Diabetes gestacional

Dr. Jorge Avalos

Diabetes gestacional

medicina maternofetal

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EUROPE

Safeblood

supplies

19902013

523 000

289 000

Almost 800 women die every

day due to complications in

pregnancy and childbirth.

ONE THIRDof total global deaths are in two countries

MATERNALDEATHS IN 2013

YEAR DEATHS

INDIA50 000

NIGERIA

1 in 40AFRICA

1 in 3300

40 000

The most dangerous place for a woman tohave a baby is in sub-Saharan Africa.

WHAT ARE PREGNANT WOMEN DYING FROM?

WHAT IS NEEDED TO SAVE MORE LIVES?

Quality care before,during & after

childbirth

Contraception& safe abortion

services

Essential medicinessuch as antibiotics

and oxytocin

Lifetime risk of dyingduring pregnancy

and childbirth

Every death is counted & its cause recorded

Pre-existing medicalconditions exacerbatedby pregnancy(such as diabetes,malaria, HIV, obesity)

28%

14%Pregnancy-induced

high bloodpressure

Severebleeding

27%

9%Obstructed labourand other direct causes

Blood clots

Abortion complications

Infections(mostly after

childbirth)

11%

3%

8%

© World Health Organization 2014

OMS : http://www.who.int/reproductivehealth/publications/monitoring/infographic/en/


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http://www.who.int/reproductivehealth/publications/monitoring/infographic/en/


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% Prevalence of Adult Obesity (BMI ≥ 30 kg/m ²) 1960’s – 90’s

<5%

5-9.9%

10-14.9%

15-19.9%

20-24.9%

25+ %

© World Obesity Federation, London October 2014. No reproduction without permission. For permissions please email [email protected] with detail of use for reproduction. For the most recent data available please view the adult maps and click on the country of interest at www.worldobesity.org


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Prevalence of Adult Obesity (BMI ≥ 30 kg/m ²*) 2000* to date

<5%

5-9.9%

10-14.9%

15-19.9%

20-24.9%

25+ %

© World Obesity Federation, London October 2014 No reproduction without permission. For permissions please email [email protected] with detail of use for reproduction. For the most recent data available please view the adult maps and click on the country of interest at www.worldobesity.org * Please note in China the Asia specfic cut off of applied (BMI ≥ 27 kg/m²)

http://www.worldobesity.org/


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36% sobrepeso 20% obesidad

Peru 2013 : mujeres 15-49a

obesidad : 3.76 OR DG


Gestational Diabetes, Maternal Obesity, and the NCD Burden . CLINICAL OBSTETRICS AND GYNECOLOGY Volume 56, Number 3 2014


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• en los últimos 30 años la población con DM se ha duplicado • disminución en la edad de inicio de la enfermedad • la diabetes gestacional, diabetes materna y la obesidad están asociados a

consecuencias adversas en la infancia

magnitud

Los grandes síndromes obstétricosDiabetes gestacional, RCIU y toxemia

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Los grandes síndromes obstétricosDiabetes gestacional, RCIU y toxemia

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Adversamente interactua con la unidad materno-

feto

sub-clinica a clinica con compromiso fetal

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+

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resistencia a la insulina

Bhcg progesterona

Lactogeno placentario

interaccion periconcepcion

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Bhcg progesterona

Lactogeno placentario

incremento de los niveles

de insulina

Insensibilidad preexistente a la insulina efecto superimpuesto relacionado al embarazo

interaccion periconcepcion

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severidad

la placenta diabetica

estructura y función función

macroscopica: placenta grande

incremento de ratio feto/placenta

microscopica: corioangiosis

isquemi/infarto inmadurez

incremento globulos rojos

largo plazo: disfuncion endotelio/vascular

HTA, DM y obesidad

corto plazo macrosomia DM2 madre muerte fetal

complicaciones metabolicas RN

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dialogo: feto-placenta

proteccion o respuestas adaptativas garantizar el desarrollo fetal en un medio estable

The rapid increase in the prevalence of diabesity, that is, obesity, type 2 diabetes and associatedcomplications, is a major problem for global health worldwide. The developmental origins of healthand adult disease (DOHaD) concept puts pregnancy and its influences on the mother and the devel-oping fetus in the focus of the transgenerational transmission of diabesity risk. Thus, the maternale-placentalefetal interaction has received increasing research interest.

The placenta is interposed between the maternal and fetal blood stream and thus constitutes thephysical link between the two generations. The maternal environment associated with diabetes (type1, type 2 and gestational) mellitus and/or obesity has an influence on placental development, structureand function, which has been summarized in several articles [1e14].

These placental alterations may be protective or adaptive responses to the maternal environment,with the ultimate purpose of allowing the fetus to grow and develop in a stable environment. Alter-natively, these changes might be mechanistically linked to the fetal phenotype associated withmaternal diabesity. It is not the purpose of this review to summarize once again placental changesassociated with diabesity. Rather, we will focus on one particular concept, with the focus on thematernal and fetal glucose/insulin axis and its effects on the placenta and the fetus. This concept mayexplain the fetal phenotype and some aspects of intrauterine programming of childhood obesity in thewake of maternal diabesity. We further intend to discuss options to prevent this from happening.

The fetal phenotype in diabesity

Much work has been published demonstrating the increased incidence of ‘macrosomia’ and large-for-gestational age neonates, that is, >90th birth-weight centile, born to diabesity pregnancies. Thisresearch focus is largely based on the obstetric complications associated with a macrosomic neonatesuch as an increased rate of caesarean sections, shoulder dystocia and others. However, there is agrowing body of evidence showing that the neonate of a diabetic mother, even when born in theappropriate-for-gestational age range (between the 5th or 10th and 90th birth-weight centile), has aphenotype different from those born to normal pregnancies. The major difference and thus the majoreffect of maternal diabesity on the neonate is on body composition: These neonates are born with ahigher proportion of body fat independent of their birth weight or birth-weight category [15e18],whereas the fat-free mass appears unaltered (Fig. 1). Interestingly, gestational diabetes and maternalobesity are independent risk factors for neonatal percentage body fat and contribute additively [19].

The higher neonatal body fat is of key importance because the number of adipocytes for a humanbeing seems to be determined very early in the life cycle if not already in utero [20]. The trajectory of

Fig. 1. Proportion (%) of body fat in neonates born to pregnancies with normal glucose tolerance of the mother (NGT) and motherswith gestational diabetes mellitus (GDM). GDM neonates have more body fat not only when born large-for-gestational age (LGA) butalso with appropriate-for-gestational age birth weight (AGA). No data are available for small-for-gestational age (SGA) neonates inGDM pregnancies (left panel). Neonates from lean (BMI < 25) mothers have a lower percentage body fat than their counterpartsborn to overweight (BMI ! 25) mothers (right panel). Data taken from Refs. [15,18].

G. Desoye, M. van Poppel / Best Practice & Research Clinical Obstetrics and Gynaecology 29 (2015) 15e2316

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dialogo: feto-placenta

proteccion o respuestas adaptativas garantizar el desarrollo fetal en un medio estable

The rapid increase in the prevalence of diabesity, that is, obesity, type 2 diabetes and associatedcomplications, is a major problem for global health worldwide. The developmental origins of healthand adult disease (DOHaD) concept puts pregnancy and its influences on the mother and the devel-oping fetus in the focus of the transgenerational transmission of diabesity risk. Thus, the maternale-placentalefetal interaction has received increasing research interest.

The placenta is interposed between the maternal and fetal blood stream and thus constitutes thephysical link between the two generations. The maternal environment associated with diabetes (type1, type 2 and gestational) mellitus and/or obesity has an influence on placental development, structureand function, which has been summarized in several articles [1e14].

These placental alterations may be protective or adaptive responses to the maternal environment,with the ultimate purpose of allowing the fetus to grow and develop in a stable environment. Alter-natively, these changes might be mechanistically linked to the fetal phenotype associated withmaternal diabesity. It is not the purpose of this review to summarize once again placental changesassociated with diabesity. Rather, we will focus on one particular concept, with the focus on thematernal and fetal glucose/insulin axis and its effects on the placenta and the fetus. This concept mayexplain the fetal phenotype and some aspects of intrauterine programming of childhood obesity in thewake of maternal diabesity. We further intend to discuss options to prevent this from happening.

The fetal phenotype in diabesity

Much work has been published demonstrating the increased incidence of ‘macrosomia’ and large-for-gestational age neonates, that is, >90th birth-weight centile, born to diabesity pregnancies. Thisresearch focus is largely based on the obstetric complications associated with a macrosomic neonatesuch as an increased rate of caesarean sections, shoulder dystocia and others. However, there is agrowing body of evidence showing that the neonate of a diabetic mother, even when born in theappropriate-for-gestational age range (between the 5th or 10th and 90th birth-weight centile), has aphenotype different from those born to normal pregnancies. The major difference and thus the majoreffect of maternal diabesity on the neonate is on body composition: These neonates are born with ahigher proportion of body fat independent of their birth weight or birth-weight category [15e18],whereas the fat-free mass appears unaltered (Fig. 1). Interestingly, gestational diabetes and maternalobesity are independent risk factors for neonatal percentage body fat and contribute additively [19].

The higher neonatal body fat is of key importance because the number of adipocytes for a humanbeing seems to be determined very early in the life cycle if not already in utero [20]. The trajectory of

Fig. 1. Proportion (%) of body fat in neonates born to pregnancies with normal glucose tolerance of the mother (NGT) and motherswith gestational diabetes mellitus (GDM). GDM neonates have more body fat not only when born large-for-gestational age (LGA) butalso with appropriate-for-gestational age birth weight (AGA). No data are available for small-for-gestational age (SGA) neonates inGDM pregnancies (left panel). Neonates from lean (BMI < 25) mothers have a lower percentage body fat than their counterpartsborn to overweight (BMI ! 25) mothers (right panel). Data taken from Refs. [15,18].

G. Desoye, M. van Poppel / Best Practice & Research Clinical Obstetrics and Gynaecology 29 (2015) 15e2316

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The Feto-placental Dialogue and Diabesity. Best Practice & Research Clinical Obstetrics and Gynaecology 29 (2015)

fenotipo fetal en diabesidad

hiperglicemia - hiperinsulinemia

aminoacidos y acidos grasos

arginina

gradiente glucosa

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Hipersinsulinemia

cremiento de la placenta crecimiento del corazón fetal

deposito de glicogeno en el endotelio placentario

incremento metabolismo aerobico fetal

incremento demanda de oxigeno

incremento HbA disminuye capacidad

transporte oxigenodisbalance entre demanda y soporte de oxigeno

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Hipersinsulinemia

cremiento de la placenta crecimiento del corazón fetal

deposito de glicogeno en el endotelio placentario

incremento metabolismo aerobico fetal

eritropoyesiscrecimiento vascular y angiogenesis placentaria disbalance entre demanda y soporte de oxigeno

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Hipersinsulinemia

gradiente glucosa

incremento consumo glucosa a los tejidos fetales

hipertrofia pancreatica

“fenomeno del robo de glucosa”

11 semanas

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defined as diabetes. Any elevation in maternal glucose and/or insulin early in gestation modifiesplacental growth and development. These alterations in the placenta may or may not (unclear yet)imply a change in transplacental glucose transfer, which along with a higher glucose concentrationgradient will increase glucose flux to the fetus. At what period in gestation this happens willdepend on the maternal glucose/insulin axis. Continuous glucose flux across the placenta will leadto stimulation of beta-cell growth and insulin secretion. Fetal insulin promotes glucose uptake intoperipheral tissues and steepens the maternal-to-fetal glucose concentration gradient with ensuingglucose flux to the fetus, which also becomes dependent on fetal insulin levels. Fetal insulin alsoincreases the number of adipocytes and triglyceride deposition in them. Importantly, insulin isable to malprogram the neuroendocrine systems regulating body weight, food intake and meta-bolism, at least in the rat [59]. This increases the risk of becoming obese and of developingdiabetes throughout life, also because of the ß-cell hyperplasia developed in utero which may leadto their earlier exhaustion.

This concept thus links early maternal derangements of the glucose/insulin axis with events in thefetus later in gestation or even postnatally. The placenta directly affects fetal development early inpregnancy by responding to the maternal environment. At later stages in pregnancy, it will primarilyrespond to fetal signals and adapt its structure, for example, by hypervascularization, and likely also itsfunction to fetal needs. Thus, maternal influences diminish from early to late gestation whereas thefetus gradually takes over control. Insulin plays a central role. The shift in insulin receptors from thetrophoblast, that is, the surface facing the maternal circulation to the endothelial cells interacting withor sensing circulating fetal insulin, provides the molecular basis for the topological change of insulinregulation [36,37,60,61].

On purpose, this concept is reductionistic in its design. By putting the glucose/insulin axis in itsfocus, it can explain some of the factors that have been shown to be associated with neonatal birthweight or adiposity and obesity risk in later life. For example, high triglyceride levels in the firsttrimester are just a manifestation of insulin resistance, and high neonatal leptin levels are theconsequence of adiposity and thus correlate with cord blood insulin [62]. Most importantly, fetalinsulin levels already at around weeks 32e34 of gestation, measured in the amniotic fluid, areassociated with the risk of impaired glucose tolerance at age 10e16 years [63] and childhood obesity(age 5e15 years: Ref. [64]; age 6 years: Ref. [65]) further demonstrating the relevance of fetal insulinand the need to prevent high levels of fetal insulin. The concept described above can only explain oneof the principal mechanisms associated with the risk of obesity-associated chronic diseases later inlife, which is based on fetal overnutrition (‘fuel-mediated in utero hypothesis’). However, offspringborn with a low birth weight also have an increased later risk of non-communicable diseases. Forthese associations, other concepts are in place such as fetal undernutrition and postnatal over-nutrition (‘mismatch hypothesis’) and the postnatal overnutrition (‘accelerated postnatal growthhypothesis’) [66].

Fig. 2. The mothereplacentaefetus dialogue. The scheme links early maternal metabolism to neonatal adiposity and obesity risk inlater life. For details, see text.

G. Desoye, M. van Poppel / Best Practice & Research Clinical Obstetrics and Gynaecology 29 (2015) 15e23 19

trigliceridos - leptina

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+

transmision transgeneracional de la diabesidad

diabetes exclusivamente precipitada por el embarazo

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¿como prevenir?disminución de la obesidad pre-gestacional y en etapas tempranas del embarazo

Radiel Study / LIFESTYLE study

The first trimester: Prediction and prevention of the great obstetrical syndromes.Best Practice & Research Clinical Obstetrics and Gynaecology 29 (2015)


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PRENATAL DIAGNOSISPrenat Diagn 2011; 31: 3–6.Published online in Wiley Online Library(wileyonlinelibrary.com) DOI: 10.1002/pd.2685

EDITORIAL

A model for a new pyramid of prenatal care basedon the 11 to 13 weeks’ assessment

Kypros H. Nicolaides1,2*1Harris Birthright Research Centre of Fetal Medicine, King’s College Hospital, London, UK2Department of Fetal Medicine, University College Hospital, London, UK

One century ago it was recognized that with the methodsand material at our disposal we were not making allthe progress possible toward solving many problemsof prenatal diagnosis and treatment (Ballantyne, 1901,1921). In order to achieve these objectives it was urgedthat a new means of investigation should be undertakenwhich had not yet been tried, at least not yet attemptedon a large scale and in a systematic fashion. This ledto the introduction of prenatal care which constituted amajor advance in the care of pregnant women and playeda pivotal role in the substantial reduction in maternal andperinatal mortality achieved during the last century.

In 1929, the Ministry of Health in the UK issueda Memorandum on Antenatal Clinics recommendingthat women should first be seen at 16 weeks, then at24 and 28 weeks, fortnightly thereafter until 36 weeksand then weekly until delivery (Figure 1) (Ministry ofHealth Report, 1929). No explicit rationale was offeredfor either the timing or clinical content of visits, yetthese guidelines established the pattern of prenatal careto be followed throughout the world until now. Thehigh concentration of visits in the late third trimesterimplies that most complications occur toward the endof pregnancy and most adverse outcomes cannot bepredicted from the first trimester. However, is this reallythe case? Scientific advances in the last 20 years haveraised the hope that many pregnancy complications arepotentially detectable from at least as early as the 12thweek of gestation. It has become apparent that mostmajor aneuploidies can be identified at 11 to 13 weeks’gestation by a combination of maternal characteristics,ultrasound findings and biochemical testing of maternalblood. It is also becoming increasingly apparent thatan integrated first hospital visit at 11 to 13 weekscombining data from maternal characteristics and historywith findings of biophysical and biochemical tests candefine the patient-specific risk for a wide spectrumof pregnancy complications, including miscarriage andfetal death, preterm delivery, preeclampsia, gestationaldiabetes, fetal growth restriction and macrosomia.

*Correspondence to: Prof. Kypros H. Nicolaides, Harris BirthrightResearch Centre for Fetal Medicine, King’s College Hospital,Denmark Hill, London SE5 9RS, UK.E-mail: [email protected]

Figure 1—Pyramid of prenatal care: past (left) and future (right)

FETAL ANEUPLOIDIES

We have learnt that about 90% of fetuses with major ane-uploidies can be identified by a combination of maternalage, fetal nuchal translucency (NT) thickness and mater-nal serum-free ß-hCG and PAPP-A at 11 to 13 weeks(Nicolaides, 2011). Improvement in the performance offirst-trimester screening can be achieved by first carry-ing out the biochemical test at 9 to 10 weeks and theultrasound scan at 12 weeks and second, inclusion inthe ultrasound examination assessment of the nasal boneand flow in the ductus venosus, hepatic artery and acrossthe tricuspid valve. A similar performance of screeningcan be achieved by examining the additional ultrasoundmarkers in all cases and by a contingent policy in whichfirst-stage combined screening classifies the patients ashigh-, intermediate- and low-risk and the new markersare examined only in the intermediate-risk group whichis then reclassified as low- or high-risk.

FETAL STRUCTURAL ABNORMALITIES

We have learnt that at the 11 to 13 weeks’ scan itis possible to diagnose or suspect the presence ofmost major abnormalities, which are either lethal orassociated with severe handicap, so that the parentscan have the option of earlier and safer pregnancytermination. Major fetal abnormalities fall into essen-tially three groups in relation to whether they can bedetected at the 11 to 13 weeks’ scan (Syngelaki et al.,2011): first, those which are always detectable abnor-malities, including body stalk anomaly, anencephaly,

Copyright © 2011 John Wiley & Sons, Ltd. Received: 30 November 2010Revised: 5 December 2010

Accepted: 5 December 2010

el test universal solo diagnostica al 50% de las DG

Prediccion y prevencion de DMG

prevenir incrementos leves de glucosa 1T prevenir riesgo de DM2 en la gestante

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primer trimestre tercer trimestresegundo trimestre

glucosametabolica?? screening universal 12ss??

PaPP-A PIGF

HAPO

La Era pre-HAPO

IADPSG

O`Sullivan

HAPO Study Cooperative Research Group- Metzger BE, Lowe LP, Dyer AR, et al. Hyperglycemia and adverse pregnancy outcomes.N Engl J Med. 2008

• Multicentrico 25000 mujeres, 75mg TOT 2hrs. • 24 -28 semanas de gestacion• Peso fetal, peptido C en cordon umbilical,

hipoglicemia neonatal, parto por cesarea• Parto pretermino, preeclampsia, distocia de

hombros o trauma obstetrico, hiperbilirrubinemia, admision a UCI-N

HAPO

HAPO Study Cooperative Research Group- Metzger BE, Lowe LP, Dyer AR, et al. Hyperglycemia and adverse pregnancy outcomes.N Engl J Med. 2008

• Hiperglicemia, IMC – Preeclampsia• Hiperglicemia materna - Peptido C neonatal • IMC independientemente de la

hiperglicemia – GEG y PE

• peptido C - hipoglicemia

HAPO

ACOGAmerican College Obstetrics and Ginecology

• Screening : Test O`Sullivan• TOG : 100mg / CC o NDDG

IADPSGInternational association of diabetes and pregnancy study groups

• Percentil de peso >90• Peptido C en cordon umbilical

1.75 veces el riesgo

International association of diabetes and pregnancy study groupsIADPSG

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Diabetes gestacional

Health & Medicine