Insulin initiation recommendations.
\\n\\n
Released this past November, the list is based on data collected from the Web of Science and highlights some of the world’s most influential scientific minds by naming the researchers whose publications over the previous decade have included a high number of Highly Cited Papers placing them among the top 1% most-cited.
\\n\\nWe wish to congratulate all of the researchers named and especially our authors on this amazing accomplishment! We are happy and proud to share in their success!
\\n"}]',published:!0,mainMedia:null},components:[{type:"htmlEditorComponent",content:'IntechOpen is proud to announce that 179 of our authors have made the Clarivate™ Highly Cited Researchers List for 2020, ranking them among the top 1% most-cited.
\n\nThroughout the years, the list has named a total of 252 IntechOpen authors as Highly Cited. Of those researchers, 69 have been featured on the list multiple times.
\n\n\n\nReleased this past November, the list is based on data collected from the Web of Science and highlights some of the world’s most influential scientific minds by naming the researchers whose publications over the previous decade have included a high number of Highly Cited Papers placing them among the top 1% most-cited.
\n\nWe wish to congratulate all of the researchers named and especially our authors on this amazing accomplishment! We are happy and proud to share in their success!
\n'}],latestNews:[{slug:"stanford-university-identifies-top-2-scientists-over-1-000-are-intechopen-authors-and-editors-20210122",title:"Stanford University Identifies Top 2% Scientists, Over 1,000 are IntechOpen Authors and Editors"},{slug:"intechopen-authors-included-in-the-highly-cited-researchers-list-for-2020-20210121",title:"IntechOpen Authors Included in the Highly Cited Researchers List for 2020"},{slug:"intechopen-maintains-position-as-the-world-s-largest-oa-book-publisher-20201218",title:"IntechOpen Maintains Position as the World’s Largest OA Book Publisher"},{slug:"all-intechopen-books-available-on-perlego-20201215",title:"All IntechOpen Books Available on Perlego"},{slug:"oiv-awards-recognizes-intechopen-s-editors-20201127",title:"OIV Awards Recognizes IntechOpen's Editors"},{slug:"intechopen-joins-crossref-s-initiative-for-open-abstracts-i4oa-to-boost-the-discovery-of-research-20201005",title:"IntechOpen joins Crossref's Initiative for Open Abstracts (I4OA) to Boost the Discovery of Research"},{slug:"intechopen-hits-milestone-5-000-open-access-books-published-20200908",title:"IntechOpen hits milestone: 5,000 Open Access books published!"},{slug:"intechopen-books-hosted-on-the-mathworks-book-program-20200819",title:"IntechOpen Books Hosted on the MathWorks Book Program"}]},book:{item:{type:"book",id:"2699",leadTitle:null,fullTitle:"Biomedical Tissue Culture",title:"Biomedical Tissue Culture",subtitle:null,reviewType:"peer-reviewed",abstract:"This book describes many aspects of tissue culture models in an extensive manner. 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Solutions",subtitle:null,fullTitle:"Applied Electromechanical Devices and Machines for Electric Mobility Solutions",slug:"applied-electromechanical-devices-and-machines-for-electric-mobility-solutions",publishedDate:"March 25th 2020",bookSignature:"Adel El-Shahat and Mircea Ruba",coverURL:"https://cdn.intechopen.com/books/images_new/9290.jpg",licenceType:"CC BY 3.0",editedByType:"Edited by",editors:[{id:"193331",title:"Dr.",name:"Adel",middleName:null,surname:"El-Shahat",slug:"adel-el-shahat",fullName:"Adel El-Shahat"}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"}}},ofsBook:{item:{type:"book",id:"9952",leadTitle:null,title:"Pyrophosphate Biology and Medicine - Advances, Applications and Challenges",subtitle:null,reviewType:"peer-reviewed",abstract:"\r\n\tPyrophosphate (PPi) has long been recognized as a by-product of diverse biosynthetic reactions and was initially identified as a key endogenous inhibitor of biomineralization. PPi is synthesized from extracellular ATP by ecto-nucleotide pyrophosphatase/phosphodiesterase from extracellular ATP hydrolysis. Vascular calcification refers to the deposition of calcium phosphate, mainly in the form of hydroxyapatite crystals, in cardiovascular tissues including arteries and myocardium. It is correlated with an elevated risk of cardiovascular disease and myocardial infarction in diabetic patients and in those with chronic kidney disease. Many enzymes implicated in the metabolism of pyrophosphate have been associated with vascular calcifications. Pyrophosphate may also act as a signaling molecule to regulate gene expression. Thus, it is necessary to outline our current insight regarding pyrophosphate metabolism and how it regulates bone mineralization and inhibits harmful soft tissue calcification. Therapies based on pyrophosphate metabolism have been compelling in animal models, including renal failure, and hold hope as promising therapies to prevent vascular calcification. This work intends to summarize recent progress and future directions for the study of pyrophosphate metabolism and how it regulates bone mineralization and prevents harmful soft tissue calcification, how dysregulation of PPi results in human diseases as well as the development of novel molecules and strategies that can interrogate and manipulate the cellular actions of pyrophosphate.
",isbn:null,printIsbn:"979-953-307-X-X",pdfIsbn:null,doi:null,price:0,priceEur:0,priceUsd:0,slug:null,numberOfPages:0,isOpenForSubmission:!1,hash:"a92844c6dd3fd62f42adecd405e4a314",bookSignature:"Mr. Abdullah Al Hasan",publishedDate:null,coverURL:"https://cdn.intechopen.com/books/images_new/9952.jpg",keywords:"Biology of Pyrophosphate, Pyrophosphate-Dependent Metabolism, Inositol Pyrophosphate Pathway, Pathological Perspectives, Calcium Pyrophosphate Deposition, Vascular Calcification,, Medical Perspectives, Epidemiology, Pharmacological Perspectives, Ferric Pyrophosphate Citrate, Pyrophosphate Metabolites, Thiamine Pyrophosphate Riboswitches, Terpene Byiosynthesis",numberOfDownloads:null,numberOfWosCitations:0,numberOfCrossrefCitations:null,numberOfDimensionsCitations:null,numberOfTotalCitations:null,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"November 12th 2019",dateEndSecondStepPublish:"March 24th 2020",dateEndThirdStepPublish:"May 23rd 2020",dateEndFourthStepPublish:"August 11th 2020",dateEndFifthStepPublish:"October 10th 2020",remainingDaysToSecondStep:"a year",secondStepPassed:!0,currentStepOfPublishingProcess:5,editedByType:null,kuFlag:!1,biosketch:null,coeditorOneBiosketch:null,coeditorTwoBiosketch:null,coeditorThreeBiosketch:null,coeditorFourBiosketch:null,coeditorFiveBiosketch:null,editors:[{id:"228533",title:"Mr.",name:"Abdullah",middleName:null,surname:"Al Hasan",slug:"abdullah-al-hasan",fullName:"Abdullah Al Hasan",profilePictureURL:"https://mts.intechopen.com/storage/users/no_image.jpg",biography:"Abdullah Al Hasan received his MPharm degree in Pharmaceutical Chemistry at the University of Dhaka, Bangladesh. During his study, he worked on the biology of natural products at the Department of Pharmaceutical Chemistry, University of Dhaka. After his post-graduation, he got a permanent position in the Department of Pharmacy, Southeast University, Bangladesh in 2013. He established his own research group in 2016 in that department with the main objective of studying the structural biology of drug action with a particular focus on drug design and drug discovery. 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From chapter submission and review to approval and revision, copyediting and design, until final publication, I work closely with authors and editors to ensure a simple and easy publishing process. I maintain constant and effective communication with authors, editors and reviewers, which allows for a level of personal support that enables contributors to fully commit and concentrate on the chapters they are writing, editing, or reviewing. I assist authors in the preparation of their full chapter submissions and track important deadlines and ensure they are met. I help to coordinate internal processes such as linguistic review, and monitor the technical aspects of the process. As an ASM I am also involved in the acquisition of editors. Whether that be identifying an exceptional author and proposing an editorship collaboration, or contacting researchers who would like the opportunity to work with IntechOpen, I establish and help manage author and editor acquisition and contact."}},relatedBooks:[{type:"book",id:"1591",title:"Infrared Spectroscopy",subtitle:"Materials Science, Engineering and Technology",isOpenForSubmission:!1,hash:"99b4b7b71a8caeb693ed762b40b017f4",slug:"infrared-spectroscopy-materials-science-engineering-and-technology",bookSignature:"Theophile Theophanides",coverURL:"https://cdn.intechopen.com/books/images_new/1591.jpg",editedByType:"Edited by",editors:[{id:"37194",title:"Dr.",name:"Theophanides",surname:"Theophile",slug:"theophanides-theophile",fullName:"Theophanides Theophile"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"3092",title:"Anopheles mosquitoes",subtitle:"New insights into malaria vectors",isOpenForSubmission:!1,hash:"c9e622485316d5e296288bf24d2b0d64",slug:"anopheles-mosquitoes-new-insights-into-malaria-vectors",bookSignature:"Sylvie Manguin",coverURL:"https://cdn.intechopen.com/books/images_new/3092.jpg",editedByType:"Edited by",editors:[{id:"50017",title:"Prof.",name:"Sylvie",surname:"Manguin",slug:"sylvie-manguin",fullName:"Sylvie Manguin"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"3161",title:"Frontiers in Guided Wave Optics and Optoelectronics",subtitle:null,isOpenForSubmission:!1,hash:"deb44e9c99f82bbce1083abea743146c",slug:"frontiers-in-guided-wave-optics-and-optoelectronics",bookSignature:"Bishnu Pal",coverURL:"https://cdn.intechopen.com/books/images_new/3161.jpg",editedByType:"Edited by",editors:[{id:"4782",title:"Prof.",name:"Bishnu",surname:"Pal",slug:"bishnu-pal",fullName:"Bishnu Pal"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"72",title:"Ionic Liquids",subtitle:"Theory, Properties, New Approaches",isOpenForSubmission:!1,hash:"d94ffa3cfa10505e3b1d676d46fcd3f5",slug:"ionic-liquids-theory-properties-new-approaches",bookSignature:"Alexander Kokorin",coverURL:"https://cdn.intechopen.com/books/images_new/72.jpg",editedByType:"Edited by",editors:[{id:"19816",title:"Prof.",name:"Alexander",surname:"Kokorin",slug:"alexander-kokorin",fullName:"Alexander Kokorin"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"1373",title:"Ionic Liquids",subtitle:"Applications and Perspectives",isOpenForSubmission:!1,hash:"5e9ae5ae9167cde4b344e499a792c41c",slug:"ionic-liquids-applications-and-perspectives",bookSignature:"Alexander Kokorin",coverURL:"https://cdn.intechopen.com/books/images_new/1373.jpg",editedByType:"Edited by",editors:[{id:"19816",title:"Prof.",name:"Alexander",surname:"Kokorin",slug:"alexander-kokorin",fullName:"Alexander Kokorin"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"57",title:"Physics and Applications of Graphene",subtitle:"Experiments",isOpenForSubmission:!1,hash:"0e6622a71cf4f02f45bfdd5691e1189a",slug:"physics-and-applications-of-graphene-experiments",bookSignature:"Sergey Mikhailov",coverURL:"https://cdn.intechopen.com/books/images_new/57.jpg",editedByType:"Edited by",editors:[{id:"16042",title:"Dr.",name:"Sergey",surname:"Mikhailov",slug:"sergey-mikhailov",fullName:"Sergey Mikhailov"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"371",title:"Abiotic Stress in Plants",subtitle:"Mechanisms and Adaptations",isOpenForSubmission:!1,hash:"588466f487e307619849d72389178a74",slug:"abiotic-stress-in-plants-mechanisms-and-adaptations",bookSignature:"Arun Shanker and B. Venkateswarlu",coverURL:"https://cdn.intechopen.com/books/images_new/371.jpg",editedByType:"Edited by",editors:[{id:"58592",title:"Dr.",name:"Arun",surname:"Shanker",slug:"arun-shanker",fullName:"Arun Shanker"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"878",title:"Phytochemicals",subtitle:"A Global Perspective of Their Role in Nutrition and Health",isOpenForSubmission:!1,hash:"ec77671f63975ef2d16192897deb6835",slug:"phytochemicals-a-global-perspective-of-their-role-in-nutrition-and-health",bookSignature:"Venketeshwer Rao",coverURL:"https://cdn.intechopen.com/books/images_new/878.jpg",editedByType:"Edited by",editors:[{id:"82663",title:"Dr.",name:"Venketeshwer",surname:"Rao",slug:"venketeshwer-rao",fullName:"Venketeshwer Rao"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"4816",title:"Face Recognition",subtitle:null,isOpenForSubmission:!1,hash:"146063b5359146b7718ea86bad47c8eb",slug:"face_recognition",bookSignature:"Kresimir Delac and Mislav Grgic",coverURL:"https://cdn.intechopen.com/books/images_new/4816.jpg",editedByType:"Edited by",editors:[{id:"528",title:"Dr.",name:"Kresimir",surname:"Delac",slug:"kresimir-delac",fullName:"Kresimir Delac"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"3621",title:"Silver Nanoparticles",subtitle:null,isOpenForSubmission:!1,hash:null,slug:"silver-nanoparticles",bookSignature:"David Pozo Perez",coverURL:"https://cdn.intechopen.com/books/images_new/3621.jpg",editedByType:"Edited by",editors:[{id:"6667",title:"Dr.",name:"David",surname:"Pozo",slug:"david-pozo",fullName:"David Pozo"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}}]},chapter:{item:{type:"chapter",id:"65616",title:"Insulin Therapy in Gestational Diabetes",doi:"10.5772/intechopen.84569",slug:"insulin-therapy-in-gestational-diabetes",body:'\nGestational diabetes (GD) is one of the most common pathologies in pregnancy. Gestational diabetes has been defined as any degree of glucose intolerance with onset or first recognition during pregnancy [1]. In pregnancy, there are multiple hormonal changes, including hyperinsulinemia and an insulin-resistant state; thus the pancreatic beta cell function becomes insufficient to meet the body’s reasonable needs, and insulin must be injected.
\nThere is also the possibility that hyperglycemia was present before the pregnancy; therefore International Association of Diabetes and Pregnancy Study Groups (IADPSG) defined the pregnancy hyperglycemia as either ‘overt diabetes’ or ‘gestational diabetes mellitus’ (GDM) [2].
\nConsidering the ascending trend of type 2 diabetes mellitus and obesity from the last decades, GD has intuitively the same tendency [3, 4]. The prevalence of GD is estimated at approximately 135,000 cases per year in the US [5], representing on average 3–8% of all pregnancies [6]. It is estimated that the prevalence of GD has increased by 10–100% in several racial groups during the past 20 years, increasing direct and indirect healthcare costs [5].
\nThe goal of treatment for women with GD (recommended by both American Diabetes Association-ADA, and the American College of Obstetricians and Gynecologists-ACOG) is a fasting plasma glucose level <95 mg/dl, a 1-hour post-prandial glucose level of less than 140 mg/dl and a 2-hour post-prandial glucose level of less than 120 mg/dl, whereas for the HbA1c the target is <6–6.5% (42–48 mmol/mol); lower HbA1c—6% (42 mmol/mol) is optimal if it can be achieved without significant hypoglycemia; also, the target may be relaxed to 7% (53 mmol/mol) in order to prevent hypoglycemia [7, 8].
\nAfter diagnosis GD, to reach the goals for plasma glucose levels, the first step is the initiation of a lifestyle intervention program (including medical nutrition therapy—MNT and physical activity—PA).
\nMNT is the cornerstone of the GDM treatment. MNT alone can assure glycemic targets in 80–90% of GDM patients [9]. Maternal height and weight are key factors for the medical nutrition therapy, providing adequate calories and nutrients for both maternal and fetal nutrition, maintaining glycemic targets and the absence of ketones with appropriate weight gain [10, 11, 12]. For a GDM mother with a normal body mass index (BMI) of 18.5–24.9 kg/m2, the number of adequate calories is about 30 kcal/kg [9]. Nevertheless, since more than 60% of women diagnosed with GDM are overweight or obese, a caloric restriction is needed. The ADA states that no research identifies a specific optimal calorie intake for women with GDM and that the calorie needs are no different from those of pregnant women without GDM [7]. Therefore, ADA issued only general recommendations (following the dietary reference intakes) for 175 g of carbohydrate, 71 g of protein, 28 g of fiber, emphasizing the importance of the amount and type of carbohydrate with significant impact concerning the glucose levels, especially postprandial glucose peak [7]. ADA recommends individualized nutrition plan developed by a registered dietitian familiar with the management of GDM [7]. The National Institute for Health and Care Excellence (NICE) guidelines recommend a healthy diet, emphasizing the importance of low glycemic index foods (that should replace those with a high glycemic index) for GDM women; also there is the recommendation for a dietitian when GDM is present [13].
\nThe carbohydrate intake should be reduced to 33–45% of the total calories, and distributed over 3 meals, and 2–4 snacks/day, thus reducing postprandial glucose peak [8, 14], while as the rest of the calories should be divided between protein (20%) and lipids (40%) [15].
\nExcessive weight gain during pregnancy should be avoided for GDM women [16]. The weight gain during pregnancy depends on pre-pregnancy BMI:
\n12.5–18 kg of weight gain for underweight women (BMI <18.5 kg/m2);
11.5–16 kg for normal weight (BMI 18.5–24.9 kg/m2);
7–11.5 kg for overweight (BMI 25–29.9 kg/m2)
5–9 kg for obese (BMI ≥30.0 kg/m2) [17]
Physical activity improves glycemic control in GDM women. The generally accepted recommendation is daily moderate-intensity regular exercise (walking 30 minutes/day or more—if no medical contraindications) improves blood glucose control [13, 14].
\nPharmacological treatment is recommended when lifestyle intervention does not reduce hyperglycemia to reach the glycemic target. There is no international consensus on when to start pharmacological treatment of GDM [18]. The Canadian Diabetes Association (CDA) and NICE guidelines, both recommend beginning pharmacological treatment if glycemic control is not achieved after 1–2 weeks of lifestyle intervention [13, 19].
\nOral antidiabetic medication has been described in a previous chapter. The authors want to resume the most important clinical implications and the comparisons with insulin treatment.
\nThe use of metformin in GDM after the glycemic target is not reached with lifestyle intervention is recommended by the NICE guidelines [13]. Metformin is classified as a category B drug, which implies that there is no evidence of animal, or fetal toxicity or teratogenicity. In general, metformin appears to be a safe alternative to insulin for the GDM treatment, but it crosses the placenta, and it may be present in a higher concentration in the fetal circulation than in the maternal circulation [19]. Studies were performed for the assessment of metformin exposure in-utero. There is no evidence that the metformin is affecting the fetus with regards to an early motor, linguistic, social, [20], metabolic [20, 21], and neurodevelopmental [22, 23] outcomes, but long-term follow up studies are needed. The metformin was associated with a lower risk of neonatal hypoglycemia and less maternal weight gain than insulin in two systematic reviews [24, 25]. Almost half of the patients with GDM who were initially treated with metformin needed insulin to achieve acceptable glucose control [26]. Metformin remains an option as a second line treatment in GDM women who refuse insulin treatment or who are unable to administer insulin safely.
\nGlyburide (glibenclamide) was associated with increased birth weight, macrosomia and neonatal hypoglycemia compared with insulin [20, 25], and similar to metformin, crosses the placenta [27]. Glyburide therapy during pregnancy is not recommended as first- or second-line treatment, but it may be used as third-line treatment if insulin is refused, and metformin is either refused or insufficient to reach targeted glycemic control [19].
\nThere is no human data for the use of any other antihyperglycemic medication in the treatment of GDM (DPP-4 inhibitors, GLP-1 receptor agonists or SGLT2 inhibitors) [19]. Patients treated with oral therapy should be informed that they cross the placenta. No adverse effects on the fetus have been demonstrated; long-term studies are lacking [7].
\nInsulin is the first-line antihyperglycemic medication recommended for treatment of GDM [7, 19]. None of the currently available insulin preparations has been demonstrated to cross the placenta [7]. If glycemic control is not achieved after 1–2 weeks of lifestyle intervention, insulin treatment should be initiated [19]. Insulin remains the gold standard treatment for GDM women that do not reach glycemic targets with lifestyle intervention, as recommended by several guidelines (see Table 1 below). Insulin use reduces fetal and maternal morbidity [28, 29].
\nInternational Federation of Gynecology and Obstetrics (FIGO), 2015 | \n\n
| \n
Canadian Diabetes Association (CDA), 2018 | \nIf glycemic control is not achieved in 2 weeks after the initiation of medical, nutritional intervention | \n
American Diabetes Association (ADA), 2018 | \nFirst line therapy if glycemic control is not achieved after diet intervention | \n
American College of Obstetricians and Gynecologists (ACOG), 2018 | \nFirst line therapy if glycemic control is not achieved after diet intervention | \n
Insulin initiation recommendations.
Regular insulin (U-100, U-500) is identical to human insulin, and it is used as mealtime insulin to cover postprandial hyperglycemia. Its time to onset is about 30 minutes (10–75 minutes), the peak effect is in 3 hours (2.5–5 hours), and the effect ends at about 8 hours (up to 24 hours for U500). The FDA pregnancy category is B [30].
\nHuman insulin inhalation (nasal insulin) is equivalent unit-for-unit to insulin lispro. Its onset is 15 minutes, and its peak action time is ∼50 minutes. Duration of action is about 2 hours. Inhaled human insulin carries a boxed warning for bronchospasms in patients with chronic lung disease. It is a pregnancy category C drug [30].
\nAnother analog of human insulin is insulin aspart produced from Saccharomyces cerevisiae, a type of yeast. Aspart should be taken 5–10 minutes before a meal. It can be used like for multiple subcutaneous injections or in insulin pumps. Its peak action time is 40–50 minutes, and its duration of action is 3–5 hours. Insulin aspart produce less hypoglycemia than the regular insulin [31]. The FDA pregnancy category is B and can be used in pregnancy. Data from two clinical trials (349 exposed pregnancies) do not indicate any adverse effect on pregnancy or fetal/neonatal health compared with human insulin [30].
\nInsulin aspart was introduced on the market with nicotinamide and L-arginine hydrochloride as excipients to enhance its absorption. Although the active molecule is identical, there are no available data for its use in pregnancy and its excretion in human milk [30].
\nInsulin lispro (U-100 and U-200) is an analog produced in Escherichia coli cultures. Its onset of action is 10–15 minutes. The peak is at 30–90 minutes, and its duration of action is 3–4 hours. Also, it can be used in insulin pumps or pens. The U-100 and U-200 formulations have the same bioequivalence and pharmacokinetics. The FDA pregnancy category is B and can be used in pregnancy. The data from a large number of exposed pregnancies do not indicate any adverse effect on pregnancy or fetal/neonatal health [30].
\nInsulin glulisine is a recombinant insulin. It is obtained using Escherichia coli. It works fast nearly in 10–15 minutes. Its peak installs in 55 minutes, and its full duration is 4–5 hours. Although it can be used in some insulin pumps, it is not approved for all pump brands. The FDA pregnancy category is C. In this case, the vigilance should be given when prescribing glulisine to pregnant women, and the drug should only be used if the potential benefit justifies the potential risk to the fetus. There are limited data (less than 300 pregnancy outcomes) from the use of insulin glulisine in pregnant women [30].
\nInsulin isophane (NPH) is an intermediate-acting insulin. It is also produced in Escherichia coli. It is similar to human insulin and is presented in a liquid suspension. Its onset of action is maximum 2 hours, with an average peak of 4 hours. NPH full duration of action is 10–20 hours. No restrictions on use in gestational diabetes or pregnancy; do not cross the placental barrier. The FDA pregnancy category is B [30].
\nInsulin detemir (U-100) is a long-acting analog produced in Saccharomyces cerevisiae. Detemir insulin lacks a defined peak and lasts for up to 24 hours, and time to onset of action can be 1–2 hours. The detemir insulin has less incidence of hypoglycemia compared to NPH regimen in pregnant women [32]. The FDA pregnancy category is B; considered during pregnancy. The potential benefit must be considered against the possible increased risk of adverse pregnancy outcomes. One clinical trial suggests a possible increased risk of serious adverse maternal outcomes compared with isophane insulin and data from an additional 250 outcomes from pregnant women exposed to insulin detemir suggest no maternal or fetal/neonatal toxicity [30].
\nInsulin glargine (U-100) is a long-acting analog produced in Escherichia coli. The acidic solution is neutralized in subcutaneous tissue, and micro precipitates are formed. These micro precipitates slowly release glargine over 24 hours. Its onset of action is 1–2 hours, its duration of action are 24 hours and has no peak. The FDA pregnancy category was previously C, no human pregnancy data. May be considered during pregnancy, if necessary, but we do not have clinical data on exposed pregnancies from controlled clinical studies available. The data from pregnant women (between 300 and 1000 pregnancy outcomes) indicate no adverse effects on pregnancy, nor malformations or feto-neonatal toxicity [30].
\nInsulin glargine (U-300) is a long-acting insulin. It is not bioequivalent to glargine U-100, but it had the same structure and was approved in February 2015. Glargine U-300 is produced in Escherichia coli. Its peak action develops over 6 hours and continues for an entire 24 hours. The serum concentrations decline after 16–36 hours. It is dosed once daily. There is no clinical experience until now with the use of insulin glargine (U-300) in pregnant women [30].
\nInsulin degludec U-100 and U-200 are considered bioequivalent. The insulin degludec’s mode of slow absorption and prolonged action is based on the formation of soluble multi-hexamers. Insulin degludec onset of action is nearly 1 hour and has no peak. It is dosed once daily. It can be dosed at any time of the day because of its long duration of action. There is no clinical experience in pregnant women [30].
\nThere are many insulin regimens proposed for treating hyperglycemia, but the multiple daily injections (MDI) is by far the most efficient and the most flexible [33].
\nThe insulin regimen should be chosen based on the blood glucose profile. Therefore, if fasting glycaemia is higher than 90–95 mg/dl, basal insulin should be initiated. It can be a long-acting insulin analog or neutral protamine Hagedorn. The basal insulin dose can be calculated according to the weight: 0.2 units/kg/day.
\nIf the hyperglycemia follows a meal, than rapid-acting insulin or regular insulin should be initiated before that m74eal (begin with 1 u of insulin for 10–15 g of carbohydrates).
\nSometimes both fasting and postprandial glycaemia are elevated, thereby needing MDI: 3 mealtime insulin and basal insulin. The total daily insulin requirement during the first trimester, is 0.7 units/kg/day, while in the second trimester it is 0.8 units/kg/day, and in the third trimester, it is 0.9–1.0 units/kg/day. This does not necessarily fit all pregnancies. Usually, in pregestational diabetes, the total insulin dose is up to twice higher than in GDM.
\nIn the case of morbid obesity, the initial doses of insulin can be increased to 1.5–2.0 units/kg to overcome the combined IR of pregnancy and obesity [9].
\nUsually, the calculated total daily dose of insulin should be divided in two as for type 1 and type 2 diabetes: 50% as basal insulin at bedtime, and 50% divided between 3 meals and given as rapid-acting, or regular insulin before meals.
\nThe doses of insulin have to be continuously optimized, so the self-monitoring blood glucose is essential.
\nRapid-acting insulin analogs are preferred over regular insulin in pregnancy because there is a lower risk of hypoglycemia, and because they provide a better postprandial blood glucose control [29, 33].
\nInsulin initiation is synthesized in Table 1.
\nBlood glucose control in important in gestational diabetes because it confers the future mother a sense of disease control and validation that diet and treatment are doing their effect as the glycemic control improves, the risk of maternal and fetal complications decreases, a principle that was demonstrated by HAPO study results [34]. The results of this landmark study and other seven randomized trials have been included in a Cochrane analysis that compared the treatment of gestational diabetes mellitus (GDM) with standard care. It demonstrated a lower risk of a composite endpoint (death, shoulder dystocia, humerus, clavicle fracture or nerve palsy), and also a lower risk of pre-eclampsia and macrosomia (birth weight over 4000 g or 90th percentile), with no differences between oral and injectable treatment [35].
\nThereby, gestational auto monitoring and surveillance by an obstetrician in collaboration with the diabetologist, nutritionist and midwife is essential for achieving glycemic targets during pregnancy, labor and after birth. These targets are synthesized in Tables 2 and 3.
\n5th International Workshop Conference Gestational Diabetes and International Association of Diabetes and Pregnancy Study Group, 2007 | \nCapillary pre-prandial glucose <95 mg/dl (5.3 mmol/l) Capillary 1 hour post-prandial glucose <140 mg/dl (7.8 mmol/l) Capillary 2 hour post-prandial glucose <120 mg/dl (6.7 mmol/l) | \n
FIGO, 2015 | \nCapillary pre-prandial glucose <95 mg/dl (5.3 mmol/l) Capillary 1 hour post-prandial glucose <140 mg/dl (7.8 mmol/l) Capillary 2 hour post-prandial glucose <120 mg/dl (6.7 mmol/l) | \n
CDA, 2018 | \nCapillary pre-prandial glucose <95 mg/dl (5.3 mmol/l) Capillary 1 hour post-prandial glucose <140 mg/dl (7.8 mmol/l) Capillary 2 hour post-prandial glucose <120 mg/dl (6.7 mmol/l) | \n
ADA, 2018 | \nCapillary pre-prandial glucose <95 mg/dl (5.3 mmol/l) Capillary 1 hour post-prandial glucose <140 mg/dl (7.8 mmol/l) Capillary 2 hour post-prandial glucose <120 mg/dl (6.7 mmol/l) | \n
Glycemic targets during pregnancy.
FIGO, 2015 | \nCapillary glucose 72–126 mg/dl (4–7 mmol/l) | \n
ACOG, 2018 | \nCapillary glucose 70–110 mg/dl (3.9–3.1 mmol/l) | \n
Glycemic targets during labor.
Although glycated hemoglobin values must be interpreted with caution in patients with dilution anemia, iron deficiency anemia or other hematological pathologies like minor thalassemia [36, 37], it proves to be useful in checking the self-reported date by the pregnant, especially if she is treated with insulin.
\nOther parameters that could be used for short-term (2–3 weeks) evaluation of blood glucose control is glycated albumin. It is not influenced by iron deficiency, but the values are low in nephrotic syndrome or thyroid disorders that sometimes are present in pregnancy. This marker was studied in GDM, but the cutoff limits are not precisely known with consideration of some population differences [38]. Molecules like fructosamine or 1,5-anhydroglucitol have not proven their utility [39, 40, 41].
\nThe efficiency of capillary blood testing (8 determinations per day) in pregnant diabetes patients has been demonstrated since the 1980s [42]. Current guidelines [7, 8, 12, 18] mention in general terms the frequency and optimal period (fasting, 1 or 2 hours postprandial) when a test should be done without customizing for treatment, previous glycemic control.
\nIn healthy adult pregnant women, 1-hour glycemia during a glucose challenge test was a better marker for insulin sensibility, being correlated with a fetal abdominal circumference in echography [43]. In Jovanovic and collab study [42], glycemia at 1 hour after food intake in the third trimester was the best predictor for birth weight. Combs et al. used the same 1-hour glycemia to establish the best threshold (130 mg/dl) for which the risk for macrosomia and small for gestational age (SGA) is reduced [44]. Metzger was the one that proposed that 2-hours postprandial glycemia should be used in GDM with the limit of 120 mg/dl [34]. Two clinical studies compared the blood glucose determination concluding that 1-hour glycemia is superior, but with two important biases—lack of randomization and low statistical power [45, 46].
\nA randomized clinical trial demonstrated that patients who adjusted insulin doses based on 1-hour postprandial glycemia had a lower risk of giving birth to a macrosomia, or to have a cesarean procedure; also, the risk for neonatal hypoglycemia was smaller [47]. Not only the glycemic values per se is important, but also the pregnant women with GDM should be taught to estimate their carbohydrate intake and physical activity and adjust the insulin doses. Other factors that cannot be influenced are a hormonal secretion from the placenta, daily cortisol secretion variability that contributes to glucose excursions. Sivan et al. observed in their study a pattern in which 1-hour postprandial glycemia is abnormally raised in the morning, and 2 hours postprandial glycemia is abnormally raised in the evening [48].
\nThe frequency of determination is as much as necessary. Based on a randomized control trial (RCT) the initial recommendation for SMBG is 4 tests per day, with the possibility to lessen the number of determinations according to if the patient has good control and the fetal morphology is normal [49]. In basal-bolus insulin-treated GDM 7 tests per day are recommended, but patient adherence is weak (a mean of 4.2 in an observational study) [50].
\nThe limit for SMBG consists in the accuracy bias: lowering hematocrit by dilution makes the capillary glucose to be overestimated. Some glucometers have included in their software functions to correct the hematocrit values, but the majority uses colorimetric and amperometric methods that depend on it. Considering the tight glycemic control required during pregnancy and the fact that insulin doses are adjusted based on SMBG, some researchers recommend that the bias and imprecision should be set at below 2% and the meters be verified according to international quality criteria [51].
\nSystems for interstitial glucose monitoring have been used together with insulin pumps in type 1 diabetes pregnancies in RCTs and observational studies [52, 53]. In GDM pregnancies data come from small observational studies where they showed benefit for disclosing high and low glycemic excursions missed by SMBG [54].
\nGlycemic sensors can be used as a guide for therapy initiation, as demonstrated by Kestilä et al. [55]. The anti-diabetes medication was introduced in a higher proportion of GDM women with CGMS versus SMBG. Nevertheless, there were not any significant differences for the perinatal endpoints. The long-term impact of glycemic control during pregnancy is not known; therefore, the benefit of this intervention must be balanced with unnecessary treatment. The techniques for monitoring blood glucose are summarized in Table 4.
\nRegimen | \nSBGM | \nCGMS | \n
---|---|---|
GDM with diet or oral antidiabetics | \nFasting 1 hour postprandial | \nFine-tune insulin dosing Nocturnal hypoglycemia Nocturnal hyperglycemia Postprandial hyperglycemia | \n
GDM with basal insulin | \nFasting | \n|
\n | 1 hour postprandial | \n|
\n | Bedtime | \n|
GDM with premixed insulin | \nFasting | \n|
\n | 1 hour postprandial | \n|
\n | Dinner preprandial | \n|
\n | 1 hour postprandial | \n|
GDM with basal bolus | \nFasting | \n|
\n | Preprandial (lunch, dinner) | \n|
\n | 1 hour postprandial | \n
Insulin glucose monitoring techniques [adapted from American Association of Clinical Endocrinologist and American College of Endocrinology].
All these efforts in using the best method for monitoring insulin therapy in GDM are to maintain glycemic control for preventing fetal and maternal complications.
\nGlucose is a nutrient that freely crosses the placenta from maternal to fetal circulation, to assure the energy required for growth. Immediately after birth, the glucose source disappears with a physiologic “hypoglycemia” in the blood of the newborn that triggers the secretion of counterregulatory hormones (glucagon, steroids, catecholamines, growth hormone). In GDM pregnancies, the glycemia is continuously raised and determines a consecutive higher secretion of insulin that makes hypoglycemia more severe and prolonged than in normal newborns [56, 57, 58, 59].
\nNeonatal transient hypoglycemia could have implications in the neurocognitive development as was shown by magnetic resonance imaging [60]. Also, it has psychological implications on the mother-child relationship because they are separated after birth for treatment. Hence, based on their study results, Voormolen et al. recommend screening all newborns from GDM women in the first 12 hours after birth because the majority of the events occur in this interval, with a higher incidence being in the insulin-treated group [58].
\nA series of studies demonstrated that newborns of GDM patients that were treated with metformin had fewer hypoglycemic events than those of women treated with insulin [21, 61]. Insulin analogs have a lower rise in postprandial glycemic values without elevating hypoglycemic risk and should be preferred to human insulins [29, 33].
\nRegarding sulfonylureas, a meta-analysis demonstrated that glyburide treatment GDM had a higher risk of neonatal hypoglycemia and also macrosomia that the metformin-treated GDM [62].
\nThe relationship between insulin therapy and congenital anomalies was studied, especially in type 1 diabetes. The most important confounding factor is glycemic control. Although some case reports indicate an association between the use of insulin lispro and the risk of teratogenesis [63], another meta-analysis supports the fact that it is safe for use [64]. This risk could be explained by mitogenesis stimulation by binding with a higher affinity for IGF-1 receptors. Lispro insulin has a 1.5 and insulin glargine a 6.5 fold increase of receptor binding [65]. There are only retrospective studies that indicate glargine as safe insulin in pregnancy [66].
\nA Cochrane analysis of 1481 women with GDM showed that in the treatment group there was a higher number of induced labors versus the group with standard antenatal care, but with no difference regarding the number of births by CS [35]. Another meta-analysis did not demonstrate a correlation between the use of different types of insulin-like aspart, lispro and the birth by CS [67, 68]. Although the risk is not influenced by insulin treatment, it can be reduced by induction of labor (IOL) in 38th–39th week of gestation with better outcomes for the fetus [69].
\nAlthough pre-gestational diabetes raises the risk for vacuum assisted birth (shoulder dystocia, humerus, clavicle, skull fracture, Erb’s palsy, subarachnoidian or subdural hemorrhages, asphyxia, convulsion), in GDM the risk was similar to that in the general population and could not be related to insulin therapy [68, 70]. A particular situation is with GDM that appeared in pregnancies obtained by assisted reproductive technology where the risk for perinatal and obstetrical complications is probably increased by the adverse effect of hyperglycemia, not by insulin treatment [71].
\nEvidence that indicates a higher risk for fetal morbidity and mortality in GDM a scarce and less pronounced as in pre-gestational diabetes. Current decisions of IOL as compared to expectant management should be individualized because the studies lack in this area. An RCT that showed that there is no difference between the two strategies regarding morbidity, but the IOL reduces the risk for shoulder dystocia in the macrosomic fetus [72]. The use of insulin analogs like detemir does not influence the morbidity [73].
\nHypoglycemia threshold is specific for every individual. In pregnancy, there is a reduction of this threshold by 20% [74]. Patients with GDM that are treated with insulin must maintain a glycemia above 3.7 mmol/l (66 mg/dl) according to CDA, or above 3.9 mmol/l (70 mg/dl) according to ADA [7].
\nInsulin analogs are superior to human insulin because the hypoglycemic events are less frequent in type 1 diabetic pregnancies [75]. The use of multiple daily injections is as effective as continuous subcutaneous insulin infusion [76].
\nMaternal hypoglycemia affects the fetus just in severe cases when is associated with loss of consciousness or secondary to trauma. Also, it was observed that repeated episodes could lead to growth over the 90th percentile [77]. These episodes are more likely to be present in the first trimester in women who had pregestational diabetes than in GDM [74].
\nThere is moderate quality evidence that indicates higher hypertension associated hypertension without giving details in insulin-treated GDM. This fact should be further researched because it is in contradiction with a non-modified risk for pre-eclampsia [68].
\nDuring the latent phase of labor hepatic gluconeogenesis is sufficient for providing the caloric requirements, but becomes exiguous during the active phase when intravenous glucose is perfused.
\nThe study of Rosenberg and collab. demonstrated there is no significant difference in neonatal hypoglycemia, neonatal injury, Apgar score at 1–5 minutes in patients with insulin therapy that were managed with two approaches: dextrose 5% 125 ml/h with a simultaneous insulin drip (adjustable rate 0.5–2.5 u/h) or dextrose 5% alternating with ringer lactate (125 ml/h) and insulin introduction when the targets are exceeded [77]. Other researchers recommend dextrose 10% with an insulin drip [78].
\nLowering maternal glycemia is necessary for preventing neonatal hypoglycemia, balancing this risk with that for ketosis. Capillary blood glucose should be tested every hour and urinary ketone bodies every time is possible [77]. ACOG agreed to the protocol proposed by Coustan [79] for maintaining a mean intrapartum glycemic value of 100 mg/dl. For this, blood glucose should be tested every 2 hours with adjustments in insulin perfusion rates.
\nWomen with GDM or type 2 diabetes, which were treated with oral therapy have a low insulin requirement and in most cases do not need treatment during labor. Thus, CDA recommends a “watchful waiting” and insulin initiation just in cases where glycemia is above 146 mg/dl (7.0 mmol/l) [19]. Ryan mentions the same principle in a review published before—if GDM pregnant had a necessary below 0.5 u/kg/day, they could be initially monitored. Otherwise, patients with type 1 diabetes or type 2, GDM with a necessary above this limit will need insulin perfusions [78]. Insulin perfusion rates could be adjusted using sliding scales as proposed by Dude [80].
\nAlthough most of the studies use protocols for intravenous insulin administration, patients with insulin pumps can choose to keep their device during labor [81, 82]. This is recommended in centers with experience because during labor they can become unable to handle the pump given the pain, or some incidents like catheter avulsion could appear. In these cases, the patient is informed that a switch to an insulin drip is needed [19].
\nAnother problem comes out when betamethasone is administered for premature birth. In patients with type 1 diabetes, an increase up to 40% of all doses during the next 5 days assures an adequate glycemic control [83]. A retrospective analysis of insulin drips in pregnant with GDM injected by a standard anticipatory protocol and with higher doses was associated with improving glycemic variability and decreasing by 25% the absolute risk for neonatal hypoglycemia [84].
\nInsulin requirements drop quickly after giving birth and women are exposed to hypoglycemia. Patients with GDM usually do not need insulin, and women with type 1 and type 2 diabetes return to the previous regimen, but at doses that are at 60% of the antepartum necessary [85]. In the case where the doses are not remembered, half of the third-trimester dose could be injected. Another alternative is calculating dose per kilogram. With an insulin pump, the doctor will titrate downward the basal rate and boluses on a similar algorithm or adjust based on the information from glucose sensors for newer models.
\nBreastfeeding influences insulin sensibility: as the frequency of lactation increases, the HOMA and ISI (0, 120) have better values [86], so during breastfeeding the insulin requirement falls by 10% [87].
\nThere is a lot of missing evidence in optimal treatment for GDM. Insulin treatment could be improved by developing automatic algorithms for calculating the appropriate doses like that proposed by Dinglas [88]. Moreover, fetal morbidity can be influenced by better monitoring like using glucose sensors that are more accurate in the hypoglycemic range [89, 90, 91].
\nMicro-RNAs are now extensively studied in different domains and might apply to diagnosing and selecting GDM patients that require insulin treatment [92].
\nNot eventually, the whole perspective of insulin therapy will change if the oral bioavailability of this peptide hormone will be enhanced. Polymeric nanocarriers and mucoadhesive discs were studied in diabetic rats and are the future expectation for mothers with diabetes [93].
\nAll authors had an equal contribution and shared the first authorship.
\nNone.
This chapter was financed by Novo Nordisk.
\nNonclassical photon sources are fundamental resources for researches in quantum information science and technology (QIST), which are widely used for applications like quantum communications, computations, sensing, and studying fundamental physics of quantum mechanics [1, 2, 3]. Therefore the ability to generate and manipulate single photon determines how far we can go in QIST. Generally, there are two distinct methods for generating single photons: one is based on excitation-reemission of photon in a semiconductor quantum dot [4], a single defect in NV center [5], or a single atom [6]; another convenient method is based on spontaneous emission based on a second- [7] or a third-order nonlinear process [8]. In this chapter, we will focus on single photon generation by using nonlinear processes. Usually, there are two nonlinear processes for generating nonclassical photon pairs: (1) spontaneous parametric down-conversion (SPDC), which is a second-order nonlinear process; (2) spontaneous four-wave mixing (SFWM), which is a third-order nonlinear process. In both SPDC and SFWM, energy, linear momentum, and angular momentum conservations should be fulfilled. Due to these conservation laws and the technology of quantum interference used, two photons in each pair generated in SPDC and SFWM can be correlated in various degrees of freedoms, for example, polarization, energy-time, orbital angular momentum, position-linear momentum, angular momentum, and photon number and path [1]; we can utilize these freedoms in a specific application scenario in QIST.
\nIn the subsequent section, we will first introduce the basic principle of SPDC and SFWM for generating photon pairs and then the various materials used for SPDC and SFWM. In the key part of this chapter, we will review the developments of various entangled photon pair sources and methods for charactering these sources. After that we will introduce a nonlinear method for transducing the wavelength of the photon from one to another while keeping its quantum properties unchanged, which is suitable for building up a quantum interface to connect different quantum systems. Finally, we will give a brief summary in which some future perspectives for nonclassical photon pair generation and potential applications are discussed.
\nSPDC is realized in a second-order nonlinear process (see Figure 1 left image), in which a pump photon at higher frequency (ωp\n) is split into two daughter photons at lower frequencies with certain probability in a nonlinear crystal; these two daughter photons are usually called signal (ωs\n) and idler (ωi\n) photons. The conservation laws of energy, linear momentum, and angular momentum require that the frequency, linear momentum (k), and angular momentum (l) of the pump, signal, and idler photon fulfill the following conditions: ωp = ωs + ωi\n; kp = ks + ki\n; lp = ls + li\n. These conservation laws are responsible for the generation of various entangled sources.
\nA simple diagram for SPDC and SFWM. The conservation of energy, linear momentum, and angular momentum holds in both nonlinear processes.
In correspondence to SPDC, SFWM is a third-order nonlinear process; a big difference is that there are two pump beams in SFWM (see Figure 1 right image), in comparison to SPDC in which only one pump beam is used. The conservation laws in SFWM require that the corresponding parameters of the pump, signal, and idler photons have the following relationships: ω\n\np1 + ω\n\np2 = ωs + ωi\n; k\n\np1\n+ k\n\np2 = ks + ki\n; l\n\np1\n+ l\n\np2 = ls + li\n.
\nFor quantum optical description of SPDC and SFWM, the Hamiltonian of the two processes can be expressed as [9]:
\nwhere ξ depends on the pump intensity, the nonlinear coefficient of the crystal, crystal length, and focusing parameters. Therefore the photon states generated in SPDC and SFWM can be expressed in Fock state basis as [9]:
\nIt can be seen from Eq. (2) that we obtain a vacuum state with a high probability if the pump is weak. The second term is the photon pair state we need, and the other terms are multiphoton states which should be avoided. It is clear from Eq. (2) that the pump beam should be at a moderate intensity level in order to eliminate the effects of higher photon number states. The photon pair generated in SPDC and SFWM is of probability and is undetermined, which is a disadvantage for photon sources generated from nonlinear processes. For this reason, one needs to choose a proper pump intensity level in order to balance between different experimental parameters.
\nAll materials have third-order nonlinearity, but only those materials that are central asymmetric have second-order nonlinearity. The commonly used materials for SPDC can be divided into two kinds according to different phase matching: one is birefringent angle phase-matching materials, such as LBO, BBO, KTP, and LN [10]; another is quasi-phase-matching (QPM) crystals such as PPKTP and PPLN [11]. QPM crystals have the advantages of high generation rate and narrow bandwidth, which are frequently used in photon pair generation in modern quantum optics experiments [12, 13, 14, 15, 16, 17, 18, 19]. For SFWM, the commonly used materials are hot or cold atomic ensembles [20, 21, 22, 23, 24] and guided-wave materials such as dispersion-shifted fibers (DSF) [25, 26, 27, 28, 29], photonic crystal fibers (PCF), [30, 31, 32], and silicon-on-insulator (SOI) waveguide [33, 34, 35, 36, 37, 38, 39, 40, 41]. To look for new kinds of nonlinear materials for generating high-quality photon sources is still a very hot topic in QIST.
\nBecause of the conservation of energy, linear momentum, and angular momentum in SPDC and SFWM, various kinds of nonclassical sources can be generated; in this section we will review the recent development and key points in generating various kinds of nonclassical photon sources.
\nA polarization-entangled photon source (PEPS) is one of the most important entangled photon sources that have been studied for decades of years. In the literatures, people generate PEPS using different materials with different experimental configurations [12, 13, 14, 15, 16, 17, 18, 19, 42, 43]. For SPDC, in the early times, PEPSs are created using birefringence phase-matching (BPM) crystals, for example, a type-II phase-matched BBO crystal is used to create a PEPS in the first practical and effective experiment, in which orthogonal polarized photons are emitted at the intersection cones [42]. Later on, a beam-like design is used for high-brightness photon pair generation, which is widely used in multiphoton quantum experiments [44]. The significant progress in nonlinear crystal fabrication makes a QPM crystal a better choice for researchers in many nonlinear optics applications [11]. The most important merit of using QPM crystals in generation photon pairs is its high spectral brightness in contrast to BPM crystals, due to its large effective nonlinear coefficient and long allowable interaction length.
\nRecently, to generate PEPS by placing a QPM crystal inside a Sagnac interferometer configuration has been demonstrated to be superior to other configurations (see Figure 2). The basic idea for a Sagnac loop-based PEPS is as the following: a pump beam is split into two beams by a double polarized beam splitter (DPBS) and counter-propagates in the Sagnac loop; each beam generates a pair of photon with orthogonal polarization, in one circulation direction; the photon pair is rotated by a double half wave plate; then two pairs of photons are recombined in the DPBS; and a PEPS with a form of \n
The experimental setup for a typical polarization-entangled source based on Sagnac interferometer (figure cited from [13]).
In SFWM, PEPS is generated using an atomic ensemble with different configurations. The PEPS generated with the atomic ensemble has narrow bandwidth; the wavelength is fixed to specific atomic transition lines [50, 51]. Many works report PEPS generation based on guided-wave materials such as DSF [8, 25, 27, 28], PCF [30], and SOI waveguide [37, 52], the advantages of using guided-wave materials are free of free-space coupling, low loss, low cost, and easy to integrate. The guided-wave platform is very promising in large-scale applications which require hundreds of optical components. It is also convenient for building up a compact, versatile photonic source platform for various kinds of applications in QIST.
\nBecause of conservation of energy in nonlinear processes, the two photons in each pair generated are correlated in frequency and are also generated simultaneously. Although the uncertainty in time and frequency domain for individual particle should meet the requirement of uncertainty principle, the sum of the frequency of signal and idler multiplies the difference between arrive times of the two photon should have a very small value, and violates an inequality for two photons existed classical correlations [53]. A two-photon Franson-type interference is used to characterize the correlations between the two photons; the phases between the two unbalanced Michelson interferometers (UMI) are correlated [54, 55]. To generate a time-energy entangled photon pair, a laser with long coherent time is needed (see Figure 3(a)); the time difference between two paths in UMI should be much larger than the coherence time of the single photon but much shorter than the coherent time of the pump laser [53]. A similar kind of entangled photon source is a time-bin entangled photon source [56], in which a pulse pump is split into two pulses in an UMI, and then these two pulses have a certain probability to generate a pair of photon separately; the photon pairs generated by these two pulses are indistinguishable after passing through two UMIs (the time difference of the UMI in measurement part is the same as the UMI in pump part, see Figure 3(b)). The quantum states for a time-energy or a time-bin entangled photon source can be expressed as \n
Simplified diagrams for (a) time-energy; (b) time-bin entangled photon generation. A narrow bandwidth CW laser is used for generating of time-energy entangled photon pair, while a pulse laser is used for generating time-bin entangled photon pair.
Another important degree of freedom of photon is orbital angular momentum (OAM), which has been widely investigated since 1992 [59]. OAM has unbounded dimensions, which is very promising for high-capacity communication task in both classical and quantum optical communications [60, 61, 62]. OAM entangled photon pairs can be generated in SPDC and SFWM based on crystals [48, 63, 64, 65, 66, 67, 68, 69] and atomic vapors [70, 71]. The quantum state for an OAM entangled photon pair generated directly by pumping a nonlinear crystal (Figure 4, left image) can be expressed as \n
Generate HD OAM entangled state directly from SPDC (left image); 2D OAM entangled state generation by converting a polarized entangled state into 2D subspace of OAM entangled state (right image, cited from [48]).
Nonclassical photon sources can be characterized from different aspects. For characterizing the properties of a heralded single photon, the heralded efficiency [72], the coincidence to accidental coincidence ratio (CAR) [73], and the single photon Glauber function [74, 75] are important parameters. The heralded efficiency is the probability of detecting the second photon when the first photon is detected. It is a measurement of the photon collection efficiency, filter and transmission losses, and the single photon detector efficiency. The heralded efficiency is the ratio of the coincidence count to the single count rate of the first detected photon. CAR is a measurement of the signal to background noise ratio for a two-photon experiment; high CAR can ensure the quantum nature existed between the two photons. CAR depends on pump power and detector performance. Usually, CAR will increase when the pump power is increased in the low pump power regime. After reaching the maximum value, CAR will decrease with the increase of the pump power [76]. The single photon Glauber function can be measured as shown in [74]. The measured photon is firstly split by a beam splitter, and then by measuring the three party coincidence, single count and two-photon coincidence, we can calculate the single photon g(2) function (see Figure 5). A near zero g(2)(0) indicates the high quality of single photon nature. For a pulse pumped photon source, the single photon purity is also an important parameter [17, 77]. The purity of photon is a measurement of spectral correlations between two photons; the purity is determined by the Schmitt number in the Schmitt decomposition. The unity single photon purity indicates that the two-photon spectral can be factorized into product of two separate functions of the signal and idler photons. The high single photon purity is very important for realizing high visibility HOM interference between two independent single photon sources, which is the key technique for realizing high photon number entangled states.
\nExperimental setup for measuring heralded single photon autocorrelation function for single photon generated from SPDC (image cited from [74]).
There are various available and faithful methods to characterize the quality of entanglement of an entangled two-photon source, including two-photon interference fringes [65, 78], Bell CHSH inequality [79, 80], and quantum state tomography (QST) [81]. Two-photon interference fringe is much easier to measure; through calculating the interference visibility from the measured data, we can evaluate the quality of an entangled source. A high visibility indicates a high quality of the generated state by comparing the ideal maximum Bell states. When the visibility is greater than a threshold value, the two photons have Bell nonlocality; the threshold value is different for two-photon states in different dimension. For two photons existing in classical correlation, the Bell CHSH parameter S is not greater than a certain value. The violation of this value indicates a nonclassical correlation between the two-photon states. Bell CHSH parameter S is an indicator of whether the two-photon state has Bell nonlocality and how strong this kind of nonlocal correlation is. The violation of Bell inequality has been widely studied in literatures for a 2D and a HD entangled state. To fully know the content of a generated quantum state, QST can be used to reconstruct the density matrix of a certain quantum state. By the density matrix of a quantum state, all the properties of the quantum state can be predicted.
\nThere are many quantum systems for QIST based on different materials, including atomic ensembles, trapped ions, solid-state materials, and fibers for transmission [82, 83, 84, 85, 86]. Each quantum system has some advantages in QST, and these systems usually work at different frequencies, which may have a big frequency mismatching. To build up a quantum network consisting of various quantum systems for information encoding, storage, transmission, and processing, a quantum frequency converter (QFC) to link different quantum systems is indispensable. Such a frequency transducer can be realized by utilizing nonlinear processes such as sum frequency generation (SFG) and Bragg reflection in four-wave mixing. The theory of quantum frequency conversion for SFG was first proposed by P. Kumar in 1990 [87]. In SFG, a strong pump laser can convert a weak signal beam with high quantum efficiency; the unity quantum efficiency can be reached when the pump beam is strong enough (see Figure 6 left image), and the quantum correlations are unchanged after frequency conversion. Since it has been proposed, some significant progresses have been made in this field; researchers have realized that frequency up-conversion and down-conversion for a single photon generated from quantum dot, and various qubit states or entangled states such as polarization, time-energy, and OAM entangled state [39, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101] have been up- or down-converted. A typical setup for QFC of an OAM qubit, an OAM-polarization hybrid entangled state, and an OAM-OAM entangled state is shown in Figure 6 (right image). For frequency down-conversion, the visible single photons generated from atomic ensemble, trapped irons, or NV centers have been converted to telecom band successfully [102, 103, 104, 105]. In all these demonstrations, the single photon properties and entanglement are preserved in the conversion processes, which ensures that quantum information can be coupled to different quantum systems by using a quantum frequency interface.
\nLeft image: simple diagram for sum frequency generation in QPM crystal. Right image: experimental setup of QFC for an OAM qubit, an OAM-polarization hybrid entangled state, and an OAM-OAM entangled state (cited from [99]).
In QFC, there are four parameters to evaluate the quality of a converter: quantum conversion efficiency, noise level, spectral bandwidth, and spatial bandwidth. These parameters are not independent; therefore in practical applications, one needs to balance between different parameters [98]. A longer nonlinear crystal is preferred to reach maximum conversion efficiency when the pump power is limited, but a longer nonlinear crystal would lead to a smaller spectral bandwidth and spatial bandwidth; a proper crystal length should be chosen to balance conversion efficiency and spectral bandwidth. The noise in QFC comes from SPDC and SRS of the intense pump beam; therefore a longer pump wavelength is preferred to reduce the noise photon in QFC [106]. The noise photon can also be dramatically reduced by using a narrow bandwidth filters to filter out the converted photon.
\nNonclassical photon sources are used in almost all fields of QIST; the ability to generate and control its properties is at the heart for applications in QIST. Though many progresses have been made in single photon generation and manipulation in nonlinear processes, lots of further techniques should be developed to harness the quality of single photon generated in SPDC or SFWM. The detailed techniques for optimizing the parameter of the photon source depend on the specific applications. For a pulsed heralded single photon source, the heralded efficiency and total photon count are important parameters, but the probability of single photon generation per pulse is very low, which limits the flux of photon pair generation. These defects can be overcome by using time, frequency, and OAM multiplexing to enhance the photon generation probability per pulse and total count rate [41, 107, 108, 109, 110, 111, 112]. When the optical elements for multiplexing have low losses, the heralded efficiency and rate can be increased substantially [112]. For applications taking advantages of the sharp time correlations in SPDC, a broadband spectrum of the photon pair is needed. Such a broadband photon pair can be realized with an ultrathin nonlinear crystal or using a chirp quasi-phase-matching crystal; the bandwidth of the photon pair generated can be greater than 100 nm, which has a time correlation of sub-femtosecond [113]. For quantum information applications, a multiplexed time-energy and polarized entangled photon pair is preferred for high-capacity quantum communication by using dense-wave division multiplexing technique. The multiplexed entangled sources are easier to be realized using a waveguide platform such as a PPLN waveguide, a DSF, or SOI waveguide. A SOI ring cavity is also preferred in generating frequency comb entangled states [114]. For generating HD entangled states, by shaping the profile of a pump beam, a much greater Hilbert space can be reached [115, 116]. For QFC of OAM entangled states, the mode-dependent conversion efficiency has not been solved yet. We recently proposed and demonstrated that if we use a flat-top beam to pump the SFG crystal, then we can solve the problem of mode-dependent conversion efficiency by using a Gaussian pump beam [117].
\nFor a compact application, integrated optics will offer a great advantage over free-space implementation; the trends of modern optics are to convert a free-space module to an equivalent integrated optical device, which will be of high compact, robust to environment fluctuations and much easier for larger amounts of fabrication [118, 119].
\nIn conclusion, most of the advances and progresses for generation and manipulation of single photon sources in nonlinear processes are briefly reviewed in this chapter; this review will provide a glance at the current status, and challenges remain to be solved in this field. The general properties for single photon generation in nonlinear processes are introduced firstly; then we introduce the development of various entangled states and the methods to characterize nonclassical photonic states. Next, we review the progresses for frequency conversion of a photonic state in nonlinear processes. Finally, we give comprehensive discussions about the remaining challenges in generating high-quality and HD entangled states, the unsolved problems for QFC of HD OAM photonic states, and the development of integrated optics for small footprint optical devices and large-scale quantum information processing on chip. This book chapter should be helpful for new researchers working in this field.
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