MEDICINA FETAL: PRESENTE Y FUTURO

Eduard Gratacos

www.medicinafetalbarcelona.org/

MEDICINA FETAL: !PRESENTE Y FUTURO

BCNatal – Centre de Medicina Maternofetal i Neonatologia de Barcelona!Hospital Sant Joan de Déu i Hospital Clínic!

Universitat de Barcelona


Fetal Medicine & Therapy§ recent development!

§ high tech!

§ multidisciplinarity!

§ fetal surgery!

§ referral activity!

§ increasing importance!

§ high legal pressure


Evolution of social demands in Fetal Medicine & Therapy: !the fetus as a patient

society of information

perception fetus as a person

capacity !Dx & Tx

DEMANDS


Levels in Fetal Medicine!integration in public health

Advanced studies

Diagnosis1

2

3

US-guided fetal therapy

Endoscopic therapy & Fetal Surgery

Primary level

Tertiary Hospital!(1 in 300,000)

Fetal surgery Center!(1 in 15-20 million)



Complexity!Multidisciplinarity

Pregnancies

0.2%!(1 in >1,000)

5 % Advanced Fetal Medicine !Tertiary Center

Fetal surgery center!National or transnational level

Public Health System

100 %



FETAL MEDICINE

FETAL THERAPYPRENATAL DIAGNOSIS

QUANTITATIVE IMAGING

PREDICTION AND PREVENTION

FETAL PROGRAMMING


FETAL MEDICINE




FETAL PROGRAMMING


Detección prenatal de alteraciones cromosómicas!Screening de aneuploidías

100.000 embarazos

Detectados PérdidasBC / Amnio

Sistemático200 1000100% 100.000100%

Trisomía 21!N=200

Normal!N=99.800

Edad60 30 % 5.000 505%

Bioquímica II-T120 80% 7.000 707%

Combinado 1T180 90+% 3.000 303%

de todo un poco180 90 % 40.000 40040%


Prenatal detection of chromosomal abnormalities!cfDNA (NIPS)

MaternalFetal

Digital PCR Sequencing


Prenatal detection of chromosomal defects!Karyotype: cytogenetic vs. molecular (array-CGH)

Abnormal 100 % abnormal

N + Echo anomaly 6% relevant anomalies

N + Echo N + Age OR risk on screening 1.7% relevant anomalies

Wapner et al, NEJM 2012


FETAL MEDICINE




FETAL PROGRAMMING


La “piramide invertida” del control gestacional

1929

12

16 20 24

28 32 36!37 39 40 41

12

20

34

41

ESP

• 70% malformaciones • Anomalías crómosómicas • Preeclampsia/CIR precoz • Prematuridad • Diabetes

• 85% malformaciones • Prematuridad / Diabetes

• Preeclampsia tardía • CIR tardío

2000+


Fetal Medicine Unit

GENERAL POPULATION

Ultrasound Unit

Ultrasound Unit

Ultrasound Unit

Ultrasound Unit

Ultrasound Unit

Ultrasound Unit

Ultrasound Unit

FETAL MEDICINE DOES NOT EXIST WITHOUT DETECTION!THE CRITICAL NEED OF REDUCING VARIABILITY


Prediction of PE

PE

Detection Rates (for FPR 10%)

11-14w

LATE PE!40-55 %

EARLY PE! 80-90 %

INTEGRATED FIRST TRIMESTER APPROACH!maternal + UtA Doppler + biomarkers

Yu CK 2006, Poon LC 2009, Khalil A 2010, Poon LC 2010, Scazzocchio AJOG 2013


Hofmeyr G, Cochrane Database Syst Rev 2006 Askie LM, Lancet 2007 Bujold, Eur Obstet Gynecol 2010

Calcium (only if low intake=suppl. 1gr/24h)!!!

Vitamin C + E (no reduction risk, possible secondary effects)!!!

Aspirin (75-300 mg/d): reduction global risk!! if start <16w! ! !

! ! if high risk ! !! ! ! ! !

High risk of PE: management

10%!47%!60%


Prediction of PE

PE

Detection Rates (for FPR 10%)

32-34w

LATE PE!70-75 %

Lai et al. Fetal Diagn Ther 2013!(BP, UtA Doppler, sEng)!

Chaiworapongsa et al. AJOG 2013!(PlGF, sFlt-1, sEng)

THIRD TRIMESTER APPROACH!maternal OR UtA Doppler OR biomarkers


Nicolaides 2013

First T prediction of PD < 34w!n= 16,496 singletons with 178 (1.1%) deliveries <34w

CL<27 mm (5th centile)0

0

0

0

1

Maternal History Cervical Length

55%

33%

DR for FPR 10%Maternal History!

previous SPD, high BMI, smoking, maternal age, black race, nulliparity,


Study N Cut-off End point Placebo / Control Intervention Effect

Progesterone 200 mg (Fonseca)

250 <15 <34 36% 21% 0.58

Progesterone 90 mg (Hassan)

465 10-20 <33 16% 8,9% 0.55

Pessary (Goya) 385 <25 <34 27% 6% 0.18

Pessary (Hui) 108 <25 <34 5.5% 9.4% 1.7

Pessary (Nicolaides) 903 <25 <34 8.9% 9.0% 1.01

Interventions in patients with short cervix 18-24w


Extreme!0.2%

<28 28-31 34-3632-33

Severe!1%

Moderate!2%

Late!3%

The syndrome of !preterm delivery

Preterm delivery (<37 w)!7-12% of all pregnancies

Infection

Multiple!(overdistention)

Iatrogenic!35% maternal/fetal conditions

Spontaneous (SPD) !25% PROM ! ! ! ! ! !

! 40% intact membranes

“Life style”

inefficient M-F interaction !(assoc. pregn. complications)!polymorphisms/mutations!(assoc. severe malformations)

Idiopathic!(with short/normal cervix)




FETAL MEDICINE




FETAL PROGRAMMING


Key Hole Surgery

FETAL SURGERY ≈ FETOSCOPY!!

• fetus ≠ smaller neonate!!

• uterus and mother not operable


FETAL THERAPY MUST BE NICE FOR PATIENTS NOT FOR DOCTORS ( “PIONEERS TIME” IS OVER)


TTTS: laser therapy

Laser = best treatment option!NEJM 2004!!Barcelona, N=648!!Current survival of at least one fetus in 88%!!Literature: 80-85%!J Perinat Med 2013


Percutaneous Feto-Endoscopic Tracheal Occlusion!

Deprest J, Gratacos E, Nicolaides K. UOG 04

• increase airways pressure

• accelerated growth • first case: oct 01 • currently >500 !

TOTAL RCT international trial ongoing


LUNG DEFECTS

Bronchial atresia

Martinez et al. Fetal Diagn Ther 2013



Fetal surgery for spina bifida (NEJM 11)!• Deambulation 20% vs 40% in treated!• Need Shunt 85% vs 35%!• Maternal-fetal complications > 50%

http://www.emedicine.com/cgi-bin/foxweb.exe/makezoom@/em/makezoom?picture=%255Cwebsites%255Cemedicine%255Cped%255Cimages%255CLarge%255C2396SBA-MR-sag.jpg&template=izoom2


Fetal surgery for spina bifida


fetal surgery centers

Spain and influence area n=250-300 / year • excellence, not distance is a problem!• ideal scenario:!

• minimal politics!• “market” regulation!• accreditation and national registry

The problem of regulating a low-volume + high-complexity activity


FETAL MEDICINE




FETAL PROGRAMMING


NEONATAL RESPIRATORY MORBIDITY

FETAL LUNG MATURITY PROBLEMS AFFECT NEARLY 10%!LARGEST CAUSE OF PERINATAL MORBIDITY PRE- AND NEAR

Testing to be Performed on amniotic fluid ¨ 32-386/7 weeks of gestation


N=950!(expected >1,500)

FETAL LUNG MATURITY BY US TEXTURE ANALYSIS: !

MULTICENTER INTERNATIONAL STUDY

FETAL LUNG MATURITY PROBLEMS AFFECT NEARLY 10%!LARGEST CAUSE OF PERINATAL MORBIDITY PRE- AND NEAR (ACOG 2008)


(Submitted)

Clinical validation!n=144


FETAL MEDICINE




FETAL PROGRAMMING


Fetus Young OldChild Mature

IMPACT OF ENVIRONMENT

BIOLOGIC PROGRAMMING AND AGE

OPPORTUNITY FOR CORRECTION


Hediger 2013!Satchev, 2012!

Figueras 2006-2011!Baschat 2009, 2011!

Vohr 2004!Geva 2002-2011

Direct risk factors:!Growth restriction!

Prematurity!Cardiac Malformations!

Infections!Drugs

Indirect risk factors:!Multiple pregnancy!

Maternal age!Maternal diseases!

Obesity!ART


1986 Barker (MRC Unit, Southampton, UK): Coronary heart disease mortality rates


ART

1442

Assisted reproductive technologies (ARTs), mainly stan-dard in vitro fertilization or intracytoplasmic sperm

injection, permit childbirth in many infertile couples and nowadays represent 1% to 4% of births in developed coun-tries.1 Although these technologies are generally considered safe, the potential association of ART with poorer pregnancy outcomes has long been investigated. There is evidence that ART is associated with increased risk for adverse perinatal outcome and congenital malformations.2 This notwithstand-ing, it is not possible to separate ART-related risks from those secondary to the underlying reproductive pathology

of the infertile couple.3–5 In this scenario, preliminary evi-dence has recently suggested that ART could be associated with long-term cardiovascular changes. Ceelen et al6 first suggested the presence of increased blood pressure in late childhood after ART conception. More recently, another study demonstrated the presence of signs of systemic and pulmonary vascular dysfunction in 12-year-old children conceived by ART.7

Editorial see p 1398 Clinical Perspective on p 1450

Background—Assisted reproductive technologies (ARTs) have been shown to be associated with general vascular dysfunction in late childhood. However, it is unknown whether cardiac remodeling is also present and if these changes already manifest in prenatal life. Our aim was to assess fetal and infant (6 months of age) cardiovascular function in ART pregnancies.

Methods and Results—This prospective cohort study included 100 fetuses conceived by ART and 100 control pregnancies. ART fetuses showed signs of cardiovascular remodeling, including a more globular heart with thicker myocardial walls, decreased longitudinal function (tricuspid ring displacement in controls: median, 6.5 mm [interquartile range, 6.1–7.1 mm]; tricuspid ring displacement in ART: 5.5 mm [interquartile range, 5.1–6.1]; P<0.001), impaired relaxation, and dilated atria (atrial area in controls, 1.46 cm2 [interquartile range, 1.2–1.5 cm2]; atrial area in ART, 1.6 cm2 [interquartile range, 1.3–1.8 cm2]; P<0.001). Additionally, ART infants showed persistence of most cardiac changes and a significant increase in blood pressure and aortic intima-media thickness (systolic blood pressure in controls, 74 mm Hg [interquartile range, 67–83 mm Hg]; systolic blood pressure in ART, 83 mm Hg [interquartile range, 75–94 mm Hg]; P<0.001; aortic intima-media thickness in controls, 0.52 mm [interquartile range, 0.45–0.56 mm]; aortic intima-media thickness in ART, 0.64 mm [interquartile range, 0.62–0.67]; P<0.001). We could not demonstrate that our findings were directly caused by ART because of their association with various confounding factors, including intrauterine growth restriction or factors related to the cause of infertility.

Conclusions—Children conceived by ART manifest cardiac and vascular remodeling that is present in fetal life and persists in postnatal life, suggesting opportunities for early detection and potential intervention. The underlying mechanisms and the effect of potential confounders such as growth restriction or prematurity remain to be elucidated. (Circulation. 2013;128:1442-1450.)

Key Words: fertilization in vitro ◼ pediatrics ◼ pregnancy ◼ reproductive techniques, assisted ◼ ventricular remodeling

© 2013 American Heart Association, Inc.

Circulation is available at http://circ.ahajournals.org DOI: 10.1161/CIRCULATIONAHA.113.002428

Received March 5, 2013; accepted July 30, 2013.From the Institut Clínic de Ginecologia, Obstetrícia i Neonatologia, Hospital Clinic, Fetal and Perinatal Medicine Research Group (B.V.-A., F.C.,

M.C.-L., M.C., S.C., J. Balasch, E.G.) and Cardiology Department, Thorax Institute, Hospital Clínic (M.S.), Institut d’Investigacions Biomèdiques August Pi i Sunyer, University of Barcelona, Barcelona, Spain; Centro de Investigación Biomédica en Red en Enfermedades Raras, Barcelona, Spain (F.C., E.G.); Institució Catalana de Recerca i Estudis Avançats, Universitat Pompeu Fabra, Barcelona, Spain (B.B.); and Department of Pediatric Cardiovascular Surgery, University Hospital Sant Joan de Déu, Esplugues de Llobregat, Barcelona, Spain (J. Bartrons).

Drs Valenzuela-Alcaraz and Crispi contributed equally.The online-only Data Supplement is available with this article at http://circ.ahajournals.org/lookup/suppl/doi:10.1161/CIRCULATIONAHA.

113.002428/-/DC1.Correspondence to Eduard Gratacós, MD, Department of Maternal–Fetal Medicine (ICGON), Hospital Clinic, Sabino de Arana 1, 08028, Barcelona,

Spain. E-mail [email protected]

Assisted Reproductive Technologies Are Associated With Cardiovascular Remodeling In Utero That

Persists PostnatallyBrenda Valenzuela-Alcaraz, MD; Fàtima Crispi, MD; Bart Bijnens, PhD;

Monica Cruz-Lemini, MD; Montserrat Creus, MD; Marta Sitges, MD; Joaquim Bartrons, MD; Salvadora Civico, PhD; Juan Balasch, MD; Eduard Gratacós, MD

Pediatric CardiologyCeelen 2008, Scherrer 2012

ART: hypertension in childhood and adolescence

BP 90/65

cIMT = 0.386 mm

BP 95/75

cIMT = 0.434 mm


Fetus Child

Problem evident

WINDOW OF OPPORTUNITY

Func.onal / structural organ remodeling

BIRT

HIDENTIFICATION OF RISK

INDIVIDUAL BIOMARKERS

INTERVENTION

fetal composite CV score for the prediction of postnatal

hypertension !sensitivity 90%, specificity 77%

% polyunsaturated fats

AGA

IUGRcIMT

Cruz-‐Lemini FMF 2013, Skilton Pediatric 2012, Rodriguez 2013

4P medicine!• Predictive!• Preventive!• Personalized!• Participatory



FETAL MEDICINE




FETAL PROGRAMMING

Documents

MEDICINA FETAL: PRESENTE Y FUTURO