",isbn:"978-1-83969-150-8",printIsbn:"978-1-83969-149-2",pdfIsbn:"978-1-83969-151-5",doi:null,price:0,priceEur:0,priceUsd:0,slug:null,numberOfPages:0,isOpenForSubmission:!1,hash:"7409b2acd5150a93004300800918b736",bookSignature:"Prof. Karmen Pažek",publishedDate:null,coverURL:"https://cdn.intechopen.com/books/images_new/10548.jpg",keywords:"Lean Manufacturing, Agriculture, Production and Process, Costs Reduction, Lean Principles, Industry, Tools, Implementation, Sustainability, Modeling, Environment, Planning",numberOfDownloads:7,numberOfWosCitations:0,numberOfCrossrefCitations:0,numberOfDimensionsCitations:0,numberOfTotalCitations:0,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"October 20th 2020",dateEndSecondStepPublish:"November 17th 2020",dateEndThirdStepPublish:"January 16th 2021",dateEndFourthStepPublish:"April 6th 2021",dateEndFifthStepPublish:"June 5th 2021",remainingDaysToSecondStep:"2 months",secondStepPassed:!0,currentStepOfPublishingProcess:4,editedByType:null,kuFlag:!1,biosketch:"Dr. Pažek is Head of the undergraduate study program Agricultural economics and rural development and Vice-dean for education. 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\n
1. Introduction
\n
Since Karl Landsteiner discovered the human ABO blood groups in 1901 [1], ABO-incompatible transplantation has been considered as an immunological contraindication because of the risk of forming antibodies against ABO blood group antigens in the grafts, leading to hyperacute rejection followed by the loss of the kidney graft function. In Japan, kidney transplantation (KTx) using deceased donors is uncommon because the number of organ donations is very low. However, the number of end-stage renal disease (ESRD) patients who require a transplant is high. This situation required us to broaden the indications for living-donor KTx.
\n
To expand the use of living-donor transplantation, ABO-incompatible KTx has been performed in Japan since 1989. In recent years, the outcome of ABO-incompatible KTx has improved to the point that it is now in no way inferior to ABO-compatible KTx. The number of cases using incompatible transplants per year now exceeds that using deceased-donor transplants, and incompatible KTx accounts for approximately 30% of all living-donor KTx. As of 2014, more than 3500 patients have been saved by this treatment in Japan.
\n
In this chapter, we review ABO-incompatible transplantation and describe a strategy to overcome antibody-mediated rejection (AMR) after ABO-incompatible KTx.
\n
\n
\n
2. History of ABO-incompatible KTx
\n
The first ABO-incompatible KTx was performed by Yu Yu Voronoy in Ukraine in 1933 on a 26-year-old acute renal failure patient. The recipient with type O blood group received a blood type B kidney graft from a 64-year-old male donor. One of the donor’s kidneys was harvested within 6 h of his death and grafted into the recipient’s femoral region, but the patient died 2 days after transplantation. In this case, the failure of the graft to function was probably due to prolonged ischemic time rather than incompatibility [2]. Thereafter, some cases of ABO-incompatible KTx achieved long graft survival [3,4]. However, in 1967, Gleason and Murray [5] compiled the statistics on KTx, applied statistical analysis to ABO-incompatible cases, and reported very discouraging results.
\n
Some years later, in 1981, Slapak et al. [6] of the University of Portsmouth, UK, published the remarkable finding that plasma exchange effectively reduced acute AMR in a transplant from a deceased donor when, because of a procedural error, the donor and recipient were of incompatible blood types. This was the first report that clearly showed the effectiveness of plasma exchange to remove antibody for ABO-incompatible KTx.
\n
Alexandre et al. [7–10] from Belgium were the first to design a transplantation procedure using plasma exchange for pretransplantation removal of anti-A and -B antibodies. They also strongly emphasized the importance of splenectomy in achieving long-term graft survival. However, at that time, deceased-donor KTx was the mainstream procedure in Europe, and the techniques outlined in Alexandre et al.’s study were not widespread.
\n
In Japan, the number of deceased-donor kidney donations has always been extremely low. KTx is an absolute indication for children with chronic renal insufficiency because of their need for healthy growth and development. Thus, to broaden the indications for living-donor KTx, ABO-incompatible KTx has mainly been developed in Japan since 1989 [11–21].
\n
\n
\n
3. AMR
\n
Anti-A and/or -B antibodies are present in the recipients, and ABO histo-blood group antigens are expressed on endothelial cells of kidney grafts [22]. In ABO-incompatible transplantation, these antibodies react to ABO histo-blood group antigens followed by complement activation. Bleeding and thrombosis develop, which eventually lead to graft loss [23,24] (Figure 1). As observed in 441 cases of ABO-incompatible KTx from Japan [15], no incidence of hyperacute rejection occurred within 48 h of transplantation [24] (Figure 2). Many cases of acute AMR occurred during the first 2–7 days after transplantation. After this period, the incidence of AMR decreased, and rejection ceased to occur 1 month after transplantation. Based on the results of this study, we divided the posttransplantation clinical course into three periods: a 48-h “silent period” with no sign of hyperacute rejection, an 18-day “critical period” from days 2 to 19 (average, day 7) when acute AMR is most likely to develop, and a subsequent “stable period” during which acute AMR no longer occurs because transplant accommodation has been established [24]. Accommodation is defined as a phenomenon in which no clinical grafted organ injury occurs despite the presence of antibodies in the recipient’s body against the ABO histo-blood group antigens of the graft [15].
\n
Figure 1.
Acute AMR in ABO-incompatible KTx and its mechanism [23].
\n
Figure 2.
Onset of acute AMR [15,24].
\n
AMR in ABO-incompatible KTx is classified into two types based on antigen stimulation and the immunological response to such stimulation [25] (Table 1). Type I acute AMR is caused by resensitization due to ABO histo-blood group antigens on the endothelial cells of the kidney graft. In patients at high immunological risk with high antibody titer, ABO histo-blood group antigens of the grafts can directly stimulate immunological responses, resulting in the explosive production of antibodies and leading to acute AMR. Typically, IgG antibody titers increase, accompanied by a parallel increase in IgM antibody titers. Once rejection develops, its course is dramatic, with no response to currently available therapy and ultimately leading to graft loss. Because serum IgG antibody titers are generally high before transplantation and a “rebound” in antibody production often occurs after pretransplantation antibody removal, desensitization therapy, including the suppression of memory cells, should be administered before transplantation (detailed in a later section).
\n
\n\n
\n
\n
Type I
\n
Type II
\n
\n\n\n
\n
Occurrence of critical period
\n
Early phase
\n
Late phase
\n
\n
\n
Recipient
\n
Immunologically high-risk host
\n
Immunocompromised host
\n
\n
\n
Immunosuppression
\n
Inadequate
\n
Possible immunosuppression
\n
\n
\n
Antigens
\n
ABO histo-blood group antigens
\n
ABO blood group-associated antigens
\n
\n
\n
Sensitization
\n
Resensitization
\n
Primary sensitization
\n
\n
\n
Response
\n
Secondary and severe
\n
Primary and less than type I
\n
\n
\n
Antibody production
\n
Explosive
\n
Slow
\n
\n
\n
Antibody titer
\n
IgG↑> IgM↑
\n
IgG→ IgM↑
\n
\n
\n
Treatment
\n
Unresponsive
\n
Responsive in early period
\n
\n
\n
Prophylaxis
\n
Desensitization
\n
Prevention of infection
\n
\n
\n
Prognosis
\n
Graft loss
\n
Possible graft survival
\n
\n\n
Table 1.
Classification of acute AMR due to ABO blood group antigens in ABO-incompatible KTx [23].
\n
Type II AMR is caused by a primary sensitization by ABO blood group-associated antigens. In response to bacterial infections, such as sepsis, ABO antigen-like substances on the surface of bacterial cells act as cross-reacting antigens, causing sensitization and antibody production. Type II AMR usually progresses more slowly and is less severe than type I AMR [25]. A major difference from type I rejection is the elevation of IgM antibody titers. Type II AMR also has a greater chance of responding to currently available treatment. Antibody removal and anticoagulation therapy should therefore be promptly administered.
\n
\n
\n
4. Development of desensitization therapy for ABO-incompatible KTx
\n
In this section, we summarize the history of ABO-incompatible KTx performed at our institute, Niigata University, focusing on the transition of immunosuppressive therapy as well as on the development and implementation of desensitization therapy [21].
\n
Figure 3.
Immunosuppression protocol, early phase, period 1, extending from April 1996 to January 1997. Antibody removal with DFPP started from 5 to 7 days before transplantation, without any immunosuppression. FK506 and AZ were started 2 days before transplantation and splenectomy was “routinely” performed at the time of transplantation. MP, methylprednisolone.
\n
In 1996, tacrolimus (FK506), azathioprine (AZ), steroids, and antilymphocyte globulin (ALG) were used for ABO-incompatible KTx (Figure 3). FK506 and AZ were initiated 2 days before surgery, splenectomy was performed at the time of transplantation, and ALG was administered for 14 days after KTx. For antibody removal therapy, double-filtration plasmapheresis (DFPP) or plasma exchange was performed. The target anti-A and -B titer immediately before KTx was set at eightfold or less, and the antibody removal protocol was repeated until the target titer was reached because high pretransplantation antibody titer against donor blood type has been reported to correlate with acute AMR [26–30].
\n
In patients whose antibody titer rebounded after antibody removal therapies, acute AMR occurred in some cases with the increase in posttransplantation antibody titer. To avoid this, cyclophosphamide (CPA) treatment, which inhibits B cells, has been initiated along with low-dose steroids 10–14 days before transplantation since 1997 (Figure 4). Antibody removal, FK506, and splenectomy were performed in a conventional manner.
\n
Figure 4.
Immunosuppression protocol, early phase, period 2, extending from February 1997 to September 2001. CPA, a low steroid dose, and AZ were administered starting 10 days before transplantation, at the beginning of antibody removal.
\n\n
However, the new protocol seemed to be less than fully adequate because two patients lost their grafts due to AMR during this period. Mycophenolate mofetil (MMF) and basiliximab have been included since 2001. To avoid AMR, MMF and steroids were started 14–28 days before the transplantation surgery (Figure 5). Antibody removal, FK506, and splenectomy were performed in a conventional manner.
\n\n
Figure 5.
Immunosuppression protocol, early phase, period 3, extending from October 2001 to August 2004, using MMF and basiliximab. MMF and a low-dose steroid were started 2–4 weeks before transplantation. The concept of B-cell desensitization was adopted. AUC, area under the curve; CYA, cyclosporine.
\n
Figure 6.
Late phase (September 2004–). Desensitization protocol with two doses of rituximab, MMF, a steroid, and antibody removal without splenectomy. The concept of “desensitization therapy” for ABO-incompatible KTx was introduced. MMF and a low-dose steroid were started 4 weeks before transplantation, and two doses of rituximab and a minimum antibody removal session followed. Splenectomy was completely abandoned in this phase.
\n
Splenectomy has been considered a prerequisite for a successful outcome of ABO-incompatible KTx [31] because the spleen has a specific structure for entrapping extrinsic antigens and contains the largest pools of memory B cells and antibody-producing plasma cells in the body. However, splenectomy can lead to complications, including postoperative hemorrhage, pancreatic injury, and leakage of pancreatic juices [32]. Furthermore, the assumed immunological benefits of splenectomy are doubtful because severe AMR can still occur sometimes [26]. In such patients, extrasplenic memory B cells and plasma cells are activated to produce anti-A and -B antibodies in response to antigen loading after KTx. Strategies for preoperative immunosuppression must therefore be reconsidered. Instead of splenectomy, 375 mg/m2 rituximab (a chimeric mouse-human monoclonal antibody formulation directed to CD20 antigens expressed on premature and mature B cells) has been administered twice since 2004: once 2 weeks before and once on the day before ABO-incompatible KTx [33] (Figure 6). The major goal of treatment with rituximab and MMF is to suppress the induction of differentiation from memory B cells into antibody-secreting plasma cells. Antibody removal was mainly intended for the physical removal of anti-A and -B antibodies already present in the circulating blood and also to aid in assessing the suppressive effects on the B cell line by determining the extent of antibody rebound after removal. Thus, antibody removal was considered to be a form of auxiliary therapy. As a general rule, antibody removal was limited to two times because of the serious concerns regarding the side effects of antibody removal, such as allergic reactions, hemorrhagic tendency due to decreased anticoagulant factors, and decreased colloid osmotic pressure and intravascular volume depletion due to hypoalbuminemia. Calcineurin inhibitors (CNI) suppressed the differentiation of B-0 cells to B-1a cells, which would otherwise progress to be anti-A and -B antibody-producing B cells [34]. Taking this point into account, CNI was started 28 days before KTx with MMF and steroids. To avoid over-immunosuppression, the dose of rituximab was eventually reduced to 100 mg/body (Figure 7). The number of peripheral B cells was well suppressed with this strategy for approximately 6 months after ABO-incompatible KTx (data not shown).
\n\n
Figure 7.
Late phase, modified desensitization protocol (2007–). Starting in 2007, a CNI was added 4 weeks before transplantation and one dose of rituximab was reduced to 100 mg/body. Antibody removal was limited to a minimum, and splenectomy was completely avoided.
\n
\n
\n
5. Outcomes of ABO-incompatible KTx in Niigata University
\n
We show our clinical results divided into two periods, before and after 2004. As mentioned above, MMF and rituximab were used as a desensitization therapy without splenectomy since 2004. Table 2 shows the characteristics of the patients who underwent ABO-incompatible KTx in Niigata University [21].
\n
\n\n
\n
\n
1996–2004.5 (n=20)
\n
2004.9–2013 (n=60)
\n
P\n
\n
\n\n\n
\n
Recipient age
\n
33.5±11.3
\n
44.9±13.3
\n
0.069
\n
\n
\n
Donor age
\n
57.5±6.3
\n
55.2±9.1
\n
0.224
\n
\n
\n
Male recipient (%)
\n
75
\n
72
\n
0.555
\n
\n
\n
Male donor (%)
\n
50
\n
28
\n
0.037
\n
\n
\n
Graft weight (g)
\n
165.1±27.1
\n
173.4±31.3
\n
0.581
\n
\n
\n
HLA MM
\n
2.6±1.6
\n
3.2±1.3
\n
0.391
\n
\n
\n
HD duration (months)
\n
46.9±39.7
\n
36.4±48.7
\n
0.774
\n
\n
\n
TIT (min)
\n
63.3±27.6
\n
82.8±28.0
\n
0.644
\n
\n
\n
WIT (min)
\n
6.0±1.6
\n
4.1±2.1
\n
0.092
\n
\n
\n
TAC for CNI (%)
\n
85
\n
50
\n
0.000
\n
\n
\n
Preemptive KTx (%)
\n
0
\n
20.3
\n
0.000
\n
\n\n
Table 2.
Characteristics of the patients who received ABO-incompatible KTx in Niigata University.
\n
\n
5.1. Patient survival rate
\n
Patient survival rates are shown in Figure 8 [21]. Before 2004, the patient survival rate was 95% for the first year, 90% for the first 5, 7, and 10 years, and 80% for the first 15 years after transplantation. After 2004, the patient survival rate was 100% for all available study periods (1, 5, 7, and 10 years) after transplantation. A statistically significant difference in patient survival rate was observed between the late and early phases (Kaplan-Meier analysis, P=0.03).
\n
Figure 8.
Patient survival before and after 2004 in ABO-incompatible KTx (Kaplan-Meier analysis). Patient survival rate of cases after 2004 was significantly improved compared to that of cases before 2004 (log-rank, P=0.03). N.A., not yet available.
\n
\n
\n
5.2. Cause of death
\n
Four patients died after transplantation, with their causes of death (time of death) being sepsis due to pleuritis (at 4 months after transplantation), sepsis (46 months), sepsis due to gastrointestinal perforation (123 months), and brain tumor (123 months). Three of these deaths (two due to sepsis and one due to brain tumor) were deaths with functioning graft (DWFG).
\n
\n
\n
5.3. Graft survival rate
\n
Graft survival rates are shown in Figure 9 [21]. Before 2004, the death-censored graft survival rate was 80% at 1 year, 80% at 5 years, 68.6% at 7 years, 51.4% at 10 years, and 45.7% at 15 years after transplantation. After 2004, the death-censored graft survival rate was 96.7% at 1 year, 96.7% at 5 years, 96.7% at 7 years, and 87.9% at 10 years after transplantation. A statistically significant difference in graft survival rate was observed between the late and early phases (Kaplan-Meier analysis, P=0.006).
\n
Figure 9.
Graft survival before and after 2004 in ABO-incompatible KTx (Kaplan-Meier analysis). Graft survival in cases after 2004 was significantly improved compared to that of cases before 2004 (log-rank, P=0.006).
\n
\n
\n
5.4. Cause of graft loss
\n
\nTable 3 shows the cause of graft loss [21]. The graft was lost in 17 patients. The causes of graft loss were chronic allograft nephropathy in five cases (70, 98, 194, 133, and 102 months after transplantation), acute AMR in three cases (10, 10, and 9 days after transplantation), thrombotic microangiopathy (TMA) in one case (1 day after transplantation), acute rejection in one case (4 months after transplantation), recurrent membranoproliferative glomerulonephritis (MPGN) in one case (114 months after transplantation), recurrent IgA glomerulonephritis (IgAGN) in one case (114 months after transplantation), drug-induced nephropathy in one case (2 months after transplantation), graftectomy/total nephroureter/ectomy/cystectomy due to urothelial tumor in one case (76 months after transplantation), and patient death in three cases.
In our studies, the indicator for acute AMR, C4d in peritubular capillaries (PTCs), was observed by graft biopsy over time, at 0-h, 1-h, or 1-month protocol biopsy or by episode biopsy. The positive rate for C4d in PTCs at 1-h biopsy was only 16.1% [24,35]. The positive rate increased to 70.9% for the 1-month protocol or episode biopsy. Biopsy was negative at 1 h in all four cases in which acute AMR developed due to anti-A and -B antibodies after ABO-incompatible KTx in our institute but was positive 1 month later. Among the cases that turned positive after negative results, no acute AMR developed except in these four cases. Considering this fact, we made the following hypotheses: (1) preexisting anti-A and -B natural antibodies do not always bind to histo-blood group antigens on the graft vascular endothelial cells and subsequently activate complement, (2) it is likely that antibodies with high affinity to the kidney allograft are newly formed postoperatively and deposited, and (3) not all antibodies produced postoperatively elicit acute AMR, and accommodation is induced and established in cases where the graft survives [22,24,35]. The important matter is that titration of anti-A and -B antibodies is most widely performed by isohemagglutinin using red blood cells (RBCs) in ABO-incompatible KTx. Our observations also suggested the diversity of anti-A and -B antibodies and antibody-producing clones and indicated that it is more important to control postoperatively produced anti-A and -B antibodies that injure target graft vascular endothelial cells (not RBCs) than to mechanically remove preformed antibodies. Finally, we previously reported that there were differences regarding the presentation of ABO blood group antigens between RBCs and endothelial cells of the kidney [22]. According to our results, we have recently excluded, on a trial basis, antibody removal before ABO-incompatible KTx in patients with antibody titers below 64-fold [36]. In 14 patients who did not receive antibody removal, the patient and graft survival after 1 year were each 100% [36].
\n
\n
\n
7. Strategies for ABO-incompatible KTx
\n
In ABO-incompatible KTx, tissue-destroying acute AMR is elicited by an extensive antibody production. This drastic antibody elevation occurs because memory B cells and plasma cells having immunological memory are inadequately suppressed and thus can react to histo-blood group carbohydrate antigens introduced by the graft, producing a second set phenomenon (type I AMR).
Acute AMR can be elicited by anti-A and -B antibody production that has been made possible because of a prior exposure to blood group-associated carbohydrate antigens due to certain bacterial infections (type II AMR).
Effective desensitization therapy should be performed by suppressing B-cell immunity rather than by several sessions of mechanical antibody removal. The effective method to protect from AMR is a pretransplantation procedure with a combination of rituximab and MMF/CNI, which blocks the induction of B-cell differentiation. The most important consideration is to inhibit B-cell immunity to a sufficient extent before ABO-incompatible KTx and potential new antibody production in the critical period. Accommodation has been established after ABO-incompatible KTx, and the recipient’s posttransplantation antibody titer becomes less relevant.
\n
\n\n',keywords:"ABO blood group antigen, ABO-incompatible kidney transplantation, accommodation, antibody-mediated rejection, ABO kidney transplantation",chapterPDFUrl:"https://cdn.intechopen.com/pdfs/50031.pdf",chapterXML:"https://mts.intechopen.com/source/xml/50031.xml",downloadPdfUrl:"/chapter/pdf-download/50031",previewPdfUrl:"/chapter/pdf-preview/50031",totalDownloads:943,totalViews:339,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,dateSubmitted:"October 14th 2015",dateReviewed:"February 4th 2016",datePrePublished:null,datePublished:"September 7th 2016",dateFinished:null,readingETA:"0",abstract:"Previously, ABO-incompatible kidney transplantation (KTx) was believed to be a “taboo” for immunological reasons. In Japan, the Tokyo Women’s Medical University reported the first successful case of such transplantation, performed on January 19, 1989. Since then, we have been striving to improve the outcome of ABO-incompatible transplantation for a quarter of a century.",reviewType:"peer-reviewed",bibtexUrl:"/chapter/bibtex/50031",risUrl:"/chapter/ris/50031",book:{slug:"frontiers-in-transplantology"},signatures:"Masayuki Tasaki, Kazuhide Saito, Yuki Nakagawa, Yoshihiko Tomita\nand Kota Takahashi",authors:[{id:"179277",title:"Dr.",name:"Masayuki",middleName:null,surname:"Tasaki",fullName:"Masayuki Tasaki",slug:"masayuki-tasaki",email:"masa1214@med.niigata-u.ac.jp",position:null,institution:{name:"National Institute of Radiological Sciences",institutionURL:null,country:{name:"Japan"}}},{id:"184358",title:"Dr.",name:"Kazuhide",middleName:null,surname:"Saito",fullName:"Kazuhide Saito",slug:"kazuhide-saito",email:"kazsaito@med.niigata-u.ac.jp",position:null,institution:null},{id:"184359",title:"Dr.",name:"Yuki",middleName:null,surname:"Nakagawa",fullName:"Yuki Nakagawa",slug:"yuki-nakagawa",email:"yuki-naka@med.niigata-u.ac.jp",position:null,institution:null},{id:"184360",title:"Prof.",name:"Yoshihiko",middleName:null,surname:"Tomita",fullName:"Yoshihiko Tomita",slug:"yoshihiko-tomita",email:"ytomita@med.niigata-u.ac.jp",position:null,institution:null},{id:"184361",title:"Dr.",name:"Kota",middleName:null,surname:"Takahashi",fullName:"Kota Takahashi",slug:"kota-takahashi",email:"takahashi-kouta@image.ocn.ne.jp",position:null,institution:{name:"National Institute of Radiological Sciences",institutionURL:null,country:{name:"Japan"}}}],sections:[{id:"sec_1",title:"1. Introduction",level:"1"},{id:"sec_2",title:"2. History of ABO-incompatible KTx",level:"1"},{id:"sec_3",title:"3. AMR",level:"1"},{id:"sec_4",title:"4. Development of desensitization therapy for ABO-incompatible KTx",level:"1"},{id:"sec_5",title:"5. Outcomes of ABO-incompatible KTx in Niigata University",level:"1"},{id:"sec_5_2",title:"5.1. Patient survival rate",level:"2"},{id:"sec_6_2",title:"5.2. Cause of death",level:"2"},{id:"sec_7_2",title:"5.3. Graft survival rate",level:"2"},{id:"sec_8_2",title:"5.4. Cause of graft loss",level:"2"},{id:"sec_10",title:"6. Acute AMR by de novo antibody",level:"1"},{id:"sec_11",title:"7. Strategies for ABO-incompatible KTx",level:"1"}],chapterReferences:[{id:"B1",body:'\nTagareli A. Karl Landsteiner: a hundred year later. Transplantation 2001;72:3.\n'},{id:"B2",body:'\nBarry JM, Murray JE. The first human renal transplants. J Urol 2006;176:888–890.\n'},{id:"B3",body:'\nStarzl TE, Marchioro TL, HolmesJH, HermannG, BrittainRS, StoningtonOH, TalmageDW, WaddellWR. Renal homografts in patients with major donor recipient blood group incompatibilities. Surgery 1964;55:195–200.\n'},{id:"B4",body:'\nStarzl TE, Tzakis A, Makowka L, Banner B, Demetrius A, Ramsey G, Duquesnoy R, Griffin M. The definition of ABO factors in transplantation: relation of other humoral antibody states. Transplant Proc 1987;19:4492–4497.\n'},{id:"B5",body:'\nGleason RE, Murray JE. Report from kidney transplant registry: analysis of variables in the function of human kidney transplants. Transplantation 1967;52:343–359.\n'},{id:"B6",body:'\nSlapak M, Naik RB, Lee HA. Renal transplant in a patient with major donor-recipient blood group incompatibility: reversal of acute rejection by the use of modified plasmapheresis. Transplantation 1981;31:4–7.\n'},{id:"B7",body:'\nAlexandre GP, De Bruyere M, Squifflet JP, Moriau M, Latinne D, Pirson Y. Human ABO incompatible living donor renal homografts. Neth J Med 1985;28:231–234.\n'},{id:"B8",body:'\nAlexandre GPJ, Squifflet JP, De Bruyere M, Latinne D, Moriau M, Carlier M, Pirson Y, Lecomte Ch. ABO-incompatible related and unrelated living donor renal allografts. Transplant Proc 1986;18:452–455.\n'},{id:"B9",body:'\nAlexandre GP, Squifflet JP, De Bruyère M, Latinne D, Reding R, Gianello P, Carlier M, Pirson Y. Present experience in a series of 26 ABO incompatible living donor renal allografts. Transplant Proc 1987;19:4538–4542.\n'},{id:"B10",body:'\nAlexandre GPJ, Latinne D, Gianello P, Squifflet JP. Preformed cytotoxic antibodies and ABO-incompatible grafts. Clin Transplant 1991;5:583–594.\n'},{id:"B11",body:'\nTakahashi K, Agishi T, Ota K, et al. Extracorporeal plasma treatment for extending indication of kidney transplantation: ABO-incompatible and preformed antibody-positive kidney transplantation. In: Therapeutic Plasmapheresis IX. ICAOT Press, Cleveland, 1991; pp. 116–122.\n'},{id:"B12",body:'\nTakahashi K, Tanabe K, Ooba S, Yagisawa T, Nakazawa H, Teraoka S, Hayasaka Y, Kawaguchi H, Ito K, Toma H. Prophylactic use of a new immunosuppressive agent, deoxyspergualin, in patients with kidney transplantation from ABO-incompatible or preformed antibody positive donors. Transplant Proc 1991;23:1078–1082.\n'},{id:"B13",body:'\nToma H. ABO-incompatible renal transplantation. Urol Clin N Am 1994;21:299–310.\n'},{id:"B14",body:'\nTanabe K, Takahashi K, Sonda K, Tokumoto T, Ishikawa N, Kawai T, Fuchinoue S, Oshima T, Yagisawa T, Nakazawa H, Goya N, Koga S, Kawaguchi H, Ito K, Toma H, Agishi T, Ota K. Long-term results of ABO-incompatible living kidney transplantation: a single center experience. Transplantation 1998;65:224–228.\n'},{id:"B15",body:'\nTakahashi K, Saito K, Takahara S, Okuyama A, Tanabe K, Toma H, Uchida K, Hasegawa A, Yoshimura N, Kamiryo Y; Japanese ABO-Incompatible Kidney Transplantation Committee. The Japanese ABO-Incompatible Kidney Transplantation Committee. Excellent long-term outcome of ABO-incompatible living donor kidney transplantation in Japan. Am J Transplant 2004;4:1089–1096.\n'},{id:"B16",body:'\nTakahashi K. ABO-Incompatible Kidney Transplantation. Elsevier, Amsterdam, 2001; pp. 73–86.\n'},{id:"B17",body:'\nTakahashi K. Accommodation in ABO-Incompatible Kidney Transplantation. Elsevier, Amsterdam, 2004: pp. 111–124.\n'},{id:"B18",body:'\nTakahashi K. ABO-Incompatible Kidney Transplantation—Establishing a Scientific Framework. Elsevier, Amsterdam, 2007; pp. 53–72.\n'},{id:"B19",body:'\nTakahashi K. ABO-Incompatible Kidney Transplantation—Why Is Hyperacute Rejection Absent? Elsevier, Amsterdam, 2011; pp. 83–107.\n'},{id:"B20",body:'\nTakahashi K. ABO-Incompatible Kidney Transplantation—Overcoming Hyperacute Rejection and Establishing Clinical Strategies. Elsevier, Amsterdam, 2013; p. 32.\n'},{id:"B21",body:'\nTakahashi K, Saito K, Nakagawa Y, Tasaki M. ABO-Incompatible Kidney Transplantation—Moving Toward a Comprehensive and Sound Approach to Kidney Transplantation. Elsevier, Amsterdam, 2015; pp. 49–65.\n'},{id:"B22",body:'\nTasaki M, Yoshida Y, Miyamoto M, Nameta M, Cuellar LM, Xu B, Zhang Y, Yaoita E, Nakagawa Y, Saito K, Yamamoto T, Takahashi K. Identification and characterization of major proteins carrying ABO blood group antigens in the human kidney transplantation. Transplantation 2009;87:1125–1133.\n'},{id:"B23",body:'\nTakahashi K. A new concept of accommodation in ABO-incompatible kidney transplantation. Clin Transplant. 2005;19 Suppl 14:76–85.\n'},{id:"B24",body:'\nTakahashi K, Saito K, Nakagawa Y, Tasaki M. ABO-Incompatible Kidney Transplantation—Moving Toward a Comprehensive and Sound Approach to Kidney Transplantation. Elsevier, Amsterdam, 2015; pp. 11–45.\n'},{id:"B25",body:'\nTakahashi K. Recent findings in ABO-incompatible kidney transplantation: classification and therapeutic strategy for acute antibody-mediated rejection due to ABO-blood-group-related antigens during the critical period preceding the establishment of accommodation. Clin Exp Nephrol 2007;11:128–141.\n'},{id:"B26",body:'\nIshida H, Koyama I, Sawada T, Utsumi K, Murakami T, Sannomiya A, Tsuji K, Yoshimura N, Tojimbara T, Nakajima I, Tanabe K, Yamaguchi Y, Fuchinoue S, Takahashi K, Teraoka S, Ito K, Toma H, Agishi T. Anti-AB titer changes in patients with ABO incompatibility after living related kidney transplantations: survey of 101 cases to determine whether splenectomies are necessary for successful transplantation. Transplantation 2000;70:681–685.\n'},{id:"B27",body:'\nChung BH, Lim JU, Kim Y, Kim JI, Moon IS, Choi BS, Park CW, Kim YS, Yang CW. Impact of the baseline anti-A/B antibody titer on the clinical outcome in ABO-incompatible kidney transplantation. Nephron Clin Pract 2013;124:79–88.\n'},{id:"B28",body:'\nToki D, Ishida H, Setoguchi K, Shimizu T, Omoto K, Shirakawa H, Iida S, Horita S, Furusawa M, Ishizuka T, Yamaguchi Y, Tanabe K. Acute antibody-mediated rejection in living ABO-incompatible kidney transplantation: long-term impact and risk factors. Am J Transplant 2009;9:567–577.\n'},{id:"B29",body:'\nSivakumaran P, Vo AA, Villicana R, Peng A, Jordan SC, Pepkowitz SH, Klapper EB. Therapeutic plasma exchange for desensitization prior to transplantation in ABO incompatible renal allografts. J Clin Apheresis 2009;24:155–160.\n'},{id:"B30",body:'\nGloor JM, Lager DJ, Moore SB, Pineda AA, Fidler ME, Larson TS, Grande JP, Schwab TR, Griffin MD, Prieto M, Nyberg SL, Velosa JA, Textor SC, Platt JL, Stegall MD. ABO-incompatible kidney transplantation using both A2 and non-A2 living donors. Transplantation 2003;75:971–977.\n'},{id:"B31",body:'\nAlexander JW. Splenectomy as a prerequisite for successful human ABO incompatible renal transplantation. Transplant Proc 1985;17:138.\n'},{id:"B32",body:'\nAlexander JW, First MR, Majeski JA, Munda R, Fidler JP, Morris MJ, Suttman MP. The late adverse effect of splenectomy on patient survival following cadaveric renal transplantation. Transplantation 1984;37:467–470.\n'},{id:"B33",body:'\nSaito K, Nakagawa Y, Suwa M, Kumagai N, Tanikawa T, Nishiyama T, Ueno M, Gejyo F, Nishi S, Takahashi K. Pinpoint targeted immunosuppression: anti-CD20/MMF desensitization with anti-CD25 in successful ABO-incompatible kidney transplantation without splenectomy. Xenotransplantation 2006;13:111–117.\n'},{id:"B34",body:'\nIrei T, Ohdan H, Zhou W, Ishiyama K, Tanaka Y, Ide K, Asahara T. The persistent elimination of B cells responding to blood group A carbohydrates by synthetic group A carbohydrates and B-1 cell differentiation blockade: novel concept in preventing antibody-mediated rejection in ABO-incompatible transplantation. Blood 2007;110:4567–4575.\n'},{id:"B35",body:'\nTakahashi K, Saito K, Nakagawa Y, Tasaki M, Hara N, Imai N. Mechanism of acute antibody-mediated rejection in ABO-incompatible kidney transplantation: which anti-A/anti-B antibodies are responsible, natural or de novo? Transplantation 2010;89:635–637.\n'},{id:"B36",body:'\nTakahashi K, Saito K, Nakagawa Y, Tasaki M. ABO-Incompatible Kidney Transplantation—Moving Toward a Comprehensive and Sound Approach to Kidney Transplantation. Elsevier, Amsterdam, 2015; pp. 67–75.\n'}],footnotes:[],contributors:[{corresp:null,contributorFullName:"Masayuki Tasaki",address:null,affiliation:'
Division of Urology, Department of Regenerative & Transplant Medicine, Niigata Graduate School of Medical and Dental Sciences, Niigata, Japan
Division of Urology, Department of Regenerative & Transplant Medicine, Niigata Graduate School of Medical and Dental Sciences, Niigata, Japan
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\n
1. Introduction
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Gestational 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.
\n
There 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].
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Considering 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].
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The 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].
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\n
\n
2. Lifestyle intervention
\n
After 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).
\n
MNT 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].
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The 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].
\n
Excessive weight gain during pregnancy should be avoided for GDM women [16]. The weight gain during pregnancy depends on pre-pregnancy BMI:
\n
12.5–18 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);
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].
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3. Pharmacological treatment
\n
Pharmacological 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].
\n
Oral 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.
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3.1 Metformin
\n
The 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.
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3.2 Glyburide
\n
Glyburide (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].
\n
There 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].
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3.3 Insulin therapy
\n
Insulin 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].
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\n
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International Federation of Gynecology and Obstetrics (FIGO), 2015
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Oral therapy failure or
One of the risk factors:
Diagnosing diabetes before 20 weeks of gestation
Oral therapy for more than 30 weeks
Fasting plasma blood glucose above 110 mg/dl
1-hour postprandial glycemia above 140 mg/dl
Weight gain over 12 kilograms during pregnancy
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Canadian Diabetes Association (CDA), 2018
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If glycemic control is not achieved in 2 weeks after the initiation of medical, nutritional intervention
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American Diabetes Association (ADA), 2018
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First line therapy if glycemic control is not achieved after diet intervention
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American College of Obstetricians and Gynecologists (ACOG), 2018
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First line therapy if glycemic control is not achieved after diet intervention
\n
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Table 1.
Insulin initiation recommendations.
\n
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3.3.1 Types of insulin
\n
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3.3.1.1 Human insulin
\n
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3.3.1.1.1 Regular insulin
\n
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].
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3.3.1.1.2 Human insulin inhalation (nasal insulin)
\n
Human 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].
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3.3.1.2 Rapid-acting insulin analogs
\n
Another 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].
\n
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3.3.1.2.1 Insulin aspart
\n
Insulin 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].
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3.3.1.2.2 Insulin lispro
\n
Insulin 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].
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3.3.1.2.3 Insulin glulisine
\n
Insulin 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].
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3.3.1.3 Intermediate insulin
\n
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3.3.1.3.1 Insulin isophane
\n
Insulin 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].
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3.3.1.4 Basal analogs
\n
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3.3.1.4.1 Insulin detemir
\n
Insulin 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].
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3.3.1.4.2 Insulin glargine
\n
Insulin 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].
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3.3.1.4.3 Insulin glargine
\n
Insulin 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].
\n
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3.3.1.4.4 Insulin degludec
\n
Insulin 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].
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3.3.2 Insulin regimens
\n
There 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].
\n
The 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.
\n
If 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).
\n
Sometimes 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.
\n
In 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].
\n
Usually, 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.
\n
The doses of insulin have to be continuously optimized, so the self-monitoring blood glucose is essential.
\n
Rapid-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].
Blood 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].
\n
Thereby, 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.
\n
\n
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\n\n
\n
5th International Workshop Conference Gestational Diabetes and International Association of Diabetes and Pregnancy Study Group, 2007
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.
\n
Other 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].
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3.5.2 Self-monitoring of capillary blood glucose (SMBG)
\n
The 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.
\n
In 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].
\n
A 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].
\n
The 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].
\n
The 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].
Systems 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].
\n
Glycemic 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.
Insulin glucose monitoring techniques [adapted from American Association of Clinical Endocrinologist and American College of Endocrinology].
\n
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.
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3.6 Fetal complications associated with insulin therapy
\n
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3.6.1 Neonatal hypoglycemia
\n
Glucose 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].
\n
Neonatal 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].
\n
A 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].
\n
Regarding 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].
\n
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3.6.2 Congenital anomalies
\n
The 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].
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3.7 Birth complications associated with insulin therapy
\n
\n
3.7.1 Cesarean section (CS)
\n
A 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].
\n
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3.7.2 Vacuum-assisted birth
\n
Although 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].
\n
\n
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3.7.3 Fetal morbidity
\n
Evidence 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].
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3.8 Maternal complications associated with insulin therapy
\n
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3.8.1 Maternal hypoglycemia
\n
Hypoglycemia 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].
\n
Insulin 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].
\n
Maternal 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].
\n
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3.8.2 Hypertension
\n
There 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].
\n
\n
\n
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3.9 Intrapartum management
\n
During 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.
\n
The 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].
\n
Lowering 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.
\n
Women 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].
\n
Although 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].
\n
Another 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].
\n
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3.10 Postpartum management
\n
Insulin 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.
\n
Breastfeeding 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].
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3.11 Future research directions
\n
There 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].
\n
Micro-RNAs are now extensively studied in different domains and might apply to diagnosing and selecting GDM patients that require insulin treatment [92].
\n
Not 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].
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Acknowledgments
\n
All authors had an equal contribution and shared the first authorship.
\n
Conflict of interest
None.
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Notes/thanks/other declarations
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This chapter was financed by Novo Nordisk.
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\n',keywords:"gestational diabetes, insulin therapy, macrosomia, neonatal hypoglycemia",chapterPDFUrl:"https://cdn.intechopen.com/pdfs/65616.pdf",chapterXML:"https://mts.intechopen.com/source/xml/65616.xml",downloadPdfUrl:"/chapter/pdf-download/65616",previewPdfUrl:"/chapter/pdf-preview/65616",totalDownloads:848,totalViews:0,totalCrossrefCites:0,dateSubmitted:"October 1st 2018",dateReviewed:"January 20th 2019",datePrePublished:"March 1st 2019",datePublished:"February 5th 2020",dateFinished:null,readingETA:"0",abstract:"The prevalence of gestational diabetes risen in several populations during the past 20 years, and increased direct and indirect healthcare costs, including those for insulin treatment. Establishing the optimal treatment and initiation momentum are critical to achieve glycemic control and minimize the impact on fetal development and perinatal complications. Insulin is the only therapy that does not cross the placenta, and some of its types were proved to be safe in pregnancy. Intrapartum management is based on intravenous insulin administration, and standard protocols should be implemented in every center. Postpartum management requires special attention, as insulin necessary has a fast decline exposing mothers to hypoglycemia.",reviewType:"peer-reviewed",bibtexUrl:"/chapter/bibtex/65616",risUrl:"/chapter/ris/65616",signatures:"Anca Pantea-Stoian, Roxana Adriana Stoica and Simona Diana Stefan",book:{id:"7143",title:"Gestational Diabetes Mellitus",subtitle:"An Overview with Some Recent Advances",fullTitle:"Gestational Diabetes Mellitus - An Overview with Some Recent Advances",slug:"gestational-diabetes-mellitus-an-overview-with-some-recent-advances",publishedDate:"February 5th 2020",bookSignature:"Amita Ray",coverURL:"https://cdn.intechopen.com/books/images_new/7143.jpg",licenceType:"CC BY 3.0",editedByType:"Edited by",editors:[{id:"251100",title:"Prof.",name:"Amita",middleName:null,surname:"Ray",slug:"amita-ray",fullName:"Amita Ray"}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"}},authors:[{id:"243049",title:"Dr.",name:"Anca",middleName:null,surname:"Pantea Stoian",fullName:"Anca Pantea Stoian",slug:"anca-pantea-stoian",email:"ancastoian@yahoo.com",position:null,institution:{name:"Carol Davila University of Medicine and Pharmacy",institutionURL:null,country:{name:"Romania"}}},{id:"281997",title:"Dr.",name:"Roxana Adriana",middleName:null,surname:"Stoica",fullName:"Roxana Adriana Stoica",slug:"roxana-adriana-stoica",email:"roxana88stoica@gmail.com",position:null,institution:null},{id:"282066",title:"Dr.",name:"Simona Diana",middleName:null,surname:"Stefan",fullName:"Simona Diana Stefan",slug:"simona-diana-stefan",email:"simona_ds2002@yahoo.com",position:null,institution:{name:"Babeș-Bolyai University",institutionURL:null,country:{name:"Romania"}}}],sections:[{id:"sec_1",title:"1. Introduction",level:"1"},{id:"sec_2",title:"2. Lifestyle intervention",level:"1"},{id:"sec_3",title:"3. Pharmacological treatment",level:"1"},{id:"sec_3_2",title:"3.1 Metformin",level:"2"},{id:"sec_4_2",title:"3.2 Glyburide",level:"2"},{id:"sec_5_2",title:"3.3 Insulin therapy",level:"2"},{id:"sec_5_3",title:"3.3.1 Types of insulin",level:"3"},{id:"sec_5_4",title:"3.3.1.1 Human insulin",level:"4"},{id:"sec_5_5",title:"3.3.1.1.1 Regular insulin",level:"5"},{id:"sec_6_5",title:"3.3.1.1.2 Human insulin inhalation (nasal insulin)",level:"5"},{id:"sec_8_4",title:"3.3.1.2 Rapid-acting insulin analogs",level:"4"},{id:"sec_8_5",title:"3.3.1.2.1 Insulin aspart",level:"5"},{id:"sec_9_5",title:"3.3.1.2.2 Insulin lispro",level:"5"},{id:"sec_10_5",title:"3.3.1.2.3 Insulin glulisine",level:"5"},{id:"sec_12_4",title:"3.3.1.3 Intermediate insulin",level:"4"},{id:"sec_12_5",title:"3.3.1.3.1 Insulin isophane",level:"5"},{id:"sec_14_4",title:"3.3.1.4 Basal analogs",level:"4"},{id:"sec_14_5",title:"3.3.1.4.1 Insulin detemir",level:"5"},{id:"sec_15_5",title:"3.3.1.4.2 Insulin glargine",level:"5"},{id:"sec_16_5",title:"3.3.1.4.3 Insulin glargine",level:"5"},{id:"sec_17_5",title:"3.3.1.4.4 Insulin degludec",level:"5"},{id:"sec_20_3",title:"3.3.2 Insulin regimens",level:"3"},{id:"sec_21_3",title:"3.3.3 Insulin initiation",level:"3"},{id:"sec_23_2",title:"3.4 Glycemic targets and control",level:"2"},{id:"sec_24_2",title:"3.5 Methods for glucose monitoring",level:"2"},{id:"sec_24_3",title:"3.5.1 Glycated hemoglobin (HbA1c)",level:"3"},{id:"sec_25_3",title:"3.5.2 Self-monitoring of capillary blood glucose (SMBG)",level:"3"},{id:"sec_26_3",title:"Table 4.",level:"3"},{id:"sec_28_2",title:"3.6 Fetal complications associated with insulin therapy",level:"2"},{id:"sec_28_3",title:"3.6.1 Neonatal hypoglycemia",level:"3"},{id:"sec_29_3",title:"3.6.2 Congenital anomalies",level:"3"},{id:"sec_31_2",title:"3.7 Birth complications associated with insulin therapy",level:"2"},{id:"sec_31_3",title:"3.7.1 Cesarean section (CS)",level:"3"},{id:"sec_32_3",title:"3.7.2 Vacuum-assisted birth",level:"3"},{id:"sec_33_3",title:"3.7.3 Fetal morbidity",level:"3"},{id:"sec_35_2",title:"3.8 Maternal complications associated with insulin therapy",level:"2"},{id:"sec_35_3",title:"3.8.1 Maternal hypoglycemia",level:"3"},{id:"sec_36_3",title:"3.8.2 Hypertension",level:"3"},{id:"sec_38_2",title:"3.9 Intrapartum management",level:"2"},{id:"sec_39_2",title:"3.10 Postpartum management",level:"2"},{id:"sec_40_2",title:"3.11 Future research directions",level:"2"},{id:"sec_42",title:"Acknowledgments",level:"1"},{id:"sec_45",title:"Conflict of interest",level:"1"},{id:"sec_42",title:"Notes/thanks/other declarations",level:"1"}],chapterReferences:[{id:"B1",body:'World Health Organisation and Department of Non-Communicable Disease Surveillance. 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DOI: 10.1007/s11892-013-0450-4\n'},{id:"B79",body:'Coustan DR, Carpenter MW. The diagnosis of gestational diabetes. Diabetes Care. 1998;21(Suppl 2):B5-B8. PMID: 9704220\n'},{id:"B80",body:'Dude A, Niznik CM, Szmuilowicz ED, Peaceman AM, Yee LM. Management of diabetes in the intrapartum and postpartum patient. American Journal of Perinatology. 2018;35(11):1119-1126. DOI: 10.1055/s-0038-1629903\n'},{id:"B81",body:'Drever E, Tomlinson G, Bai AD, et al. Insulin pump use compared with intra-venous insulin during labour and delivery: The INSPIRED observational cohort study. Diabetic Medicine. 2016;33:1253-1259\n'},{id:"B82",body:'Fresa R, Visalli N, Di Blasi V, et al. Experiences of continuous subcutaneous insulin infusion in pregnant women with type 1 diabetes during delivery from four Italian centers: A retrospective observational study. Diabetes Technology & Therapeutics. 2013;15:328-334\n'},{id:"B83",body:'Mathiesen ER, Christensen AB, Hellmuth E, Hornnes P, Stage E, Damm P. Insulin dose during glucocorticoid treatment for fetal lung maturation in diabetic pregnancy: Test of an algorithm [correction of analgoritm]. Acta Obstetricia et Gynecologica Scandinavica. 2002;81(9):835-839\n'},{id:"B84",body:'Rowe CW, Putt E, Brentnall O, Gebuehr A, Allabyrne J, Woods A, et al. An intravenous insulin protocol designed for pregnancy reduces neonatal hypoglycaemia following betamethasone administration in women with gestational diabetes. Diabetic Medicine. 2018. DOI: 10.1111/dme.13864\n'},{id:"B85",body:'Ringholm L, Mathiesen ER, Kelstrup L, Damm P. Managing type 1 diabetes mellitus in pregnancy-from planning to breastfeeding. Nature Reviews. Endocrinology. 2012;8(11):659-667. DOI: 10.1038/nrendo.2012.154\n'},{id:"B86",body:'Gunderson EP, Hedderson MM, Chiang V, Crites Y, Walton D, Azevedo RA, et al. Lactation intensity and postpartum maternal glucose tolerance and insulin resistance in women with recent GDM: The SWIFT cohort. Diabetes Care. 2012;35:50-56\n'},{id:"B87",body:'Riviello C, Mello G, Jovanovic LG. Breastfeeding and the basal insulin requirement in type 1 diabetic women. Endocrine Practice. 2009;15:187-193\n'},{id:"B88",body:'Dinglas C, Muscat J, Adams T, Peragallo-Dittko V, Vintzileos A, Heo HJ. Software-guided insulin dosing improves intrapartum glycemic management in women with diabetes mellitus. American Journal of Obstetrics and Gynecology. 2018;219(2):191.e1-191.e6. DOI: 10.1016/j.ajog.2018.05.003\n'},{id:"B89",body:'Harris DL, Bartin MR, Weston PJ, Harding JE. Continuous glucose monitoring in newborn babies at risk of hypoglycemia. The Journal of Pediatrics. 2010;157:198-202.e1\n'},{id:"B90",body:'Perri A, Giordano L, Corsello M, et al. Continuous glucose monitoring (CGM) in very low birth weight newborns needing parenteral nutrition: Validation and glycemic percentiles. Italian Journal of Pediatrics. 2018;44(1):99. DOI: 10.1186/s13052-018-0542-5\n'},{id:"B91",body:'McKinlay CJD, Chase JG, Dickson J, et al. Continuous glucose monitoring in neonates: A review. Maternal Health, Neonatology and Perinatology. 2017;3:18. DOI: 10.1186/s40748-017-0055-z\n'},{id:"B92",body:'Ibarra A, Vega-Guedes B, Brito-Casillas Y, Wägner AM. Diabetes in pregnancy and microRNAs: Promises and limitations in their clinical application. Non-Coding RNA. 2018;4(4):pii: E32. DOI: 10.3390/ncrna4040032\n'},{id:"B93",body:'Gedawy A, Martinez J, Al-Salami H, Dass CR. Oral insulin delivery: Existing barriers and current counter-strategies. The Journal of Pharmacy and Pharmacology. 2018;70(2):197-213. DOI: 10.1111/jphp.12852\n'}],footnotes:[],contributors:[{corresp:"yes",contributorFullName:"Anca Pantea-Stoian",address:"ancastoian@yahoo.com",affiliation:'
Nutrition and Metabolic Diseases Department, “Carol Davila” University of Medicine and Pharmacy Diabetes, Bucharest, Romania
Nutrition and Metabolic Diseases Department, “Carol Davila” University of Medicine and Pharmacy Diabetes, Bucharest, Romania
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UK Research and Innovation (former Research Councils UK (RCUK) - including AHRC, BBSRC, ESRC, EPSRC, MRC, NERC, STFC.) Processing charges for books/book chapters can be covered through RCUK block grants which are allocated to most universities in the UK, which then handle the OA publication funding requests. It is at the discretion of the university whether it will approve the request.)
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