” In their introduction the authors specify that the review is … limited to maternal aspects of lactation physiology and biochemistry. This commenter supports their approach as it enables focus on one aspect of the breastfeeding dyad at a time. A mother may be able to lactate normally (i.e., produce milk of sufficient quality and quantity, however one defines “sufficient”), and even have normal external anatomy, but even so, there may be barriers to the mother-infant dyad being able to breastfeed comfortably. One of the most frequent reasons for the latter is a newborn with a tight lingual frenulum. Furthermore, normal physiology sometimes includes discomfort. Childbirth is an obvious example, but as any experienced breastfeeding mother can attest to, normal lactation can certainly be uncomfortable at times (e.g., a strong milk ejection reflex, or breast overfullness during phases of milk supply recalibration to infant demand). Boss, et al ., further defines normal lactation as the production of milk that supports “optimal growth and development.” This is indeed an important dimension of normal lactation. Typically, when growth of the exclusively breastfed infant is faltering, the clinician will consider those factors that impact caloric intake first and foremost (adequate frequency and thoroughness of breast emptying, adequate maternal milk volume, and rarely, lipid concentration). All of these angles are reviewed in Normal Human Lactation: Closing the Gap. An emerging area of consideration are the maternal diet-dependent micronutrients in human milk. While reasonably beyond the scope of the current review, vitamin and mineral composition of human milk is an important dimension of milk that supports “optimal growth and development. Notably, others are now addressing this important topic (3). The above considerations may seem like splitting hairs, but these are the details needed on parameters that define normal lactation. Addressing diagnostics, Boss, Gardner, and Hartmann, provide strong rationale for several of the proposed indicators of normal function, including maternal plasma hormone levels and milk biochemistry across the progression of lactation. A key diagnostic that was not covered in their review is sufficiency of mammary glandular tissue. With a diagnosis of insufficient milk production, the “triple feeding” process for increasing milk output requires extraordinary commitment on the part of a new mother (every 2-3 hours, breastfeed, followed by breast pumping, followed by supplemental feeds of infant formula to the newborn). A diagnostic test for evaluating glandular tissue sufficiency would go a long way towards facilitating an individualized and sustainable breastfeeding management plan for affected mothers. The use of reference values versus standards is the third example of the need for further consensus on defining normal lactation. The authors do rightly provide the WHO Child Growth Standards (4) as a frame of reference for defining the production of milk that supports “optimal growth and development.” Notably, the Child Growth Standards were explicitly designed to be just that—standards. The WHO team was very intentional in differentiating the 2003 standards on how children should grow from previous child growth reference values which simply depict what is occurring in a given place at a given time . The authors rightly declare that the reference values provided in this review are a starting point of values available today. It is very exciting to look to the future as our community of lactation scientists hone in on the outcome measures, timing, and selection criteria, for sampling milk volume and composition across the stages of lactation in mothers across the globe with “normal lactation.” It took a 3-day conference with much belabored contributions by over 50 authors to produce Human Lactation: Milk Components and Methodologies , and surely consensus on globally relevant reference values for normal human lactation will likely take a similarly collaborative effort. ISRHML…this is your call to action! References IG Macy, HJ Kelly, and RE Sloan (1953). The composition of milks. A compilation of the comparative composition and properties of human, cow, and goat milk, colostrum, and transitional milk. Bulletin of the National Research Council, No. 254 (revised), Washington, D.C. RG Jensen and MC Neville, Editors (1985). Human Lactation: Milk Components and Methodologies. Plenum Press, London. Establishing Global Reference Values for Human Milk. A protocol published at: https://clinicaltrials.gov/ct2/show/NCT03254329 . Accessed on May 12, 2018. The World Health Organization Child Growth Standards. http://www.who.int/childgrowth/mgrs/en/ . Accessed on May 12, 2018. Normal Human Lactation: Closing the Gap , is groundbreaking and sure to spark healthy debate on the development of globally relevant parameters for defining normal lactation. Laurie A. Nommsen-Rivers, Associate Professor and Ruth Rosevear Chair of Maternal and Child Nutrition, University of Cincinnati, Cincinnati, Ohio Icie Gertrude Macy was a pioneer in the field of milk biochemistry; she published the first comprehensive collection of known research on the composition of human milk in 1953 (1). Thirty years later a new generation of visionaries organized a conference specifically focused on human lactation methodologies in Winter Park, Colorado (2). From this conference, the classic text, Human Lactation: Milk Components and Methodologies , was published in 1985 and endures as a resource for investigators in human lactation. The Winter Park conference also served as fertilizer for what became the International Society for Research in Human Milk and Lactation (ISRHML). Here we are more than 30 years since Winter Park and lacking an update specific to the components and methodologies of human lactation. After so many years, Normal Human Lactation: Closing the Gap, authored by Boss, Gardner, and Hartmann, is a groundbreaking contribution to human lactation research by an outstanding research team. Like any trailblazing undertaking, the devil is in the details. I applaud Boss, et al ., for publishing their critical review in an open forum. It is in this spirit that I respectfully posit that the greatest benefit in publishing Normal Human Lactation: Closing the Gap, is its potential to generate a consensus document by the current generation of lactation scientists on the parameters of “normal lactation.” My commentary focuses on three themes that exemplify the need for further input by a committee of lactation experts: 1) the parameters that define “normal” human lactation, 2) the selection of diagnostic indicators we use to evaluate abnormal lactation, and 3) in setting diagnostic values for normal lactation, consideration of human lactation reference values versus human lactation standards (a.k.a. global reference values). Addressing the first theme, the authors eloquently make a case for establishing a clinical definition of normal function for lactation: An objective measurement of normal function can then form the scientific basis for identification of potential abnormality (function falling outside of normal range), diagnosis of disease and the evaluation of treatments. Unfortunately, there are no tests available for the assessment of normal function for lactation. However, defining “normal” poses many challenges. For example, the first criterion listed by Boss, et al . for normal lactation is “comfortable for both mother and infant.” Is this statement perhaps conflating “normal lactation” with “normal breastfeeding?” In their introduction the authors specify that the review is … limited to maternal aspects of lactation physiology and biochemistry. This commenter supports their approach as it enables focus on one aspect of the breastfeeding dyad at a time. A mother may be able to lactate normally (i.e., produce milk of sufficient quality and quantity, however one defines “sufficient”), and even have normal external anatomy, but even so, there may be barriers to the mother-infant dyad being able to breastfeed comfortably. One of the most frequent reasons for the latter is a newborn with a tight lingual frenulum. Furthermore, normal physiology sometimes includes discomfort. Childbirth is an obvious example, but as any experienced breastfeeding mother can attest to, normal lactation can certainly be uncomfortable at times (e.g., a strong milk ejection reflex, or breast overfullness during phases of milk supply recalibration to infant demand). Boss, et al ., further defines normal lactation as the production of milk that supports “optimal growth and development.” This is indeed an important dimension of normal lactation. Typically, when growth of the exclusively breastfed infant is faltering, the clinician will consider those factors that impact caloric intake first and foremost (adequate frequency and thoroughness of breast emptying, adequate maternal milk volume, and rarely, lipid concentration). All of these angles are reviewed in Normal Human Lactation: Closing the Gap. An emerging area of consideration are the maternal diet-dependent micronutrients in human milk. While reasonably beyond the scope of the current review, vitamin and mineral composition of human milk is an important dimension of milk that supports “optimal growth and development. Notably, others are now addressing this important topic (3). The above considerations may seem like splitting hairs, but these are the details needed on parameters that define normal lactation. Addressing diagnostics, Boss, Gardner, and Hartmann, provide strong rationale for several of the proposed indicators of normal function, including maternal plasma hormone levels and milk biochemistry across the progression of lactation. A key diagnostic that was not covered in their review is sufficiency of mammary glandular tissue. With a diagnosis of insufficient milk production, the “triple feeding” process for increasing milk output requires extraordinary commitment on the part of a new mother (every 2-3 hours, breastfeed, followed by breast pumping, followed by supplemental feeds of infant formula to the newborn). A diagnostic test for evaluating glandular tissue sufficiency would go a long way towards facilitating an individualized and sustainable breastfeeding management plan for affected mothers. The use of reference values versus standards is the third example of the need for further consensus on defining normal lactation. The authors do rightly provide the WHO Child Growth Standards (4) as a frame of reference for defining the production of milk that supports “optimal growth and development.” Notably, the Child Growth Standards were explicitly designed to be just that—standards. The WHO team was very intentional in differentiating the 2003 standards on how children should grow from previous child growth reference values which simply depict what is occurring in a given place at a given time . The authors rightly declare that the reference values provided in this review are a starting point of values available today. It is very exciting to look to the future as our community of lactation scientists hone in on the outcome measures, timing, and selection criteria, for sampling milk volume and composition across the stages of lactation in mothers across the globe with “normal lactation.” It took a 3-day conference with much belabored contributions by over 50 authors to produce Human Lactation: Milk Components and Methodologies , and surely consensus on globally relevant reference values for normal human lactation will likely take a similarly collaborative effort. ISRHML…this is your call to action! References IG Macy, HJ Kelly, and RE Sloan (1953). The composition of milks. A compilation of the comparative composition and properties of human, cow, and goat milk, colostrum, and transitional milk. Bulletin of the National Research Council, No. 254 (revised), Washington, D.C. RG Jensen and MC Neville, Editors (1985). Human Lactation: Milk Components and Methodologies. Plenum Press, London. Establishing Global Reference Values for Human Milk. A protocol published at: https://clinicaltrials.gov/ct2/show/NCT03254329 . Accessed on May 12, 2018. The World Health Organization Child Growth Standards. http://www.who.int/childgrowth/mgrs/en/ . Accessed on May 12, 2018. Competing Interests: No competing interests to disclose. Close Report a concern Reviewer Response 02 Jul 2018 Guido Moro , Italian Association of Human Milk Banks (AIBLUD), Milan, Italy 02 Jul 2018 Reviewer Response Comment of the article “Normal Human Lactation: Closing the Gap”, by Melinda Boss et al. The paper by Boss et al. represents a window into the world of human lactation. In ... Continue reading Comment of the article “Normal Human Lactation: Closing the Gap”, by Melinda Boss et al. The paper by Boss et al. represents a window into the world of human lactation. In a simple and clear way, the authors discuss the present knowledge of the complex process of human lactation. Looking at recent literature, we can see that many aspects of this process are still not clear, and very often the clear ones are also not taken into consideration by the scientific community. Identifying a “normal range” in order to define “normal lactation” is not an easy job. Parameters to be considered (progesterone, prolactin, measurement of milk production, milk composition, and so on) change a lot according to the period of lactation, and also within the same period, according to the day, the time of breastfeeding (day or night), and during each feeding. It appears that there are two different approaches when talking about human lactation. The first, is the scientific approach, where people involved in this field should try to use all their efforts to cover the gap which still exists in our understanding of the mechanisms involved in the biochemistry and physiology of lactation. For this aspect, new studies should be planned with a very rigorous methodology to improve our knowledge on the aspects of human lactation that are not yet completely understood. It will give us the possibility of determining reference ranges and/or reference limits for the assessment of human lactation, as suggested by the authors of this paper. The second, is the practical approach to support mothers who strongly want to breastfeed their babies. This aspect is of fundamental importance for the success of breastfeeding, and remains the main aim of all our efforts. It means implementing practices to protect, promote and support breastfeeding, such as procedures to encourage early initiation and continuing exclusive breastfeeding, starting before pregnancy, and going on during pregnancy, immediately after delivery, and after discharge from the maternity hospital. When mothers go home from the hospital with their infants, very often they do not know what to do and where to go to solve problems connected with breastfeeding, particularly in the case of a first baby. As a consequence, even though the rate of early initiation of breastfeeding is very high in some countries (in Italy, more than 90% at discharge from the hospital), exclusive breastfeeding rates drop rapidly between 2 and 4 months (in Italy, 31% of exclusive breastfeeding at 4 months of age) and are very low at 6 months (in Italy, 10% of exclusive breastfeeding). So, the article by Boss et al . is extremely important to the understanding of the process of normal human lactation and makes scientific proposals to improve the knowledge of the mechanisms involved in this process. But, if we really want “to close the gap”, the scientific aspect should go together with the psychological and practical support to all the women who want to breastfeed their infants. Guido E. Moro, MD Italian Association of Human Milk Banks (AIBLUD), Milan, Italy Email: [email protected] Tel.: +39 348 5659614 Comment of the article “Normal Human Lactation: Closing the Gap”, by Melinda Boss et al. The paper by Boss et al. represents a window into the world of human lactation. In a simple and clear way, the authors discuss the present knowledge of the complex process of human lactation. Looking at recent literature, we can see that many aspects of this process are still not clear, and very often the clear ones are also not taken into consideration by the scientific community. Identifying a “normal range” in order to define “normal lactation” is not an easy job. Parameters to be considered (progesterone, prolactin, measurement of milk production, milk composition, and so on) change a lot according to the period of lactation, and also within the same period, according to the day, the time of breastfeeding (day or night), and during each feeding. It appears that there are two different approaches when talking about human lactation. The first, is the scientific approach, where people involved in this field should try to use all their efforts to cover the gap which still exists in our understanding of the mechanisms involved in the biochemistry and physiology of lactation. For this aspect, new studies should be planned with a very rigorous methodology to improve our knowledge on the aspects of human lactation that are not yet completely understood. It will give us the possibility of determining reference ranges and/or reference limits for the assessment of human lactation, as suggested by the authors of this paper. The second, is the practical approach to support mothers who strongly want to breastfeed their babies. This aspect is of fundamental importance for the success of breastfeeding, and remains the main aim of all our efforts. It means implementing practices to protect, promote and support breastfeeding, such as procedures to encourage early initiation and continuing exclusive breastfeeding, starting before pregnancy, and going on during pregnancy, immediately after delivery, and after discharge from the maternity hospital. When mothers go home from the hospital with their infants, very often they do not know what to do and where to go to solve problems connected with breastfeeding, particularly in the case of a first baby. As a consequence, even though the rate of early initiation of breastfeeding is very high in some countries (in Italy, more than 90% at discharge from the hospital), exclusive breastfeeding rates drop rapidly between 2 and 4 months (in Italy, 31% of exclusive breastfeeding at 4 months of age) and are very low at 6 months (in Italy, 10% of exclusive breastfeeding). So, the article by Boss et al . is extremely important to the understanding of the process of normal human lactation and makes scientific proposals to improve the knowledge of the mechanisms involved in this process. But, if we really want “to close the gap”, the scientific aspect should go together with the psychological and practical support to all the women who want to breastfeed their infants. Guido E. Moro, MD Italian Association of Human Milk Banks (AIBLUD), Milan, Italy Email: [email protected] Tel.: +39 348 5659614 Competing Interests: No competing interests. Close Report a concern Comment ADD YOUR COMMENT Author details Author details 1 M315 School of Allied Health, Faculty of Health and Medical Sciences, University of Western Australia, Crawley, Australia 2 M313 School of Molecular Sciences, Faculty of Science, University of Western Australia, Crawley, Australia Melinda Boss Roles: Conceptualization, Writing – Original Draft Preparation, Writing – Review & Editing Hazel Gardner Roles: Data Curation, Formal Analysis, Visualization Peter Hartmann Roles: Conceptualization, Supervision, Writing – Review & Editing Competing interests No competing interests were disclosed. Grant information The authors declare that no grants were involved in supporting this work. Melinda Boss gratefully acknowledges research funding from the Family Larsson-Rosenquist Foundation (PG 52000600). Hazel Gardner is supported by an unrestricted research grant from Medela AG, Switzerland (PG52085000). Peter Hartmann holds an emeritus professorial position and declares that no grants were involved in supporting his contribution to this work. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Article Versions (1) version 1 Published: 20 Jun 2018, 7:801 https://doi.org/10.12688/f1000research.14452.1 Copyright © 2018 Boss M et al . This is an open access article distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Download Export To Sciwheel Bibtex EndNote ProCite Ref. Manager (RIS) Sente metrics Views Downloads F1000Research - - PubMed Central info_outline Data from PMC are received and updated monthly. - - Citations open_in_new 0 open_in_new 0 open_in_new SEE MORE DETAILS CITE how to cite this article Boss M, Gardner H and Hartmann P. Normal Human Lactation: closing the gap [version 1; peer review: 4 approved] . F1000Research 2018, 7 (F1000 Faculty Rev):801 ( https://doi.org/10.12688/f1000research.14452.1 ) NOTE: If applicable, it is important to ensure the information in square brackets after the title is included in all citations of this article. COPY CITATION DETAILS track receive updates on this article Track an article to receive email alerts on any updates to this article. TRACK THIS ARTICLE Share Open Peer Review Current Reviewer Status: Key to Reviewer Statuses VIEW HIDE Approved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approved Fundamental flaws in the paper seriously undermine the findings and conclusions Editorial Note on the Review Process Faculty Reviews are review articles written by the prestigious Members of Faculty Opinions . The articles are commissioned and peer reviewed before publication to ensure that the final, published version is comprehensive and accessible. The reviewers who approved the final version are listed with their names and affiliations. Reviewers who approved this article Shannon L. Kelleher , Department of Biomedical and Nutritional Sciences, The University of Massachusetts Lowell, USA Competing interests: No competing interests were declared. (for version 1) Kim F Michaelsen , Department of Nutrition, Exercise and Sports, University of Copenhagen, Denmark Competing interests: No competing interests were declared. (for version 1) Guido E. Moro , Italian Association of Human Milk Banks (AIBLUD), Italy Competing interests: No competing interests were declared. (for version 1) Laurie Nommsen-Rivers , Nutritional Sciences Program, College of Allied Health Sciences, University of Cincinnati, USA Competing interests: No competing interests were declared. (for version 1) Comments on this article Comments (2) Version 1 VERSION 1 PUBLISHED 20 Jun 2018 Reviewer Response 12 Jul 2018 Laurie Nommsen-Rivers , University of Cincinnati, USA 12 Jul 2018 Reviewer Response Normal Human Lactation: Closing the Gap , is groundbreaking and sure to spark healthy debate on the development of globally relevant parameters for defining normal lactation. Laurie A. Nommsen-Rivers, Associate Professor ... Continue reading Normal Human Lactation: Closing the Gap , is groundbreaking and sure to spark healthy debate on the development of globally relevant parameters for defining normal lactation. Laurie A. Nommsen-Rivers, Associate Professor and Ruth Rosevear Chair of Maternal and Child Nutrition, University of Cincinnati, Cincinnati, Ohio Icie Gertrude Macy was a pioneer in the field of milk biochemistry; she published the first comprehensive collection of known research on the composition of human milk in 1953 (1). Thirty years later a new generation of visionaries organized a conference specifically focused on human lactation methodologies in Winter Park, Colorado (2). From this conference, the classic text, Human Lactation: Milk Components and Methodologies , was published in 1985 and endures as a resource for investigators in human lactation. The Winter Park conference also served as fertilizer for what became the International Society for Research in Human Milk and Lactation (ISRHML). Here we are more than 30 years since Winter Park and lacking an update specific to the components and methodologies of human lactation. After so many years, Normal Human Lactation: Closing the Gap, authored by Boss, Gardner, and Hartmann, is a groundbreaking contribution to human lactation research by an outstanding research team. Like any trailblazing undertaking, the devil is in the details. I applaud Boss, et al ., for publishing their critical review in an open forum. It is in this spirit that I respectfully posit that the greatest benefit in publishing Normal Human Lactation: Closing the Gap, is its potential to generate a consensus document by the current generation of lactation scientists on the parameters of “normal lactation.” My commentary focuses on three themes that exemplify the need for further input by a committee of lactation experts: 1) the parameters that define “normal” human lactation, 2) the selection of diagnostic indicators we use to evaluate abnormal lactation, and 3) in setting diagnostic values for normal lactation, consideration of human lactation reference values versus human lactation standards (a.k.a. global reference values). Addressing the first theme, the authors eloquently make a case for establishing a clinical definition of normal function for lactation: An objective measurement of normal function can then form the scientific basis for identification of potential abnormality (function falling outside of normal range), diagnosis of disease and the evaluation of treatments. Unfortunately, there are no tests available for the assessment of normal function for lactation. However, defining “normal” poses many challenges. For example, the first criterion listed by Boss, et al . for normal lactation is “comfortable for both mother and infant.” Is this statement perhaps conflating “normal lactation” with “normal breastfeeding?” In their introduction the authors specify that the review is … limited to maternal aspects of lactation physiology and biochemistry. This commenter supports their approach as it enables focus on one aspect of the breastfeeding dyad at a time. A mother may be able to lactate normally (i.e., produce milk of sufficient quality and quantity, however one defines “sufficient”), and even have normal external anatomy, but even so, there may be barriers to the mother-infant dyad being able to breastfeed comfortably. One of the most frequent reasons for the latter is a newborn with a tight lingual frenulum. Furthermore, normal physiology sometimes includes discomfort. Childbirth is an obvious example, but as any experienced breastfeeding mother can attest to, normal lactation can certainly be uncomfortable at times (e.g., a strong milk ejection reflex, or breast overfullness during phases of milk supply recalibration to infant demand). Boss, et al ., further defines normal lactation as the production of milk that supports “optimal growth and development.” This is indeed an important dimension of normal lactation. Typically, when growth of the exclusively breastfed infant is faltering, the clinician will consider those factors that impact caloric intake first and foremost (adequate frequency and thoroughness of breast emptying, adequate maternal milk volume, and rarely, lipid concentration). All of these angles are reviewed in Normal Human Lactation: Closing the Gap. An emerging area of consideration are the maternal diet-dependent micronutrients in human milk. While reasonably beyond the scope of the current review, vitamin and mineral composition of human milk is an important dimension of milk that supports “optimal growth and development. Notably, others are now addressing this important topic (3). The above considerations may seem like splitting hairs, but these are the details needed on parameters that define normal lactation. Addressing diagnostics, Boss, Gardner, and Hartmann, provide strong rationale for several of the proposed indicators of normal function, including maternal plasma hormone levels and milk biochemistry across the progression of lactation. A key diagnostic that was not covered in their review is sufficiency of mammary glandular tissue. With a diagnosis of insufficient milk production, the “triple feeding” process for increasing milk output requires extraordinary commitment on the part of a new mother (every 2-3 hours, breastfeed, followed by breast pumping, followed by supplemental feeds of infant formula to the newborn). A diagnostic test for evaluating glandular tissue sufficiency would go a long way towards facilitating an individualized and sustainable breastfeeding management plan for affected mothers. The use of reference values versus standards is the third example of the need for further consensus on defining normal lactation. The authors do rightly provide the WHO Child Growth Standards (4) as a frame of reference for defining the production of milk that supports “optimal growth and development.” Notably, the Child Growth Standards were explicitly designed to be just that—standards. The WHO team was very intentional in differentiating the 2003 standards on how children should grow from previous child growth reference values which simply depict what is occurring in a given place at a given time . The authors rightly declare that the reference values provided in this review are a starting point of values available today. It is very exciting to look to the future as our community of lactation scientists hone in on the outcome measures, timing, and selection criteria, for sampling milk volume and composition across the stages of lactation in mothers across the globe with “normal lactation.” It took a 3-day conference with much belabored contributions by over 50 authors to produce Human Lactation: Milk Components and Methodologies , and surely consensus on globally relevant reference values for normal human lactation will likely take a similarly collaborative effort. ISRHML…this is your call to action! References IG Macy, HJ Kelly, and RE Sloan (1953). The composition of milks. A compilation of the comparative composition and properties of human, cow, and goat milk, colostrum, and transitional milk. Bulletin of the National Research Council, No. 254 (revised), Washington, D.C. RG Jensen and MC Neville, Editors (1985). Human Lactation: Milk Components and Methodologies. Plenum Press, London. Establishing Global Reference Values for Human Milk. A protocol published at: https://clinicaltrials.gov/ct2/show/NCT03254329 . Accessed on May 12, 2018. The World Health Organization Child Growth Standards. http://www.who.int/childgrowth/mgrs/en/ . Accessed on May 12, 2018. Normal Human Lactation: Closing the Gap , is groundbreaking and sure to spark healthy debate on the development of globally relevant parameters for defining normal lactation. Laurie A. Nommsen-Rivers, Associate Professor and Ruth Rosevear Chair of Maternal and Child Nutrition, University of Cincinnati, Cincinnati, Ohio Icie Gertrude Macy was a pioneer in the field of milk biochemistry; she published the first comprehensive collection of known research on the composition of human milk in 1953 (1). Thirty years later a new generation of visionaries organized a conference specifically focused on human lactation methodologies in Winter Park, Colorado (2). From this conference, the classic text, Human Lactation: Milk Components and Methodologies , was published in 1985 and endures as a resource for investigators in human lactation. The Winter Park conference also served as fertilizer for what became the International Society for Research in Human Milk and Lactation (ISRHML). Here we are more than 30 years since Winter Park and lacking an update specific to the components and methodologies of human lactation. After so many years, Normal Human Lactation: Closing the Gap, authored by Boss, Gardner, and Hartmann, is a groundbreaking contribution to human lactation research by an outstanding research team. Like any trailblazing undertaking, the devil is in the details. I applaud Boss, et al ., for publishing their critical review in an open forum. It is in this spirit that I respectfully posit that the greatest benefit in publishing Normal Human Lactation: Closing the Gap, is its potential to generate a consensus document by the current generation of lactation scientists on the parameters of “normal lactation.” My commentary focuses on three themes that exemplify the need for further input by a committee of lactation experts: 1) the parameters that define “normal” human lactation, 2) the selection of diagnostic indicators we use to evaluate abnormal lactation, and 3) in setting diagnostic values for normal lactation, consideration of human lactation reference values versus human lactation standards (a.k.a. global reference values). Addressing the first theme, the authors eloquently make a case for establishing a clinical definition of normal function for lactation: An objective measurement of normal function can then form the scientific basis for identification of potential abnormality (function falling outside of normal range), diagnosis of disease and the evaluation of treatments. Unfortunately, there are no tests available for the assessment of normal function for lactation. However, defining “normal” poses many challenges. For example, the first criterion listed by Boss, et al . for normal lactation is “comfortable for both mother and infant.” Is this statement perhaps conflating “normal lactation” with “normal breastfeeding?” In their introduction the authors specify that the review is … limited to maternal aspects of lactation physiology and biochemistry. This commenter supports their approach as it enables focus on one aspect of the breastfeeding dyad at a time. A mother may be able to lactate normally (i.e., produce milk of sufficient quality and quantity, however one defines “sufficient”), and even have normal external anatomy, but even so, there may be barriers to the mother-infant dyad being able to breastfeed comfortably. One of the most frequent reasons for the latter is a newborn with a tight lingual frenulum. Furthermore, normal physiology sometimes includes discomfort. Childbirth is an obvious example, but as any experienced breastfeeding mother can attest to, normal lactation can certainly be uncomfortable at times (e.g., a strong milk ejection reflex, or breast overfullness during phases of milk supply recalibration to infant demand). Boss, et al ., further defines normal lactation as the production of milk that supports “optimal growth and development.” This is indeed an important dimension of normal lactation. Typically, when growth of the exclusively breastfed infant is faltering, the clinician will consider those factors that impact caloric intake first and foremost (adequate frequency and thoroughness of breast emptying, adequate maternal milk volume, and rarely, lipid concentration). All of these angles are reviewed in Normal Human Lactation: Closing the Gap. An emerging area of consideration are the maternal diet-dependent micronutrients in human milk. While reasonably beyond the scope of the current review, vitamin and mineral composition of human milk is an important dimension of milk that supports “optimal growth and development. Notably, others are now addressing this important topic (3). The above considerations may seem like splitting hairs, but these are the details needed on parameters that define normal lactation. Addressing diagnostics, Boss, Gardner, and Hartmann, provide strong rationale for several of the proposed indicators of normal function, including maternal plasma hormone levels and milk biochemistry across the progression of lactation. A key diagnostic that was not covered in their review is sufficiency of mammary glandular tissue. With a diagnosis of insufficient milk production, the “triple feeding” process for increasing milk output requires extraordinary commitment on the part of a new mother (every 2-3 hours, breastfeed, followed by breast pumping, followed by supplemental feeds of infant formula to the newborn). A diagnostic test for evaluating glandular tissue sufficiency would go a long way towards facilitating an individualized and sustainable breastfeeding management plan for affected mothers. The use of reference values versus standards is the third example of the need for further consensus on defining normal lactation. The authors do rightly provide the WHO Child Growth Standards (4) as a frame of reference for defining the production of milk that supports “optimal growth and development.” Notably, the Child Growth Standards were explicitly designed to be just that—standards. The WHO team was very intentional in differentiating the 2003 standards on how children should grow from previous child growth reference values which simply depict what is occurring in a given place at a given time . The authors rightly declare that the reference values provided in this review are a starting point of values available today. It is very exciting to look to the future as our community of lactation scientists hone in on the outcome measures, timing, and selection criteria, for sampling milk volume and composition across the stages of lactation in mothers across the globe with “normal lactation.” It took a 3-day conference with much belabored contributions by over 50 authors to produce Human Lactation: Milk Components and Methodologies , and surely consensus on globally relevant reference values for normal human lactation will likely take a similarly collaborative effort. ISRHML…this is your call to action! References IG Macy, HJ Kelly, and RE Sloan (1953). The composition of milks. A compilation of the comparative composition and properties of human, cow, and goat milk, colostrum, and transitional milk. Bulletin of the National Research Council, No. 254 (revised), Washington, D.C. RG Jensen and MC Neville, Editors (1985). Human Lactation: Milk Components and Methodologies. Plenum Press, London. Establishing Global Reference Values for Human Milk. A protocol published at: https://clinicaltrials.gov/ct2/show/NCT03254329 . Accessed on May 12, 2018. The World Health Organization Child Growth Standards. http://www.who.int/childgrowth/mgrs/en/ . Accessed on May 12, 2018. Competing Interests: No competing interests to disclose. Close Report a concern Reviewer Response 02 Jul 2018 Guido Moro , Italian Association of Human Milk Banks (AIBLUD), Milan, Italy 02 Jul 2018 Reviewer Response Comment of the article “Normal Human Lactation: Closing the Gap”, by Melinda Boss et al. The paper by Boss et al. represents a window into the world of human lactation. In ... Continue reading Comment of the article “Normal Human Lactation: Closing the Gap”, by Melinda Boss et al. The paper by Boss et al. represents a window into the world of human lactation. In a simple and clear way, the authors discuss the present knowledge of the complex process of human lactation. Looking at recent literature, we can see that many aspects of this process are still not clear, and very often the clear ones are also not taken into consideration by the scientific community. Identifying a “normal range” in order to define “normal lactation” is not an easy job. Parameters to be considered (progesterone, prolactin, measurement of milk production, milk composition, and so on) change a lot according to the period of lactation, and also within the same period, according to the day, the time of breastfeeding (day or night), and during each feeding. It appears that there are two different approaches when talking about human lactation. The first, is the scientific approach, where people involved in this field should try to use all their efforts to cover the gap which still exists in our understanding of the mechanisms involved in the biochemistry and physiology of lactation. For this aspect, new studies should be planned with a very rigorous methodology to improve our knowledge on the aspects of human lactation that are not yet completely understood. It will give us the possibility of determining reference ranges and/or reference limits for the assessment of human lactation, as suggested by the authors of this paper. The second, is the practical approach to support mothers who strongly want to breastfeed their babies. This aspect is of fundamental importance for the success of breastfeeding, and remains the main aim of all our efforts. It means implementing practices to protect, promote and support breastfeeding, such as procedures to encourage early initiation and continuing exclusive breastfeeding, starting before pregnancy, and going on during pregnancy, immediately after delivery, and after discharge from the maternity hospital. When mothers go home from the hospital with their infants, very often they do not know what to do and where to go to solve problems connected with breastfeeding, particularly in the case of a first baby. As a consequence, even though the rate of early initiation of breastfeeding is very high in some countries (in Italy, more than 90% at discharge from the hospital), exclusive breastfeeding rates drop rapidly between 2 and 4 months (in Italy, 31% of exclusive breastfeeding at 4 months of age) and are very low at 6 months (in Italy, 10% of exclusive breastfeeding). So, the article by Boss et al . is extremely important to the understanding of the process of normal human lactation and makes scientific proposals to improve the knowledge of the mechanisms involved in this process. But, if we really want “to close the gap”, the scientific aspect should go together with the psychological and practical support to all the women who want to breastfeed their infants. Guido E. Moro, MD Italian Association of Human Milk Banks (AIBLUD), Milan, Italy Email: [email protected] Tel.: +39 348 5659614 Comment of the article “Normal Human Lactation: Closing the Gap”, by Melinda Boss et al. The paper by Boss et al. represents a window into the world of human lactation. In a simple and clear way, the authors discuss the present knowledge of the complex process of human lactation. Looking at recent literature, we can see that many aspects of this process are still not clear, and very often the clear ones are also not taken into consideration by the scientific community. Identifying a “normal range” in order to define “normal lactation” is not an easy job. Parameters to be considered (progesterone, prolactin, measurement of milk production, milk composition, and so on) change a lot according to the period of lactation, and also within the same period, according to the day, the time of breastfeeding (day or night), and during each feeding. It appears that there are two different approaches when talking about human lactation. The first, is the scientific approach, where people involved in this field should try to use all their efforts to cover the gap which still exists in our understanding of the mechanisms involved in the biochemistry and physiology of lactation. For this aspect, new studies should be planned with a very rigorous methodology to improve our knowledge on the aspects of human lactation that are not yet completely understood. It will give us the possibility of determining reference ranges and/or reference limits for the assessment of human lactation, as suggested by the authors of this paper. The second, is the practical approach to support mothers who strongly want to breastfeed their babies. This aspect is of fundamental importance for the success of breastfeeding, and remains the main aim of all our efforts. It means implementing practices to protect, promote and support breastfeeding, such as procedures to encourage early initiation and continuing exclusive breastfeeding, starting before pregnancy, and going on during pregnancy, immediately after delivery, and after discharge from the maternity hospital. When mothers go home from the hospital with their infants, very often they do not know what to do and where to go to solve problems connected with breastfeeding, particularly in the case of a first baby. As a consequence, even though the rate of early initiation of breastfeeding is very high in some countries (in Italy, more than 90% at discharge from the hospital), exclusive breastfeeding rates drop rapidly between 2 and 4 months (in Italy, 31% of exclusive breastfeeding at 4 months of age) and are very low at 6 months (in Italy, 10% of exclusive breastfeeding). So, the article by Boss et al . is extremely important to the understanding of the process of normal human lactation and makes scientific proposals to improve the knowledge of the mechanisms involved in this process. But, if we really want “to close the gap”, the scientific aspect should go together with the psychological and practical support to all the women who want to breastfeed their infants. Guido E. Moro, MD Italian Association of Human Milk Banks (AIBLUD), Milan, Italy Email: [email protected] Tel.: +39 348 5659614 Competing Interests: No competing interests. Close Report a concern Comment ADD YOUR COMMENT keyboard_arrow_left keyboard_arrow_right Open Peer Review Reviewer Status info_outline Alongside their report, reviewers assign a status to the article: Approved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approved Fundamental flaws in the paper seriously undermine the findings and conclusions Reviewer Reports Invited Reviewers 1 2 3 4 Version 1 20 Jun 18 Faculty Reviews are review articles written by the prestigious Members of Faculty Opinions . The articles are commissioned and peer reviewed before publication to ensure that the final, published version is comprehensive and accessible. The reviewers who approved the final version are listed with their names and affiliations. Shannon L. Kelleher , Department of Biomedical and Nutritional Sciences, The University of Massachusetts Lowell, USA Competing interests: No competing interests were declared. View more View less Kim F Michaelsen , Department of Nutrition, Exercise and Sports, University of Copenhagen, Denmark Competing interests: No competing interests were declared. View more View less Guido E. Moro , Italian Association of Human Milk Banks (AIBLUD), Italy Competing interests: No competing interests were declared. View more View less Laurie Nommsen-Rivers , Nutritional Sciences Program, College of Allied Health Sciences, University of Cincinnati, USA Competing interests: No competing interests were declared. View more View less Comments on this article All Comments (2) Add a comment Sign up for content alerts Sign Up You are now signed up to receive this alert Browse by related subjects Alongside their report, reviewers assign a status to the article: Approved - the paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations - A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approved - fundamental flaws in the paper seriously undermine the findings and conclusions Adjust parameters to alter display View on desktop for interactive features Includes Interactive Elements View on desktop for interactive features Competing Interests Policy Provide sufficient details of any financial or non-financial competing interests to enable users to assess whether your comments might lead a reasonable person to question your impartiality. Consider the following examples, but note that this is not an exhaustive list: Examples of 'Non-Financial Competing Interests' Within the past 4 years, you have held joint grants, published or collaborated with any of the authors of the selected paper. You have a close personal relationship (e.g. parent, spouse, sibling, or domestic partner) with any of the authors. You are a close professional associate of any of the authors (e.g. scientific mentor, recent student). You work at the same institute as any of the authors. You hope/expect to benefit (e.g. favour or employment) as a result of your submission. You are an Editor for the journal in which the article is published. Examples of 'Financial Competing Interests' You expect to receive, or in the past 4 years have received, any of the following from any commercial organisation that may gain financially from your submission: a salary, fees, funding, reimbursements. You expect to receive, or in the past 4 years have received, shared grant support or other funding with any of the authors. You hold, or are currently applying for, any patents or significant stocks/shares relating to the subject matter of the paper you are commenting on. Stay Updated Sign up for content alerts and receive a weekly or monthly email with all newly published articles Register with F1000Research Already registered? Sign in Not now, thanks close PLEASE NOTE If you are an AUTHOR of this article, please check that you signed in with the account associated with this article otherwise we cannot automatically identify your role as an author and your comment will be labelled as a “User Comment”. If you are a REVIEWER of this article, please check that you have signed in with the account associated with this article and then go to your account to submit your report, please do not post your review here. If you do not have access to your original account, please contact us . All commenters must hold a formal affiliation as per our Policies . The information that you give us will be displayed next to your comment. User comments must be in English, comprehensible and relevant to the article under discussion. We reserve the right to remove any comments that we consider to be inappropriate, offensive or otherwise in breach of the User Comment Terms and Conditions . Commenters must not use a comment for personal attacks. When criticisms of the article are based on unpublished data, the data should be made available. I accept the User Comment Terms and Conditions Please confirm that you accept the User Comment Terms and Conditions. Affiliation ✕ refresh Please enter your institution. Note: To add your institution or organisation, start typing the name and then select the correct name from the list. Where applicable, the name will appear in both the original language and in English. Do not paste in the name. If the name does not appear in the drop-down list, we will display the information you have entered. ✕ refresh Country/Region * USA UK Canada China France Germany Afghanistan Aland Islands Albania Algeria American Samoa Andorra Angola Anguilla Antarctica Antigua and Barbuda Argentina Armenia Aruba Australia Austria Azerbaijan Bahamas Bahrain Bangladesh Barbados Belarus Belgium Belize Benin Bermuda Bhutan Bolivia Bosnia and Herzegovina Botswana Bouvet Island Brazil British Indian Ocean Territory British Virgin Islands Brunei Bulgaria Burkina Faso Burundi Cambodia Cameroon Canada Cape Verde Cayman Islands Central African Republic Chad Chile China Christmas Island Cocos (Keeling) Islands Colombia Comoros Congo Cook Islands Costa Rica Cote d'Ivoire Croatia Cuba Cyprus Czech Republic Democratic Republic of the Congo Denmark Djibouti Dominica Dominican Republic Ecuador Egypt El Salvador Equatorial Guinea Eritrea Estonia Ethiopia Falkland Islands Faroe Islands Federated States of Micronesia Fiji Finland France French Guiana French Polynesia French Southern Territories Gabon Georgia Germany Ghana Gibraltar Greece Greenland Grenada Guadeloupe Guam Guatemala Guernsey Guinea Guinea-Bissau Guyana Haiti Heard Island and Mcdonald Islands Holy See (Vatican City State) Honduras Hong Kong Hungary Iceland India Indonesia Iran Iraq Ireland Israel Italy Jamaica Japan Jersey Jordan Kazakhstan Kenya Kiribati Kosovo (Serbia and Montenegro) Kuwait Kyrgyzstan Lao People's Democratic Republic Latvia Lebanon Lesotho Liberia Libya Liechtenstein Lithuania Luxembourg Macao Madagascar Malawi Malaysia Maldives Mali Malta Marshall Islands Martinique Mauritania Mauritius Mayotte Mexico Minor Outlying Islands of the United States Moldova Monaco Mongolia Montenegro Montserrat Morocco Mozambique Myanmar Namibia Nauru Nepal Netherlands Antilles New Caledonia New Zealand Nicaragua Niger Nigeria Niue Norfolk Island North Korea North Macedonia Northern Mariana Islands Norway Oman Pakistan Palau Palestinian Territory Panama Papua New Guinea Paraguay Peru Philippines Pitcairn Poland Portugal Puerto Rico Qatar Reunion Romania Russian Federation Rwanda Saint Helena Saint Kitts and Nevis Saint Lucia Saint Pierre and Miquelon Saint Vincent and the Grenadines Samoa San Marino Sao Tome and Principe Saudi Arabia Senegal Serbia Seychelles Sierra Leone Singapore Slovakia Slovenia Solomon Islands Somalia South Africa South Georgia and the South Sandwich Is South Korea South Sudan Spain Sri Lanka Sudan Suriname Svalbard and Jan Mayen Swaziland Sweden Switzerland Syria Taiwan Tajikistan Tanzania Thailand The Gambia The Netherlands Timor-Leste Togo Tokelau Tonga Trinidad and Tobago Tunisia Turkey Turkmenistan Turks and Caicos Islands Tuvalu UK USA Uganda Ukraine United Arab Emirates United States Virgin Islands Uruguay Uzbekistan Vanuatu Venezuela Vietnam Wallis and Futuna West Bank and Gaza Strip Western Sahara Yemen Zambia Zimbabwe Please select your country/region. You must enter a comment. Competing Interests Please disclose any competing interests that might be construed to influence your judgment of the article's or peer review report's validity or importance. Competing Interests Policy Provide sufficient details of any financial or non-financial competing interests to enable users to assess whether your comments might lead a reasonable person to question your impartiality. Consider the following examples, but note that this is not an exhaustive list: Examples of 'Non-Financial Competing Interests' Within the past 4 years, you have held joint grants, published or collaborated with any of the authors of the selected paper. You have a close personal relationship (e.g. parent, spouse, sibling, or domestic partner) with any of the authors. You are a close professional associate of any of the authors (e.g. scientific mentor, recent student). You work at the same institute as any of the authors. You hope/expect to benefit (e.g. favour or employment) as a result of your submission. You are an Editor for the journal in which the article is published. Examples of 'Financial Competing Interests' You expect to receive, or in the past 4 years have received, any of the following from any commercial organisation that may gain financially from your submission: a salary, fees, funding, reimbursements. You expect to receive, or in the past 4 years have received, shared grant support or other funding with any of the authors. You hold, or are currently applying for, any patents or significant stocks/shares relating to the subject matter of the paper you are commenting on. Please state your competing interests The comment has been saved. An error has occurred. Please try again. Cancel Post var lTitle = "Normal Human Lactation: closing the gap".replace("'", ''); var linkedInUrl = "http://www.linkedin.com/shareArticle?url=https://f1000research.com/articles/7-801/v1" + "&title=" + encodeURIComponent(lTitle) + "&summary=" + encodeURIComponent('Read the article by '); var deliciousUrl = "https://del.icio.us/post?url=https://f1000research.com/articles/7-801/v1&title=" + encodeURIComponent(lTitle); var redditUrl = "http://reddit.com/submit?url=https://f1000research.com/articles/7-801/v1" + "&title=" + encodeURIComponent(lTitle); linkedInUrl += encodeURIComponent('Boss M et al.'); var offsetTop = /chrome/i.test( navigator.userAgent ) ? 4 : -10; var addthis_config = { ui_offset_top: offsetTop, services_compact : "facebook,twitter,www.linkedin.com,www.mendeley.com,reddit.com", services_expanded : "facebook,twitter,www.linkedin.com,www.mendeley.com,reddit.com", services_custom : [ { name: "LinkedIn", url: linkedInUrl, icon:"/img/icon/at_linkedin.svg" }, { name: "Mendeley", url: "http://www.mendeley.com/import/?url=https://f1000research.com/articles/7-801/v1/mendeley", icon:"/img/icon/at_mendeley.svg" }, { name: "Reddit", url: redditUrl, icon:"/img/icon/at_reddit.svg" }, ] }; var addthis_share = { url: "https://f1000research.com/articles/7-801", templates : { twitter : "Normal Human Lactation: closing the gap. Boss M et al., published by " + "@F1000Research" + ", https://f1000research.com/articles/7-801/v1" } }; if (typeof(addthis) != "undefined"){ addthis.addEventListener('addthis.ready', checkCount); addthis.addEventListener('addthis.menu.share', checkCount); } $(".f1r-shares-twitter").attr("href", "https://twitter.com/intent/tweet?text=" + addthis_share.templates.twitter); $(".f1r-shares-facebook").attr("href", "https://www.facebook.com/sharer/sharer.php?u=" + addthis_share.url); $(".f1r-shares-linkedin").attr("href", addthis_config.services_custom[0].url); $(".f1r-shares-reddit").attr("href", addthis_config.services_custom[2].url); $(".f1r-shares-mendelay").attr("href", addthis_config.services_custom[1].url); function checkCount(){ setTimeout(function(){ $(".addthis_button_expanded").each(function(){ var count = $(this).text(); if (count !== "" && count != "0") $(this).removeClass("is-hidden"); else $(this).addClass("is-hidden"); }); }, 1000); } close How to cite this report {{reportCitation}} Cancel Copy Citation Details $(function(){R.ui.buttonDropdowns('.dropdown-for-downloads');}); $(function(){R.ui.toolbarDropdowns('.toolbar-dropdown-for-downloads');}); $.get("/articles/acj/14452/15731") new F1000.Clipboard(); new F1000.ThesaurusTermsDisplay("faculty-reviews", "article", "15731"); $(document).ready(function() { $( "#frame1" ).on('load', function() { var mydiv = $(this).contents().find("div"); var h = mydiv.height(); console.log(h) }); var tooltipLivingFigure = jQuery(".interactive-living-figure-label .icon-more-info"), titleLivingFigure = tooltipLivingFigure.attr("title"); tooltipLivingFigure.simpletip({ fixed: true, position: ["-115", "30"], baseClass: 'small-tooltip', content:titleLivingFigure + " " }); tooltipLivingFigure.removeAttr("title"); $("body").on("click", ".cite-living-figure", function(e) { e.preventDefault(); var ref = $(this).attr("data-ref"); $(this).closest(".living-figure-list-container").find("#" + ref).fadeIn(200); }); $("body").on("click", ".close-cite-living-figure", function(e) { e.preventDefault(); $(this).closest(".popup-window-wrapper").fadeOut(200); }); $(document).on("mouseup", function(e) { var metricsContainer = $(".article-metrics-popover-wrapper"); if (!metricsContainer.is(e.target) && metricsContainer.has(e.target).length === 0) { $(".article-metrics-close-button").click(); } }); var articleId = $('#articleId').val(); if($("#main-article-count-box").attachArticleMetrics) { $("#main-article-count-box").attachArticleMetrics(articleId, { articleMetricsView: true }); } }); var figshareWidget = $(".new_figshare_widget"); if (figshareWidget.length > 0) { window.figshare.load("f1000", function(Widget) { // Select a tag/tags defined in your page. In this tag we will place the widget. _.map(figshareWidget, function(el){ var widget = new Widget({ articleId: $(el).attr("figshare_articleId") //height:300 // this is the height of the viewer part. [Default: 550] }); widget.initialize(); // initialize the widget widget.mount(el); // mount it in a tag that's on your page // this will save the widget on the global scope for later use from // your JS scripts. This line is optional. //window.widget = widget; }); }); } close Error Close Add Reset F1000.MICROSERVICES.AFFILIATION = ''; $(document).ready(function () { $('.js-affiliations-form').each((index, form) => { new AffiliationForm({ formId: form.id, institutionErrorSelector: '.comment-enter-institution', departmentErrorSelector: '.comment-enter-department', placeSelector: '.js-add-comment-place', stateSelector: '.js-add-comment-state', zipCodeSelector: '.js-add-comment-zipcode', countrySelector: '.js-add-comment-country', countryErrorSelector: '.comment-enter-country', }); }); }); $(document).ready(function () { var reportIds = { "35092": 0, "35093": 0, "35094": 0, "35095": 0, }; $(".referee-response-container,.js-referee-report").each(function(index, el) { var reportId = $(el).attr("data-reportid"), reportCount = reportIds[reportId] || 0; $(el).find(".comments-count-container,.js-referee-report-views").html(reportCount); }); var uuidInput = $("#article_uuid"), oldUUId = uuidInput.val(), newUUId = "b3c6511a-88e7-4f62-8484-13f2cc08cb8a"; uuidInput.val(newUUId); $("a[href*='article_uuid=']").each(function(index, el) { var newHref = $(el).attr("href").replace(oldUUId, newUUId); $(el).attr("href", newHref); }); }); An innovative open access publishing platform offering rapid publication and open peer review, whilst supporting data deposition and sharing. Browse Gateways Collections How it Works Contact For Developers Cookie Notice Privacy Notice RSS Submit Your Research Follow us © 2012-2026 F1000 Research Ltd. ISSN 2046-1402 | Legal | Partner of Research4Life • CrossRef • ORCID • FAIRSharing R.templateTests.simpleTemplate = R.template(' $text $text $text $text $text '); R.templateTests.runTests(); var F1000platform = new F1000.Platform({ name: "f1000research", displayName: "F1000Research", hostName: "f1000research.com", id: "1", editorialEmail: "[email protected]", infoEmail: "[email protected]", usePmcStats: true }); $(function(){R.ui.dropdowns('.dropdown-for-authors, .dropdown-for-about, .dropdown-for-myresearch');}); // $(function(){R.ui.dropdowns('.dropdown-for-referees');}); $(document).ready(function () { if ($(".cookie-warning").is(":visible")) { $(".sticky").css("margin-bottom", "35px"); $(".devices").addClass("devices-and-cookie-warning"); } $(".cookie-warning .close-button").click(function (e) { $(".devices").removeClass("devices-and-cookie-warning"); $(".sticky").css("margin-bottom", "0"); }); $("#tweeter-feed .tweet-message").each(function (i, message) { var self = $(message); self.html(linkify(self.html())); }); $(".partner").on("mouseenter mouseleave", function() { $(this).find(".gray-scale, .colour").toggleClass("is-hidden"); }); }); Sign In Remember me Forgotten your password? Sign In Cancel Email or password not correct. Please try again Please wait... $(function(){ // Note: All the setup needs to run against a name attribute and *not* the id due the clonish // nature of facebox... $("a[id=googleSignInButton]").click(function(event){ event.preventDefault(); $("input[id=oAuthSystem]").val("GOOGLE"); $("form[id=oAuthForm]").submit(); }); $("a[id=facebookSignInButton]").click(function(event){ event.preventDefault(); $("input[id=oAuthSystem]").val("FACEBOOK"); $("form[id=oAuthForm]").submit(); }); $("a[id=orcidSignInButton]").click(function(event){ event.preventDefault(); $("input[id=oAuthSystem]").val("ORCID"); $("form[id=oAuthForm]").submit(); }); }); If you've forgotten your password, please enter your email address below and we'll send you instructions on how to reset your password. The email address should be the one you originally registered with F1000. Email address not valid, please try again You registered with F1000 via Google, so we cannot reset your password. To sign in, please click here . If you still need help with your Google account password, please click here . You registered with F1000 via Facebook, so we cannot reset your password. To sign in, please click here . If you still need help with your Facebook account password, please click here . Code not correct, please try again Reset password Cancel Email us for further assistance. Server error, please try again. If your email address is registered with us, we will email you instructions to reset your password. If you think you should have received this email but it has not arrived, please check your spam filters and/or contact for further assistance. Please wait... Register $(document).ready(function () { signIn.createSignInAsRow($("#sign-in-form-gfb-popup")); $(".target-field").each(function () { var uris = $(this).val().split("/"); if (uris.pop() === "login") { $(this).val(uris.toString().replace(",","/")); } }); });