Best practice guidelines

Myocardial hypertrophy and dysfunction in maternal diabetes

Paulo Zielinsky ⁎, Antonio Luiz Piccoli Jr. ⁎⁎Fetal Cardiology Unit, Institute of Cardiology, Porto Alegre, Brazil

a b s t r a c ta r t i c l e i n f o

Keywords:Fetal heartFetal cardiac functionFetal diastolic dysfunctionDiabetes in pregnancy

Diabetes in pregnancy, both pre-gestational and gestational, is a frequent cause of fetal myocardial hypertrophy,partly due to fetal hyperinsulinism. In fetal life, cardiac function may be impaired, especially during diastole, as aresult of decreased left ventricular distensibility and altered left atrial dynamics secondary to myocardial hyper-trophy. In neonates, the hypertrophy is a transient disorder, with spontaneous regression of the increasedmyocardial thickness during the first months of life. Nevertheless, cardiac hypertrophy may be associatedwith neonatal cardiomegaly and respiratory distress secondary to poor left ventricular compliance.The development of a number of new echocardiographic parameters discussed in this article, and primarilybased on the pathophysiological consequences of myocardial hypertrophy, highlight an area of researchpriority: the assessment of diastolic function in fetuses of diabetic mothers with (and without) myocardialhypertrophy. A score for grading the severity of fetal diastolic dysfunction in these fetuses is proposed.

© 2012 Elsevier Ireland Ltd. All rights reserved.

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2732. Myocardial hypertrophy in fetuses of diabetic mothers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2743. Conventional Doppler assessment of ventricular diastolic function . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2744. Alternative and newer methods to assess ventricular diastolic function . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 274

4.1. Mobility of the septum primum . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2744.2. Left atrial shortening fraction (LASF) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2744.3. Impedance to foramen ovale flow . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2754.4. Impedance to pulmonary venous flow . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2754.5. Impedance to ductus venosus flow . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2764.6. Fetal ventricular diastolic function assessed by tissue Doppler . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2764.7. Fetal aortic isthmus flow index (AIFI) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 276

5. Ongoing studies on fetal diastolic function in maternal diabetes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2775.1. Left ventricular isovolumic relaxation time in the fetus. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 277

6. Key guidelines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2777. Future research directions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 277Conflict of interest statement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 277Appendix A. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 277References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 277

1. Introduction

Pre-gestational maternal diabetes is a risk factor for fetal structuralheart disease. However, fetal cardiac function may be impaired as

a result of myocardial hypertophy, which is prevalent in both gestation-al and pre-gestational diabetic pregnancies. Post-natally, theincreased myocardial thickness (often referred to as ‘diabetic hypertro-phic cardiomyopathy’) is transient, with spontaneous regression duringthefirstmonths of life. Despite this transient nature, neonates of diabet-ic mothersmay present with cardiomegaly and respiratory distress, thelatter secondary to poor left ventricular compliance. These findingsstress the need for adequate prenatal assessment of diastolic function.

In the fetus of diabetic mothers with myocardial hypertrophy,cardiac function may be impaired, especially during diastole, as a

Early Human Development 88 (2012) 273–278

⁎ Correspondence to: P. Zielinsky, Av. Cristóvão Colombo 3038 ap. 303, 90560-002Porto Alegre, RS, Brazil. Tel.: +55 51 99696227; fax: +55 51 30619997.⁎⁎ Correspondence to: A.L. Piccoli Jr, Av. Princesa Isabel 395, 90620-001 Porto Alegre,RS, Brazil. Tel.: +55 51 98182593; fax: +55 51 30619997.

E-mail addresses: zielinsky@cardiol.br (P. Zielinsky), piccolijr@via-rs.net (A.L. Piccoli).

0378-3782/$ – see front matter © 2012 Elsevier Ireland Ltd. All rights reserved.doi:10.1016/j.earlhumdev.2012.02.006

Contents lists available at SciVerse ScienceDirect

Early Human Development

j ourna l homepage: www.e lsev ie r .com/ locate /ear lhumdev

result of a decreased left ventricular distensibility and altered left atri-al dynamics secondary to myocardial hypertrophy. Assessment ofdiastolic function in these fetuses has become an area of priority forresearch due to the development of a number of new echocardio-graphic parameters, which are reviewed in this article.

2. Myocardial hypertrophy in fetuses of diabetic mothers

The most frequent cause of myocardial hypertrophy seenprenatally is observed in fetuses of diabetic mothers. It occurs as acomplication of gestational or previous maternal diabetes in about25–30% of cases [1]. The ventricular septum is preferentially affected,but both right and left ventricular free walls may be involved, pre-dominantly the left [2] (Fig. 1). In-utero manifestation of myocardialhypertrophy is often not striking, but the hypertrophy is easilydetected by standard fetal echocardiography, usually by comparingseptal thickness with established nomograms [3,4]. Septal thicknessgreater than two standard deviations for gestational age is consideredabnormal. Histological features include increased nuclear and sarco-lemmal mass, as well as vacuolization and hydrops of hyperplasticmyocardial cells [5–7]. The etiology of myocardial hypertrophy infetuses of diabetic mothers remains controversial. Although fetalhyperinsulinism has long been suggested as the cause [8], the associ-ation between hypertrophic cardiomyopathy and high insulin levelsin amniotic fluid has only recently been demonstrated [9–12]. Inkeeping with this, post-natal regression of cardiomyopathy is relatedto normalization of insulin levels [12]. However, even though macro-somia is a common finding in neonates of diabetic mothers, noassociation with the development of fetal septal hypertrophy has

been found [2]. On the other hand, the increase in septal thicknessthroughout pregnancy is associated with increased levels of insulingrowth factor-1. Fetal cardiac function is also reduced when pre-conceptual maternal glycated hemoglobin is increased [13].

3. Conventional Doppler assessment of ventriculardiastolic function

Several studies have demonstrated that left ventricular diastolicfunction is impaired in fetuses with myocardial hypertrophy [14,15].Classical echocardiographic assessment of fetal diastolic functionuses Doppler analysis of mitral and tricuspid inflow signals. Pulsedwave Doppler waveforms obtained in diastole at the tip of both atrio-ventricular valves are biphasic, with an E-wave representing earlyventricular filling velocity, and an A-wave related to flow velocityduring atrial contraction, in pre-systole. The normal E/A ratio duringpregnancy is below 1, an indication that the fetal myocardium isrelatively ‘stiff’ compared to that of newborns and older children.While an increase or inversion of the E/A ratio is related to ventriculardiastolic dysfunction [14–16], differences in the pattern of atrioven-tricular flow in fetuses of diabetic mothers do not necessarily dependonly on alterations in ventricular compliance [17].

4. Alternative and newer methods to assess ventriculardiastolic function

The fetal circulation has unique characteristic features. Thus,traditional post-natal methods to assess ventricular diastole maynot be sufficient to assess cardiac function prenatally. In fetuses of di-abetic mothers, the myocardial hypertrophy decreases myocardial dis-tensibility and causes alterations in left atrial dynamics, due to theincreased left ventricular end-diastolic pressure. The consequences ofthe increment in left atrial pressure may be assessed by alternativeparameters.

4.1. Mobility of the septum primum

The flap valve of the foramen ovale is also called septum primum.This is a left atrial structure that will close the natural interatrialcommunication after birth. Typically in the fetus, the flap valve bulgestoward the left atrial cavity throughout each cardiac cycle.

We hypothesized that the magnitude of movement of the septumprimum could be related to left atrial pressure and dynamics. Toassess this diastolic mobility, we measured its “excursion index”(EI), defined as the ratio between the maximal linear displacementof the flap valve and the left atrial diameter in a four-chamber view[18] (Fig. 2A). We have shown that the EI was lower in third trimesterfetuses of diabetic mothers with septal hypertrophy than in fetuseswithout myocardial hypertrophy and fetuses from a control groupof normoglycemic mothers. In addition, a significant inverse correla-tion between septal hypertrophy and EI of the septum primum wasobserved. In normal fetuses, no correlation between the mobility ofthe septum primum and the diameter of the foramen ovale wasfound [19]. We suggested that the increase in left atrial diastolic pres-sure as a result of the less compliant hypertrophic left ventricle inter-feres with the normal mobility of the atrial flap valve, limiting itsmovement. Similar behavior of the septum primum mobility hasbeen demonstrated in fetuses with intrauterine growth restriction,reflecting diastolic dysfunction [20].

4.2. Left atrial shortening fraction (LASF)

To assess LASF, fetal echocardiography was performed in womenwith pre-existing or gestational diabetes and in non-diabetic controlsbetween 25 weeks gestation and term [21]. In all, LASF was calculatedusing M-mode measurements according to the formula: (end-systolic

Fig. 1. A: Cross-sectional four-chamber view from a 33-week fetus of a diabetic motherwith severe septal hypertrophy. B: M-mode tracing obtained from the same case show-ing increased thickness of the interventricular septum (distance between mar-kers=6.3 mm). RV = right ventricle; LV = left ventricle; IVS = interventricularseptum.

274 P. Zielinsky, A.L. Piccoli Jr. / Early Human Development 88 (2012) 273–278

diameter−end-diastolic diameter)/end-systolic diameter (Fig. 2B),and data were compared among the three groups. We havedemonstrated that LASF is lower in fetuses with myocardial hypertro-phy than in those without hypertrophy. A significant inverse linearcorrelation between LASF and interventricular septal thickness wasalso found. This study has shown that diastolic dysfunction also occursin diabetic fetuses without myocardial hypertrophy as shown bya significantly lower LASF compared to controls [21]. Studies carriedout in adults have shown that the dynamics of the left atrial wall isrelated to left ventricular compliance, especially in patients with hyper-trophic cardiomyopathy. Thus, LASF appears to be dependent on leftventricular preload and to be proportional to ventricular compliance[22].

4.3. Impedance to foramen ovale flow

The fetal foramen ovale has anatomical and functional vascularcharacteristics during the cardiac cycle, showing a triphasic venousflow profile. For this reason, the foramen ovale pulsatility index (PI),calculated by the Doppler ratio: (peak systolic velocity−peakpre-systolic velocity)/mean velocity, may be used as a parameter toassess its vascular impedance. We have shown that fetuses of diabeticmothers with myocardial hypertrophy had significantly higherforamen ovale flow PI than fetuses without hypertrophy, both ofdiabetic and normal control mothers. This finding was due to asignificant reduction in pre-systolic velocity (“more negative” awave) observed in fetuses with increased myocardial thickness,strengthening the idea that in late diastole, during atrial contraction,the events occurring in the hypertrophic left ventricle decrease itscompliance, thus influencing the flow across the foramen ovale [23](Fig. 3A).

4.4. Impedance to pulmonary venous flow

Pulmonary venous flow pattern is mainly determined by eventsthat occur in the left side of the heart [24]. It is influenced by dynamicchanges in left atrial pressure created by contraction and relaxation ofboth atrium and ventricle. An increase in its PI is a marker ofretrograde transmission of pressure, as this index reflects the rela-tionship between systolic, pre-systolic and mean pulmonary venousflow velocity. We have demonstrated that fetuses of diabetic mothershave a higher PI in the pulmonary veins than fetuses from motherswith normal glycemia [25]. The increase in left atrial pressure leadsto a restriction of pulmonary venous emptying, resulting in either adecrease in pre-systolic velocity or reverse flow in pre-systole. Thepulmonary vein PI, also related to impedance to forward flow, is inde-pendent of the insonation angle and thus, better than absolute mea-surement values of individual waveform velocities [25,26] (Fig. 3B).In the normal fetus, the pulmonary venous flow pulsatility decreasesas the vein is sampled from the lung to the heart, being inverselycorrelated to the diameter of the pulmonary vein, which increasesfrom its proximal to distal portion [27].

Fig. 2. A: Four-chamber view obtained from a 28-week fetus. ‘A’ represents maximalexcursion of the septum primum; ‘B’ represents maximal diameter of the left atrium.The ratio A/B expresses the excursion index of the septum primum. B: M-modeimaging through the left atrium obtained from a normal fetus at 29 weeks. Markersillustrate measurements for calculation of left atrial shortening fraction, obtained bythe ratio (maximal diameter−minimal diameter)/maximal diameter. LA = leftatrium, RA = rigtht atrium; RV = right ventricle; LA = left atrium; LV = left ventricle.

Fig. 3. A: Pulsed wave Doppler across the foramen ovale obtained from the same fetusshown in Fig. 1. There is a prominent pre-systolic wave with an increased pulsatilityindex (PI=3.7 normal≤2.5), reflecting diastolic dysfunction. B: Doppler tracing ofpulmonary vein flow from a 31-week healthy fetus depicting normal PI (=0.8,normal≤1.2). The signal was obtained by placing the pulsed Doppler sample volumeover the right superior pulmonary vein, as near as possible to its junction with theleft atrium. S = systolic peak; D = diastolic peak; A = pre-systolic peak.

275P. Zielinsky, A.L. Piccoli Jr. / Early Human Development 88 (2012) 273–278

4.5. Impedance to ductus venosus flow

Ductus venosus flow plays a fundamental role in fetal hemody-namics, and its analysis has been the subject of study in severalpathological situations. Flow of highly saturated blood through theforamen ovale depends directly on the velocity of ductus venosusflow, its PI reflecting its impedance. We have assessed ductus venosusPI related to myocardial hypertrophy and fetal diastolic ventricularfunction in maternal diabetes. Fetuses of diabetic mothers with septalhypertrophy showed a significantly higher ductus venosus PI thanthose of diabetic mothers without septal hypertrophy and controlfetuses. No difference was observed in mitral and tricuspid A wavevelocities. These results suggest that ventricular compliance isimpaired as a consequence of myocardial hypertrophy and maternaldiabetes, indicating that the assessment of the ductus venosus maybe more sensitive than the analysis of atrioventricular flows fordetecting a decrease in ventricular compliance [28] (Fig. 4A).

4.6. Fetal ventricular diastolic function assessed by tissue Doppler

Tissue Doppler now represents one of the most recent echocardio-graphic approaches to study and analyze fetal cardiac diastolic

function. This technique allows direct evaluation of myocardial veloc-ities throughout the cardiac cycle and avoids the limitations imposedby high heart rate and loading conditions associated with Doppleranalysis of atrioventricular diastolic flow [29–31]. In fetuses ofdiabetic mothers, it has been suggested that diastolic dysfunctionmay precede myocardial hypertrophy. Using tissue Doppler, wehave assessed fetal diastolic function in such fetuses, with or withoutmyocardial hypertrophy and compared the findings to those obtainedin fetuses of non-diabetic mothers (Fig. 5). In controls, early diastolicvelocities (E′) at mitral, tricuspid and septal levels are almost alwayslower than late tissue velocities (A′). Additionally, right and left ven-tricular myocardial wall velocities (E′ and A′) are usually higher thanseptal velocities. Similar differences according to site of myocardialsampling are also observed in fetuses of diabetic mothers. However,when compared to normal fetuses, diastolic myocardial velocities atthe level of the aortic and mural leaflets of mitral valve and tricuspidvalve annulus, are significantly higher in fetuses of diabetic mothers.Further post-hoc analysis has also shown that these changes indiastolic function do not depend on the presence of fetal ventricularhypertrophy. Furthermore, significantly lower ratios of flow to myo-cardial velocities (E/E′ ratio) were observed in both atrioventricularvalves in fetuses of diabetic mothers compared to controls, as a resultof higher myocardial velocities (E′), rather than changes in earlyatrioventricular diastolic flow velocities (E). In adults with aortic ste-nosis, mitral E/E′ ratio has been positively correlated with increasedleft ventricular filling pressure: lower E′ velocities, higher E/E′ ratio[32]. On the other hand, significantly lower mitral valve E/E′ ratiohas been found in patients with ischemic disease and more compro-mised left ventricular function [33]. Thus, in the fetus of a diabeticmother, we can only speculate on the reasons for the higher myocar-dial velocities at the level of the atrioventricular annuli. Since duringatrial filling there is a displacement of the mitral annulus toward theapex and this effect is reversed during early ventricular filling, a lesscompliant left ventricle could favor a more abrupt return of the mitralannulus to its initial position. Since many of these patients have notshown changes in trans-mitral or trans-tricuspid flow as assessedby pulsed wave Doppler, the above data suggests that tissue Dopplermay be more sensitive than conventional Doppler for the diagnosis offetal diastolic dysfunction. It appears that maternal diabetes mellitusis associated with intrinsic alterations in fetal left ventricular diastolicfunction and not only as a result of myocardial hypertrophy [34].

4.7. Fetal aortic isthmus flow index (AIFI)

Since the early studies by Fouron and colleagues in 1993 [35–37],much have been investigated about the role of the aortic isthmusflow index on the fetal circulation, obtained by the ratio: (systolic-

Fig. 4. A: Ductus venosus Doppler flow signal from the same healthy 31-week fetus as inFig. 3B. B: Aortic isthmalflowsignal obtained from the same fetus shown in Fig. 1,with severeseptal hypertrophy. Due to a decrease in diastolic flow signal, the isthmal flow index is de-creased ((IFI=1.05, normal≥1.2). S= systolicflow;D=diastolicflow;=pre-systolicflow.

Fig. 5. Myocardial tissue Doppler signal obtained from a 30 week-fetus of a controlnon-diabetic mother. The E′/A′ ratio is normal (0.60).

276 P. Zielinsky, A.L. Piccoli Jr. / Early Human Development 88 (2012) 273–278

time integral+diastolic velocity-time integral)/systolic time integral.According to these early studies, the aortic isthmus is the only truearterial shunt in the fetus, and thus influences the balance betweencerebral and placental circulations in many pathological conditions.Since the pattern of isthmal flow includes a systolic antegrade compo-nent dependent on both left and right ventricular ejection and a dia-stolic antegrade component which depends on cerebral and placentalresistances, changes in cardiac function may influence the behavior ofthe aortic isthmus flow. We hypothesized that an increase in rightventricular output in fetuses of diabetic mothers, as a result of in-creased impedance to flow through the foramen ovale, ductus venosusand pulmonary veins, secondary to a higher left atrial pressure, couldinterfere with diastolic antegrade flow across the aortic isthmus andlead to a decrease in the AIFI (Fig. 4B). We have observed a lowerAIFI in fetuses of diabetic mothers, with or without myocardialhypertrophy, than in fetuses of normal control mothers, in keepingwith the proposed hypothesis [38].

5. Ongoing studies on fetal diastolic function in maternal diabetes

Another parameter, namely left ventricular isovolumic relaxationtime (IVRT) is the subject of an ongoing study of cardiac function indiabetic pregnancies. A summary is presented below (unpublishedobservation) We have also constructed a numerical score to quantifyfetal global diastolic function using the several parameters discussedherein and suggest that this score may be useful in monitoring suchpregnancies (see future research directions).

5.1. Left ventricular isovolumic relaxation time in the fetus

Left ventricular IVRT represents the earliest phase of diastole, corre-sponding to the time interval between closure of the aortic valve andopening of mitral valve. Changes in left ventricular compliance and re-laxation may prolong this time interval [16]. In maternal diabetes, thealtered left ventricular diastolic function is expected to increase IVRT.This is in keeping with our observations in a prospective study compar-ing fetuses of diabetic mothers, with and without hypertrophy, withcontrols. We have shown that fetuses with myocardial hypertrophyhad higher left IVRT intervals than those without. Furthermore, evenwithout increased ventricular mass, fetuses of diabetic mothers hadlarger IVRT intervals than normal controls. These observations suggestthat IVRT might be a sensitive tool to detect fetal diastolic dysfunctionin maternal diabetes, even before the appearance of myocardialhypertrophy.

6. Key guidelines

• The most frequent prenatal presentation of myocardial hypertrophyis seen in fetuses of diabetic mothers.

• Hypertrophic cardiomyopathy in neonates of diabetic mothers is atransient disorder, with spontaneous regression during the first6 months of postnatal life, related to the normalization of insulinlevels.

• However benign, this disorder may cause neonatal cardiomegaly andrespiratory distress secondary to poor left ventricular compliance.

• Cardiac function in fetuses of diabetic mothers may be altered whenmaternal glycated hemoglobin is increased.

• Myocardial hypertrophy in fetuses of diabetic mothers, leading to adecrease in myocardial distensibility, alters left atrial dynamics, dueto the increased left ventricular end-diastolic pressure.

• The fetal circulation has unique characteristic features. Assessmentof ventricular diastolic function based on atrioventricular valvesflow analysis alone is insufficient to assess fetal cardiac function.

• The consequences of the increment in left atrial pressure may beassessed by alternative parameters: mobility of the septum primum,impedance to foramen ovale flow, left atrial shortening fraction,

impedance to pulmonary venous flow, impedance to ductus venosusflow, tissue Doppler and aortic isthmus flow index.

7. Future research directions

• Additional Doppler-derived parameters such as ‘left ventricularisovolumetric relaxation time’ may prove useful in the assessmentof global fetal diastolic function.

• To evaluate means of predicting outcome in fetuses of diabeticmothers based on the degree of functional compromise. A score ofleft ventricular diastolic dysfunction based on several echocardio-graphic parameters is proposed (see Appendix A, validation of thisscore is ongoing).

• Although the proposed fetal diastolic dysfunction score has beencreated to grade fetal and neonatal risk in maternal diabetes, itmay also be tested in other clinical settings where left ventriculardiastolic function may be impaired, such as intrauterine growthrestriction.

Conflict of interest statement

There are no conflict of interest.

Appendix A

Proposed scoring system to assess fetal diastolic dysfunction.

Myocardial hypertrophy is considered a categorical variable(absent = 0, present = 1). The other seven parameters are assigned0, 1, 2 or 3 points. ‘Zero’ points equate to a normal value. One, twoor three points are arbitrarily given to different cut-off values, as ap-propriate for each parameter. Minimal score = 0, maximal score =25.

EI = excursion índex, PI = pulsatility índex, SF = shorteningfraction, AIFI = aortic isthmus flow índex.

Degree of diastolic dysfunction according to the scoring system

References

[1] Zielinsky P, Hagemann L, Daudt L, Behle I, Rodrigues R. A pre andpostnatal analysis offactors associated with fetal myocardial hypertrophy in diabetic pregnancies. JMatern Fetal Invest 1992;2:163–7.

[2] Zielinsky P. Role of prenatal echocardiography in the study of hypertrophiccardiomyopathy in the fetus. Echocardiography 1991;8:661–8.

[3] Allan LD, Joseph MC, Boyd EG, Campbell S, TynanM. M-mode echocardiography inthe developing human fetus. Br Heart J 1982;47:573–83.

[4] Leslie J, Shen S, Thornton JC, Strauss L. The human fetal heart in the secondtrimester of gestation: a gross morphometric study of normal fetuses. Am J ObstetGynecol 1983;145:312–6.

3 points 2 points 1 point 0 points

Septum primum EI b0.25 0.26–0.35 0.36–0.45 >0.45Left atrium SF b0.25 0.26–0.35 0.36–0.45 >0.45Mitral E/A ratio >1.0 0.9–1.0 0.8–0.9 b0.8Pulmonary vein PI >2.0 1.5–2.0 1.2–1.4 b1.2Ductus venosus PI >2.0 1.5–2.0 1.2–1.4 b1.2Foramen ovale PI >3.5 3.0–3.5 2.5–2.9 b2.5AIFI b1.0 1.0–1.09 1.10–1.20 >1.20Myocardial hypertrophy Present=4

Absent=0

Fetal diastolic dysfunction score

Zero points Absent1–10 points Mild11–20 points Moderate>20 points Severe

277P. Zielinsky, A.L. Piccoli Jr. / Early Human Development 88 (2012) 273–278

[5] Fenichel P, Hieronimus S, Bourlon F, Leonard J, Boutte P, Gillet JY, et al. Fetalmacrosomia in a diabetic mother. Presse Med 1990;19:255–8.

[6] Vela-Huerta MM, Vargas-Origel A, Olvera-Lopez A. Asymmetrical septal hypertro-phy in newborn infants of diabetic mothers. Am J Perinatol 2000;17:89–94.

[7] MenezesHS, BarraM, Bello AR,Martins CB, Zielinsky P. Fetalmyocardial hypertrophyin an experimental model of gestational diabetes. Cardiol Young 2001;11:609–13.

[8] Steinke J, Driscoll SG. The extractable insulin content of pancreas from fetuses andinfants of diabetic and control mothers. Diabetes 1965;14:573–8.

[9] Hagemann LL, Zielinsky P. Prenatal study of hypertrophic cardiomyopathy and itsassociation with insulin levels in fetuses of diabetic mothers. Arq Bras Cardiol1996;66:193–8.

[10] Mehta A, Hussain K. Transient hyperinsulinism associated with macrosomia,hypertrophic obstructive cardiomyopathy, hepatomegaly, and nephromegaly.Arch Dis Child 2003;88:822–4.

[11] Morville P, Gaillard D. Cardiomyopathy in children of diabetic mothers. Fetal hy-perinsulinism and cardiomyopathy. Ann Pediatr (Paris) 1985;32:363–8.

[12] Zielinsky P, da Costa MH, Oliveira LT, Bonow FP, da Silva NI, Hagemann LL. Naturalhistory of myocardial hypertrophy and its association with hyperinsulinism ininfants of diabetic mothers. Arq Bras Cardiol 1997;69:389–94.

[13] Gardiner HM, Pasquini L, Wolfenden J, Kulinskaya E, Li W, Henein M. Increasedpericonceptual maternal glycated haemoglobin in diabetic mothers reducesfetal long axis cardiac function. Heart 2006;92:1125–30.

[14] Rizzo G, Arduini D, Romanini C. Accelerated cardiac growth and abnormal cardiacflow in fetuses of type I diabetic mothers. Obstet Gynecol 1992;80:369–76.

[15] Pacileo G, Paladini D, Palmieri S, Pisacane C, Russo MG, Calabro R. Echocardio-graphic assessment of diastolic function in normal human fetuses. J Perinat Med1994;22(Suppl. 1):43–5.

[16] Tsyvian P, Malkin K, Artemieva O, Wladimiroff JW. Assessment of left ventricularfilling in normally grown fetuses, growth-restricted fetuses and fetuses of diabeticmothers. Ultrasound Obstet Gynecol 1998;12:33–8.

[17] Weiner Z, Efrat Z, Zimmer EZ, Itskovitz-Eldor J. Fetal atrioventricular blood flowthroughout gestation. Am J Cardiol 1997;80:658–62.

[18] Firpo C, Zielinsky P. Mobility of the flap valve of the primary atrial septum in thedeveloping human fetus. Cardiol Young 1998;8:67–70.

[19] Zielinsky P, Sallum M, Satler F, Gus E, Nicoloso L, Mânica JL, et al. Mobility of theseptum primum does not depend on the foramen ovale diameter in normal fe-tuses. Arq Bras Cardiol 2004;83 304–7; 0–3.

[20] Zielinsky P, Beltrame PA, Manica JL, Piccoli Jr AL, da Costa MA, Motta L, et al.Dynamics of the septum primum in fetuses with intrauterine growth restriction.J Clin Ultrasound 2009;37:342–6.

[21] Zielinsky P, Luchese S, Manica JL, Piccoli Jr AL, Nicoloso LH, Leite MF, et al. Left atri-al shortening fraction in fetuses with and without myocardial hypertrophy in di-abetic pregnancies. Ultrasound Obstet Gynecol 2009;33:182–7.

[22] Briguori C, Betocchi S, Losi MA, Manganelli F, Piscione F, Pace L, et al. Noninvasiveevaluation of left ventricular diastolic function in hypertrophic cardiomyopathy.Am J Cardiol 1998;81:180–7.

[23] Zielinsky P, Manica SJL, Piccoli Jr AL, Nicoloso LH, Scheid M, Frajndlich R, et al.Behavior of the foramen ovale flow in fetuses of diabetic mothers and myocardialhypertrophy. Rev Bras Ecocardiogr 2005;18:15–21.

[24] Keren G, Sherez J, Megidish R, Levitt B, Laniado S. Pulmonary venous flow pattern-its relationship to cardiac dynamics. A pulsed Doppler echocardiographic study.Circulation 1985;71:1105–12.

[25] Zielinsky P, Piccoli Jr AL, Teixeira L, Gus E, Mânica JL, Satler F, et al. Pulmonary veinpulsatility in fetuses of diabetic mothers: prenatal Doppler echocardiographicstudy. Arq Bras Cardiol 2003;81 604–7, 0–3.

[26] Lenz F, Chaoui R. Reference ranges for Doppler-assessed pulmonary venous bloodflow velocities and pulsatility indices in normal human fetuses. Prenat Diagn2002;22:786–91.

[27] Zielinsky P, Piccoli Jr AL, Gus E, Mânica JL, Satler F, Nicoloso LH, et al. Dynamics ofthe pulmonary venous flow in the fetus and its association with vascular diame-ter. Circulation 2003;108:2377–80.

[28] Zielinsky P, Marcantonio S, Nicoloso LH, Piccoli Jr AL, Gus E, Mânica JL, et al.Ductus venosus flow and myocardial hypertrophy in fetuses of diabetic mothers.Arq Bras Cardiol 2004;83 51–6; 45–50.

[29] Allan LD, Chita SK, Al-Ghazali W, Crawford DC, Tynan M. Doppler echocardio-graphic evaluation of the normal human fetal heart. Br Heart J 1987;57(6):528–33.

[30] McDicken WN, Sutherland GR, Moran CM, Gordon LN. Colour Doppler velocityimaging of the myocardium. Ultrasound Med Biol 1992;18:651–4.

[31] Miyatakea K, Yamagishia M, Tanakaa N, Uematsua M, Yamazakia N, Minea Y, et al.New method for evaluating left ventricular wall motion by color-coded tissueDoppler imaging: in vitro and in vivo studies. J Am Coll Cardiol 1995;25:717–24.

[32] Bruch C, Stypmann J, Grude M, Gradaus R, Breithardt G, Wichter T. Tissue Dopplerimaging in patients with moderate to severe aortic valve stenosis: clinicalusefulness and diagnostic accuracy. Am Heart J 2004;148:696–702.

[33] Baykan M, Yilmaz R, Celik S, Orem C, Kaplan S, Erdol C. Assessment of leftventricular systolic and diastolic function by Doppler tissue imaging in patientswith preinfarction angina. J Am Soc Echocardiogr 2003;16:1024–30.

[34] Hatém MA, Zielinsky P, Hatém DM, Nicoloso LH, Manica JL, Piccoli AL, et al.Assessment of diastolic ventricular function in fetuses of diabetic mothers usingtissue Doppler. Cardiol Young 2008;18:297–302.

[35] Bonnin P, Fouron JC, Teyssier G, Sonesson SE, Skoll A. Quantitative assessment ofcirculatory changes in the fetal aortic isthmus during progressive increase ofresistance to umbilical blood flow. Circulation 1993;88:216–22.

[36] Fouron JC, Siles A, Montanari L, Morin L, Ville Y, Mivelaz Y, et al. Feasibility andreliability of Doppler flow recordings in the fetal aortic isthmus: a multicenterevaluation. Ultrasound Obstet Gynecol 2009;33:690–3.

[37] Fouron JC, Zarelli M, Drblik P, Lessard M. Flow velocity profile of the fetal aorticisthmus through normal gestation. Am J Cardiol 1994;74:483–6.

[38] Zielinsky P, Frajndlich R, Nicoloso LH, Manica JL, Piccoli Jr AL, Morais M, et al. Aorticisthmus blood flow in fetuses of diabetic mothers. Prenat Diagn 2011;31:1176–80.

278 P. Zielinsky, A.L. Piccoli Jr. / Early Human Development 88 (2012) 273–278