Reference Ranges for Fetal Atrioventricular and Ventriculoatrial Time Intervals and Their Ratios during Normal Pregnancy

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1 Originl Pper Received: July 10, 2017 Accepted fter revision: September 7, 2017 Published online: October 19, 2017 Reference Rnges for Fetl Atrioventriculr nd Ventriculotril Time Intervls nd Their Rtios during Norml Pregnncy Betrice Mosimnn Georgios Armptzis b Sofi Amylidi-Mohr Anice Bessire Mriluigi Spinelli Petros Koumoutskos b Dniel Surbek Luigi Rio Deprtment of Obstetrics nd Gynecology, University Hospitl nd University of Bern, Bern, nd b Deprtment of Computtionl Science, ETH Zürich, Zurich, Switzerlnd Keywords Fetl hert rte Fetl echocrdiogrphy Prentl dignosis Atrioventriculr time Ventriculotril time Abstrct Bckground: The dignostic ssessment of fetl rrhythmis relies on the mesurements of trioventriculr (AV) nd ventriculotril (VA) time intervls. Pulsed Doppler over innd outflow of the left ventricle nd tissue Doppler imging re well-described methods, while Doppler mesurements between the left brchiocephlic vein nd the ortic rch re less investigted. The im of this study ws to compre these methods of mesurement, to find influencing fctors on AV nd VA times nd their rtio, nd to crete reference rnges. Methods: Echocrdiogrphy ws performed between 16 nd 40 weeks of gesttion in norml singleton pregnncies. Nomogrms for the individul mesurements were creted using quntile regression with Mtlb Dt Anlytics. Sttisticl nlyses were performed with GrphPd version 5.0 for Windows. Results: A totl of 329 pregnnt women were enrolled. A significnt correltion exists between AV nd VA times nd gesttionl ge (GA) ( p = to <0.0001, σ = to ). No correltion ws found between the AV:VA rtio nd GA ( p = 0.08 to 0.60). All mesurements differed significntly mongst the studied methods ( p < ). Conclusions: AV nd VA intervls increse proportionlly with GA; no other independent influencing fctors could be identified. As significnt differences exist between the three methods of ssessment, it is crucil to use pproprite reference rnges to dignose pthologies. Introduction 2017 S. Krger AG, Bsel Fetl crdic rhythm disturbnces occur in bout 2% of ll pregnncies nd ccount for 10 20% of ll referrls to fetl crdiologist [1]. While fetl electrocrdiogrphy (ECG) monitoring is difficult nd not routinely obtinble in most centres, different methods of Doppler ssessment of the fetl hert nd djcent vessels provide helpful lterntives in the differentil dignosis of fetl rrhythmis tody. M-mode nd tissue Doppler imging (TDI) enble the recording of the sequence nd time reltionship of tril nd ventriculr systolic wll movement during hert cycle [2]. The simultneous recording of blood flow by pulsed Doppler sonogrphy of dj- E-Mil krger@krger.com S. Krger AG, Bsel Betrice Mosimnn, MD Deprtment of Obstetrics nd Gynecology University of Bern, Inselspitl Effingerstrsse 102, CH 3010 Bern (Switzerlnd) E-Mil hotmil.com

2 Color version vilble online b c Fig. 1. Illustrtion of the methods of mesurement. LV in-out: AV time is mesured from the beginning of the ctive contrction of the trium (E) to the beginning of the LV outflow, VA time vice vers. b TDI: AV time is mesured from the E-wve of the tril wll movement to the ventriculr contrction movement (S), VA time vice vers. c LBCV-AoA: AV time is mesured from the ndir d of the A-wve to the ortic outflow, VA time vice vers. d Illustrtion of the intersection of the LBCV with the AoA. AoA, ortic rch; AV, trioventriculr; LBCV, left brchiocephlic vein; LBCV-AoA, intersection of the left brchiocephlic vein nd the ortic rch; LV in-out, left ventriculr in- nd outflow; SVC, superior ven cv; TDI, tissue Doppler imging; VA, ventriculotril. cent rteries nd veins follows the sme concept [3 6]. With those different methods the mechnicl trioventriculr (AV) time intervl is ssessed, which correltes with the electricl PR time on routine ECG [4]. Assessing the AV time is helpful in the differentil dignosis of brdycrdi, in prticulr in dignosing firstdegree trioventriculr blocks (AVBs) [7], nd in the differentition of blocked suprventriculr premture bets (premture tril contrctions) from second-degree AVBs [8]. The ventriculotril (VA) time, which corresponds to the RP intervl on ECG, helps to distinguish re-entry tchycrdi from sinus tchycrdi, ectopic tril tchycrdi, nd permnent junctionl reciprocting tchycrdi [8]. Mesurements of AV times with pulsed Doppler over the left ventriculr in- nd outflow (LV in-out) trct, investigtions of blood flow simultneously over djcent pirs of rteries nd veins such s the scending ort nd the superior ven cv (SVC) or over the renl rtery nd vein [9], nd TDI-bsed ssessment re well described in the literture. There is however little informtion vilble on the ssessment of AV or VA times mesured t the level of the left brchiocephlic vein (LBCV) nd ortic rch (AoA), but lso generlly on VA times nd their reltions to AV intervls. The LBCV cn be investigted t little or no ngle of insontion throughout pregnncy, nd the intersection with the AoA is found without difficulties in most cses. The im of this study ws to crete reference rnges for AV, but lso for VA times nd their rtio, compring the three described methods nd to gin insight into the reltionship of AV nd VA times throughout gesttion. 2 Mosimnn et l.

3 Mteril nd Methods In consecutive pregnnt women the fetl AV nd VA times were mesured during routine exmintion using three different methods: (1) pulsed Doppler over the LV in-out trct, (2) TDI over the tricuspid nnulus, nd (3) pulsed Doppler t the level of the intersection of the LBCV nd the AoA (LBCV-AoA) ( Fig. 1 ). All Doppler investigtions were performed during fetl quiescence nd pnoe on Voluson GE E8 nd E10 mchines (GE Helthcre Inc.), equipped with GE RM6C 3D/4D probes. The high-pss filter ws set t 60 Hz nd to minimum for TDI, respectively. For ll mesurements 3 6 hert cycles were recorded. Inclusion criteri were singleton pregnncies with structurlly norml fetuses between 16 nd 40 weeks of gesttion. Exclusion criteri were fetl growth restrictions defined s estimted fetl weight (EFW) below the 5th percentile, ny known genetic bnormlity, mniotic fluid bnormlities, nd ll cses with fetl rrhythmi or fetl nemi. All ptients with positive SSA nd SSB ntibodies or women with overt preeclmpsi were lso excluded. In cse of seril mesurements only the first vilble one ws used for further nlysis. All mesurements were obtined by two certified sonogrphers only. For the LV in-out mesurement, we obtined n picl 4-chmber view of the hert nd used pulsed Doppler with the gte set in the LV close to the crux of the hert to simultneously ssess the blood flow through the mitrl nd ortic vlve. AV intervls were mesured from the onset of the mitrl A-wve (tril systole) between the E- nd A-pek to the beginning of the ventriculr systole in the ortic outflow trct. Similrly, the VA intervls were mesured from the ventriculr to the tril systole ( Fig. 1 ). For TDI, the smple gte ws plced over the lterl tricuspid vlve nnulus. The AV time ws gin mesured between the A- nd E-pek of the wll movement to the beginning of the ventriculr contrction mrked by negtive movement of the tricuspid nnulus, method described by Nii et l. [7] s A-S mesurement (tril contrction to ventriculr systole); the VA time ws mesured vice vers ( Fig. 1 b). For the mesurement performed t the level of the LBCV nd the AoA, the smple gte ws plced t the intersection of the LBCV nd the AoA ( Fig. 1 d). As the A-wve is mostly positive, the beginning of the tril contrction is not well defined, so we decided to ssess the AV time from the ndir of the A-wve to the beginning of the ventriculr contrction; gin the VA time ws mesured vice vers ( Fig. 1 c). Sttisticl nlyses were performed with GrphPd Prism version 5.0 for Windows (GrphPd Softwre, Sn Diego, CA, USA) nd Mtlb Dt Anlytics (MthWorks) for quntile regression. Liner regression nlysis ws used to evlute the effect of gesttionl ge (GA) on AV nd VA times. Correltions were serched using the Spermn rnk test. Mnn-Whitney test, t test, nd onewy ANOVA were used to compre continuous vribles. Sttisticl significnce ws considered chieved when p ws <0.05. Reference rnges for AV, VA, nd their rtio ssessed by the vrious methods were constructed by quntile regression [10, 11]. The α% quntile curve is modeled s polynomil of degree k for k = 1,2,3, which will be denoted by p α, k (t) = c α, k t k + + c α,1 t + c α,0, where the coefficients c i re estimted by quntile regression. The optiml vlue for the degree of the polynomil k is chosen by 10- fold crossvlidtion [12]. Tble 1. Mternl nd fetl chrcteristics nd pregnncy outcomes Clinicl chrcteristics This study ws pproved by the Ethics Committee of the University of Bern (Bsec No ). Inter- nd introbserver vribility were ssessed by intrclss correltion coefficients (ICCs) clculted with SPSS 21 (IBM SPSS Sttistics for Windows, Version 21; IBM Corp., Armonk, NY, USA). Agreement ws considered slight with n ICC 0.2, fir with 0.2 < ICC 0.4, moderte with 0.4 < ICC 0.6, substntil with 0.6 < ICC 0.8, nd lmost perfect with ICC >0.8. Results During the study period we included 329 pregnncies with complete ssessment of ll three methods of AV nd VA time mesurements. Mternl history nd clinicl chrcteristics s well s pregnncy outcomes re depicted in Tble 1. The medin [IQR] AV nd VA times for ll methods re depicted in Tble 2. A significnt correltion ws found between GA nd ll performed crdic intervl mesurements ( Tble 2 ). Reference rnges were constructed, s explined, using quntile regression modeling. For ech Doppler method the 5th, 10th, 50th, 90th, nd 95th percentile for GA ws clculted ( Fig. 2 ) using the following eqution: p α,2 (t ) = c α,2 t 2 + c α,1 t + c α,0. Medin [IQR] or % Medin mternl ge, yers 32.6 [ ] Medin mternl BMI t 12 weeks 22.5 [ ] Medin GA t inclusion, weeks 27.7 [ ] Medin estimted fetl weight Absolute, kg 1.10 [ ] Percentile 36.0 [ ] Fetl hert rte t inclusion, bpm 142 [ ] Nulliprous 38.9% Cigrette smoker 8.8% Chronic hypertension 2.7% Pregesttionl dibetes mellitus 1.0% SLE/SS/APS (SSA/SSB negtive) 2.1% Medin GA t delivery, weeks 39.3 [ ] Medin birth weight, kg 3.28 [ ] Medin birth weight percentile 37.5 [ ] APS, ntiphospholipid ntibody syndrome; GA, gesttionl ge; SLE, systemic lupus erythemtosus; SS, Sjögren syndrome. The coefficients (c ) re listed in Tble 3 ; α stnds for the percentiles 5, 50, nd 95, t stnds for GA. Fetl Atrioventriculr nd Ventriculotril Times 3

4 There ws no correltion between AV or VA times nd mternl chrcteristics; correltion of the prmeters existed with EFW ( p = to <0.0001, r = 0.16 to 0.32), but not with the percentiles of the EFW. There ws lso negtive correltion of ll time intervls with fetl hert rte (FHR) ( p = to <0.0001, r = 0.16 to 0.73), but s the length of hert cycle is the sum of the respective AV nd VA times, FHR is not n independent prmeter either. The AV:VA rtio ws GA independent by ll three methods ( p = 0.08 by LV in-out, p = 0.55 by LBCV-AoA, nd p = 0.60 by TDI). Therefore, we cn conclude tht proportionl prolongtion of AV nd VA times exists throughout gesttion ( Fig. 2 c, f, i). The medin [IQR] AV:VA rtio ws 0.19 [ ] by LBCV-AoA, 0.40 [ ] by LV in-out, nd 0.44 [ ] by TDI. Tble 2. Medin [IQR] AV nd VA time mesurements by LBCV- AoA, LV in-out, nd TDI nd their correltions with GA Medin [IQR], ms Correltion with GA AV time LBCV-AoA 67 [57 80] p = ; σ = AV time LV in-out 122 [ ] p = ; σ = AV time TDI 129 [ ] p < ; σ = VA time LBCV-AoA 356 [ ] p < ; σ = VA time LV in-out 298 [ ] p < ; σ = VA time TDI 293 [ ] p < ; σ = The Spermn rnk test ws used to clculte correltions. AV, trioventriculr; GA, gesttionl ge; LBCV-AoA, intersection of the left brchiocephlic vein nd the ortic rch; LV in-out, left ventriculr in- nd outflow; TDI, tissue Doppler imging; VA, ventriculotril. When compring the different wys of mesurement, AV time, VA time, s well s AV:VA rtio were significntly different between the three groups ( p < ) (Fig. 3 ). Intr- nd interobserver vribility were ssessed for ll mesurements obtined in series of 20 fetuses. In ll mesurements ICCs were found to be >0.9, the only exception being the AV intervl ssessed by LV in-out, which performed slightly poorer. All results re depicted in Tble 4. Discussion Our study demonstrtes tht AV nd VA times re correlted with GA, EFW, nd FHR, with GA s the only independent vrible. AV nd VA times increse proportionlly, which results in GA-independent AV:VA rtio. Both intervls s well s the rtio vry mrkedly with the Doppler method used. A high intr- nd interobserver relibility ws found for ll mesurements. It is therefore importnt to use pproprite reference rnges in the differentil dignosis of fetl rrhythmis. Our results re in line with previously studies demonstrting GA dependency of AV times. While Glickstein et l. [13] first did not demonstrte correltion of AV times with GA, others found liner correltion of AV times with GA nd FHR s well s tht GA is the only independent vrible [6, 7]. Unlike in those studies, our dt collected in significntly lrger cohort re not correlted linerly, but re better described by second-order polynomil correltion to GA. To the best of our knowledge, this is the first study to hve clculted reference rnges for VA times nd AV:VA rtios s well. Tble 3. Polynomil coefficients (c) to solve the quntile regression eqution c 5,2 c 5,1 c 5,0 c 50,2 c 50,1 c 50,0 c 95,2 c 95,1 c 95,0 Coefficients for AV times LBCV-AoA LV in-out TDI Coefficients for VA times LBCV-AoA LV in-out TDI α stnds for the percentiles 5, 50, nd 95. AV, trioventriculr; LBCV-AoA, intersection of the left brchiocephlic vein nd the ortic rch; LV in-out, left ventriculr in- nd outflow; TDI, tissue Doppler imging; VA, ventriculotril. 4 Mosimnn et l.

5 The first intruterine ssessment of AV nd VA times to dignose fetl rhythm disturbnces dtes bck nerly 20 yers nd ws initilly ttempted by M-mode echocrdiogrphy [14] nd shortly therefter lso by pulsed Doppler sonogrphy [2]. Alredy these first studies demonstrted tht the mesured times depend on the method they were ssessed with [2]. Nii et l. [7] compred different wys of mesuring AV time with fetl ECG. They concluded tht TDI mesurements between the tril contrction nd isovolumetric contrction (A-IV) correlted better with the ECG thn TDI mesurement between tril nd ventriculr contrction (A-S) or LV in-out mesurements. Furthermore, they found tht mesurements between the SVC nd the ort scendens (SVC- Ao) exhibit the lest correltion with ECG [7]. While the A-IV mesurement underestimted the PR intervl, AV time, ms VA time, ms b AV:VA rtio c LBCV-AoA LV in-out TDI Gesttionl ge, weeks d Gesttionl ge, weeks g Gesttionl ge, weeks AV time, ms LBCV-AoA LV in-out TDI Gesttionl ge, weeks e Gesttionl ge, weeks h Gesttionl ge, weeks VA time, ms LBCV-AoA LV in-out TDI Gesttionl ge, weeks f Gesttionl ge, weeks i Gesttionl ge, weeks AV:VA rtio AV time, ms VA time, ms AV:VA rtio Fig. 2. Reference rnges for AV times, VA times, nd AV:VA rtios between 16 nd 40 weeks of gesttion ssessed by LBCV-AoA, LV in-out, nd TDI. AV, trioventriculr; LBCV-AoA, intersection of the left brchiocephlic vein nd the ortic rch; LV in-out, left ventriculr in- nd outflow; TDI, tissue Doppler imging; VA, ventriculotril. Fetl Atrioventriculr nd Ventriculotril Times 5

6 AV time, ms VA time, ms AV:VA rtio LBCV-AoA LV in-out TDI b 0 LBCV-AoA LV in-out TDI c 0 LBCV-AoA LV in-out TDI Fig. 3. AV nd VA times s well s AV:VA rtios re significntly different by ll three methods of ssessment ( p < 0.01). AV, trioventriculr; LBCV-AoA, intersection of the left brchiocephlic vein nd the ortic rch; LV in-out, left ventriculr in- nd outflow; TDI, tissue Doppler imging; VA, ventriculotril. Tble 4. Intrclss correltion coefficients of intr- nd interobserver vribility of ech method of AV nd VA time intervl mesurement nd their 95% confidence intervls Introbserver vribility ob server 1 observer 2 Interobserver vribility AV time LBCV-AoA 0.95 ( ) 0.90 ( ) 0.95 ( ) LV in-out 0.85 ( ) 0.75 ( ) 0.88 ( ) TDI 0.94 ( ) 0.90 ( ) 0.94 ( ) VA time LBCV-AoA 0.96 ( ) 0.96 ( ) 0.98 ( ) LV in-out 0.98 ( ) 0.91 ( ) 0.97 ( ) TDI 0.97 ( ) 0.95 ( ) 0.97 ( ) AV, trioventriculr; LBCV-AoA, intersection of the left brchiocephlic vein nd the ortic rch; LV in-out, left ventriculr in- nd outflow; TDI, tissue Doppler imging; VA, ventriculotril. they noticed n over-estimtion by ll other methods. In PD-derived mesurements this is most likely explined by the fct tht the time dely from the Q-wve to the ventriculr ejection is longer thn the dely from the P- wve to the tril ejection [15]. Interestingly, t the sme time study in newborns lso showed highly significnt positive correltion between AV times nd PR intervls, nd lso systemtic over-estimtion of the PR intervl when mesured by SVC-Ao nd even more by LV in-out [16]. So, our findings of significntly different results for ll three methods re in line with previously published dt; however, in our collective the difference between TDI nd PD ws less evident thn tht described by Nii et l. [7]. AV times mesured by LBCV-AoA, on the other hnd, were shorter thn by ny other described method. This is due to the fct tht in the LBCV, the A-wve is negtive only in bout 20% of ll mesurement (unpublished results), nd therefore not the beginning, but the ndir of the A-wve ws used for mesurement ( Fig. 1 c). In the dignosis of first-degree AVB, n AV time 150 ms by PD LV in-out ws defined in the PRIDE study [17]. The criticl time period for SSA nd/or SSB ntibodies to cuse AVBs is between 18 nd 24 weeks of gesttion [16]. It remins mtter of debte whether first-degree AVBs cn be ccurtely dignosed prentlly nd lso if they do progress to higher degree AVBs nd whether they should be treted [18, 19]. Our results show tht with LV in-out the 99th percentile reches 150 ms t 6 Mosimnn et l.

7 28.3 weeks of gesttion while the 95th percentile never crosses 150 ms. However, s AV times mesured by TDI re longer, using this method the 95th percentile is bove 150 ms lredy fter 22.5 weeks; therefore, pplying the proposed cut-off would led to over-dignosis nd eventully over-tretment of mny fetuses t risk. Considering the controversies of high-dose intruterine but lso mternl steroid exposure, this distinction is even more crucil. AV times mesured by LBCV-AoA, on the other hnd, re significntly shorter nd fr from 150 ms in the norml popultion throughout gesttion. As mesurement inccurcies re more importnt the shorter the ctul mesured time is, we believe tht the dignosis of first-degree AVB should rely on LV in-out, TDI, or similr methods first. The differentil dignosis of suprventriculr fetl tchyrrhythmis is primrily bsed on the VA intervl being shorter or longer thn the AV intervl [8]. Our results demonstrte tht under physiologicl conditions, the VA time is bout 2 5 times longer tht the corresponding AV time. Re-entry tchycrdis typiclly present with VA time tht is shorter thn the AV time becuse fst conducting ccessory connection directs the electricl impulse from the ventricle bck to the tri, nd the AV:VA rtio will therefore increse to >1.0 [20]. While ll other suprventriculr fetl tchyrrhythmis re summrised s long VA tchyrrhythmis, it will be interesting in further studies to see whether the AV:VA rtio vries ccording to the underlying pthology, nd to test the use of our reference rnges in tht setting. The FHR decreses throughout gesttion, process tht continues in infncy nd hs mostly been explined by the incresing dominnce of the prsympthetic nervous system on the hert rte s pregnncy progresses [21]. As there is not only grdul prolongtion of the AV but lso proportionl prolongtion of the VA time, the whole crdic cycle expnds symmetriclly. In distinguishing premture tril contrctions from second-degree AVBs, using rteril nd venous vessel pirs is helpful since the premture bet cn very esily be detected s reversed venous flow. While SVC-Ao mesurements were proposed s the method of choice [22], the LBCV, thnks to its trnsverse course through the fetl thorx, cn be found nd ssessed esily throughout gesttion. Recently, Rodriguez et l. [23] demonstrted tht the AV intervl is lso prolonged in pregnncies dignosed with intrheptic cholestsis of pregnncy (ICP). At 36.7 weeks of gesttion they found n AV intervl of ± 10 ms in the control group, which corresponds lmost exctly to the 50th percentile of our mesurements, while the AV intervl in ICP ws more thn 10 ms longer on verge, but still within the norml rnge ccording to our dt. Eventully the finding of n longer AV intervl in ICP ptients might be helpful to time delivery in ffected pregnncies, nd we believe it would be interesting to see whether there is correltion between AV intervls nd bile cid levels, which re usully incresed in ICP. In conclusion, we hve creted reference rnges for AV, VA times, nd AV:VA rtios using three different methods of mesuring those fctors, two more commonly used nd one less investigted method. The study demonstrtes tht fixed cut-off independent of GA nd method of mesurement cnnot be useful in dignosing first-degree AVBs. The sme is likely to be true in the differentil dignosis of fetl tchyrrhythmis. Lst, our routine use of the LBCV-AoA method proved to be esy, nd we believe it will be helpful in differentiting bigeminl premture tril contrctions from second-degree AVBs. Acknowledgement G. Armptzis nd P. Koumoutskos grtefully cknowledge support from the Europen Reserch Council (ERC) Advnced Investigtor Awrd (No ). Disclosure Sttement The uthors hve no conflicts of interest to declre. References 1 Hornberger LK, Shn DJ: Rhythm bnormlities of the fetus. Hert 2007; 93: Fouron JC, Proulx F, Miro J, Gosselin J: Doppler nd M-mode ultrsonogrphy to time fetl tril nd ventriculr contrctions. Obstet Gynecol 2000; 96: Psquini L, Sele AN, Belmr C, Oseku-Afful S, Thoms MJ, Tylor MJ, Roughton M, Grdiner HM: PR intervl: comprison of electricl nd mechnicl methods in the fetus. Erly Hum Dev 2007; 83: Glickstein J, Buyon J, Kim M, Friedmn D; PRIDE Investigtors: The fetl Doppler mechnicl PR intervl: vlidtion study. Fetl Dign Ther 2004; 19: Crvlho JE, Prefumo F, Cirdelli V, Sirm S, Bhide A, Shinebourne EA: Evlution of fetl rrhythmis from simultneous pulsed wve Doppler in pulmonry rtery nd vein. Hert 2007; 93: Fetl Atrioventriculr nd Ventriculotril Times 7

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