bnormalities of fetal growth begin in the first trimester of preg-nancy with impaired trophoblastic invasion of uterine spiral arteri-es which can be demonstrated histologically.1Fetuses that are small
for gestational age have an increased risk for perinatal morbidity and mor-tality.2Complications related to birth weight can be prevented with timely
antenatal detection and closer surveillence of pregnancies with
small-for-Low Second Trimester Estimated Fetal Weight
as a Predictor of Small-for-Gestational Age
Neonates in Patients with Low First Trimester
Serum PAPP-A Levels
AABBSS TTRRAACCTT OObb jjeecc ttii vvee:: The aim of this study was to exa mi ne fe tal growth in the se cond tri mes ter and to de tect its pre dic ti ve va lu e for de li ve ring small-for-ges ta ti o nal age ne o na tes in pa ti ents with low first tri mes ter preg nancy as so ci a ted plas ma pro te in-A (PAPP-A) le vels. MMaa ttee rrii aall aanndd M
Meett hhooddss:: We se arc hed the pa ti ent charts of our hos pi tal for first tri mes ter Down syndro me scre e -ning tests ret ros pec ti vely (n=923), we iden ti fi ed pa ti ents with PAPP-A le vels < 5th per cen ti le (n=60) and then we se arc hed the ir ul tra so und re cords for se cond tri mes ter es ti ma ted fe tal we ight (EFW) re sults (Had lock) at 18-23 we eks. RRee ssuullttss:: The sen si ti vity of a low se cond tri mes ter EFW for birth we ights <5thper cen ti le was 14.3%, spe ci fi city 90.7%, po si ti ve pre dic ti ve va lu e 33.3% and ne ga ti ve
pre dic ti ve va lu e 76.4%. CCoonncc lluu ssii oonn:: Com bi na ti on of low se cond tri mes ter EFW with low PAPP-A le vels in cre a se sen si ti vity and PPV of PAPP-A in de tec ting small-for-ges ta ti o nal age ne o na tes. KKeeyy WWoorrddss:: In fant, small for ges ta ti o nal age; preg nancy tri mes ter, se cond;
preg nancy-as so ci a ted plas ma pro te in-A Ö
ÖZZEETT AAmmaaçç:: Bu ça lış ma nın ama cı ilk üçay gebelik ilişkili plazma proteini A (PAPP-A) se vi ye le ri dü şük bu lu nan has ta lar da, ikin ci üçay tah mi ni fe tal ağır lık öl çüm le ri nin dü şük do ğum ağır lık lı fe-tüs le ri tah min et me de kul la nı la bi lir li ği ni tes pit et mek tir. GGee rreeçç vvee YYöönn tteemm lleerr:: Ret ros pek tif ola rak dü zen le nen ça lış ma da has ta ne mi zin ge be ka yıt la rı in ce len di ve ilk üçay Down sen dro mu ta ra ma test le ri nin so nuç la rı bu lu na rak (n=923), PAPP-A se vi ye le ri 5. per sen ti lin al tın da ka lan has ta lar (n=60) tes pit edil di. Bu has ta la rın ul tra son ka yıt la rın dan 18-23. haf ta lar ara sın da ya pıl mış ikin ci üçay tah mi ni fe tal ağır lık per sen til le ri (Had lock) he sap lan dı. BBuull gguu llaarr:: İkin ci üçay ul tra so nun da dü şük tah mi ni fe tal ağır lık sap tan ma sı nın 5. per sen ti lin al tın da ki ye ni do ğan do ğum ağır lık la rı nı tes pit et me du yar lı lı ğı %14,3, öz gül lü ğü %90,7, po zi tif kes ti rim de ğe ri %33,3 ve ne ga tif kes ti rim de ğe ri %76,4 ola rak bu lun du. SSoo nnuuçç:: İkin ci üçay tah mi ni fe tal ağır lık öl çü mü ile PAPPA’nın bir lik -te kul la nı mı, PAPP-A’nın dü şük do ğum ağır lık lı ye ni do ğan la rı -tes pit ede bil me du yar lı lı ğı nı ve po zi tif pre dik tif de ğe ri ni art tır mak ta dır.
AAnnaahh ttaarr KKee llii mmee lleerr:: Be bek, ges tas yo nel ya şa gö re kü çük; ge be lik tri mes tı rı, ikin ci; ge be lik iliş ki li plaz ma pro te i ni A
TTuurrkkiiyyee KKlliinniikklleerrii JJ GGyynneeccooll OObbsstt 22001133;;2233((44))::223377--4411 Nilgün GÜDÜCÜ,a
Gökçenur GÖNENÇ,a
Herman İŞÇİ,a
Alin BAŞGÜL YİĞİTER,a
İlkkan DÜNDERa
aDepartment of Obstetrics and Gynecology,
İstanbul Bilim University Faculty of Medicine, İstanbul Ge liş Ta ri hi/Re ce i ved: 30.03.2013 Ka bul Ta ri hi/Ac cep ted: 19.09.2013 Ya zış ma Ad re si/Cor res pon den ce: Nilgün GÜDÜCÜ
İstanbul Bilim University Faculty of Medicine,
Department of Obstetrics and Gynecology, İstanbul,
TÜRKİYE/TURKEY nilgun.kutay@gmail.com
ges ta ti o nal-age (SGA) fe tu ses.3With this know led
-ge in mind re se arc hers ai med to find first tri mes ter mar kers that can de tect SGA fe tu ses.
Preg nancy as so ci a ted plas ma pro te in-A (PAPPA) is a pro te i na se pro du ced by the trop -hob lasts and it cle a ves in su lin li ke growth fac tor bin ding pro te ins (IGFBPs). In cre a sed le vels of IGF-BPs or dec re a sed le vels of PAPP-A are de tec ted in preg nan ci es with fe tal growth res tric ti on.4It is a
mar ker of early pla cen ta ti on. PAPP-A is part of the first tri mes ter scre e ning for chro mo so mal ab nor ma li ti es which is re com men ded to all of our pa ti -ents. Pa ti ents with low se rum PAPP-A le vels in the ab sen ce of chro mo so mally ab nor mal fe tu ses are sug ges ted to be at risk for de li ve ring SGA fe tu -ses.5-7Com bi ned use of PAPP-A with many ot her
pa ra me ters is sug ges ted for early de tec ti on of fe tu -ses with growth re tar da ti on.8-10All of the pa ti ents
at ten ding to our cli nic un der go a se cond tri mes ter ul tra so und for the eva lu a ti on of fe tal ana tomy, du -ring this pro ce du re es ti ma ted fe tal we ight (EFW) is al so cal cu la ted. Low se cond tri mes ter EFW is sug ges ted as a pre dic tor of po or fe tal out co me.11-13
The aim of this study is to exa mi ne fe tal growth in the se cond tri mes ter and to de tect its pre dic ti ve va lu e for SGA in fants in pa ti ents with a low first tri -mes ter PAPP-A.
MA TE RI AL AND MET HODS
This was a ret ros pec ti ve study per for med by se arc -hing the da ta of wo men at ten ding to İstan bul Bi lim Uni ver sity Av ru pa Hos pi tal for Down syndro me scre e ning bet we en Ja nu ary 2006 and Au gust 2012. Ul tra so und exa mi na ti ons we re per for med ro u ti nely at 1113 we eks of ges ta ti on in the first tri mes -ter and at 18-23 we eks in the se cond tri mes -ter. All me a su re ments we re car ri ed out by thre e obs tet ri -ci ans (NG,Hİ,ABY) using the 5-MHz cur vi li ne ar tran sab do mi nal trans du cer, GE Elec tric Vo lu son 730 Ex pert. Only wo men de li ve ring at our ins ti tu -ti on we re inc lu ded. Exc lu si on cri te ri a we re the pre sen ce of in comp le te in for ma ti on, smo king, known ab nor mal fe tal kar yoty pe, con ge ni tal malfor ma ti ons and preg nan ci es with mo re than one fe -tus. We did not exc lu de any ca se on the ba sis of ab nor mal fe tal bi o metry or birth we ight. Last
men-s tru al pe ri od wamen-s re cor ded and the emen-s ti ma ted da te of de li very was cor rec ted ac cor ding to the crown-rump length (CRL) me a su re ment ob ta i ned in the first vi sit (6-8 we eks of preg nancy). All se rum analy ses we re per for med at a sing le si te and the va lu es we re cor rec ted for ma ter nal we ight. The re se -arch pro ject con forms to the et hi cal gu i de li nes of the Dec la ra ti on of Hel sin ki. Be ca u se of the ret ros -pec ti ve na tu re of study we did not ta ke et hi cal ap-pro val and in for med pa ti ent con sent.
Ma ter nal se rum samp les for PAPP-A we re as-sa yed with the che mi lu mi nes cen ce Uni celDxl 800 Beck man co ul ter and the re sults we re con ver ted in to mul tip les of me di an (MoM). For sta tis ti cal analy sis PAPP-A le vels less than the 5thper cen ti le
(≤ 0.39 MoM) we re con si de red as a risk fac tor for SGA in fants. Se cond tri mes ter fe tal growth res tric -ti on was de fi ned as an EFW< 25thper cen ti le
(Had-lock) as this was the pre vi o usly re por ted cut-off as so ci a ted with po or out co me in the se cond tri mes -ter of preg nancy.14SGA was de fi ned as a birth we
-ight less than the 10th per cen ti le for the ges ta ti o nal age at de li very, but al so sta tis ti cal analy sis for a birth we ight less than the 5thand 25thper cen ti les
we re cal cu la ted.
For sta tis ti cal analy sis we used NCSS (Num ber Crunc her Sta tis ti cal System) 2007 and PASS (Po -wer Analy sis and Samp le Si ze) 2008 Sta tis ti cal Soft-wa re (Utah, USA). Da ta sho wing ant hro po met ric pa ra me ters we re pre sen ted as me an±stan dard de-vi a ti on and me di an va lu es. For ca te go ri cal anay sis we used Mann Whit ney U Test. The re sults we re con si de red sta tis ti cally sig ni fi cant when the pva -lu e was cal cu la ted as less than 0.05 at a con fi den ce in ter val of 95%.
RE SULTS
We se arc hed da ta of 923 preg nants and inc lu ded 60 pa ti ents in our study. The de mog rap hic fe a tu res of the pa ti ents we re shown in Tab le 1. Me an mater nal age was 31.8±4.2 ye ars, me an ma mater nal he -ight was 161±1.6 cm (cm), me an ma ter nal we -ight be fo re preg nancy was 63± 11 kg (kg). Twentythre -e p-er c-ent of pa ti -ents with a low first tri m-es t-er PAPP-A le vel had a se cond tri mes ter EFW <25%. The sen si ti vity of low se cond tri mes ter EFW was
14.3%, spe ci fi city 90.7%, po si ti ve pre dic ti ve va lu e (PPV) 33.3% and ne ga ti ve pre dic ti ve va lu e (NPV) 76.4% for birth we ights <5thper cen ti le (Tab le 2).
The sen si ti vity of se cond tri mes ter EFW was 28.6%, spe ci fi city 76.7%, PPV 28.6% and NPV 76.7% for birth we ights <10thper cen ti le (Tab le 2).
The sen si ti vity of se cond tri mes ter EFW was 35.7%, spe ci fi city 67.4%, PPV 26.3% and NPV 76.3% for birth we ights <25thper cen ti le (Tab le 2).
DIS CUS SI ON
First tri mes ter preg nancy scre e ning test for Down syndro me is com monly per for med and preg nants with a low PAPP-A le vel but an eup lo id fe tus can re a dily be iden ti fi ed. The se pa ti ents mostly un der -go a se cond tri mes ter ul tra so und exa mi na ti on, whe re the ma in pur po se is the de tec ti on of fe tal ano ma li es. Low PAPP-A le vels are sug ges ted as sig-ni fi cant pre dic tors of SGA fe tu ses in the ab sen ce of pre ec lamp si a.8,15By using low PAPP-A le vels only
3% of fe tu ses with growth res tric ti on can be
pre-dic ted, which ma kes it use less as a scre e ning test.16,17In this study we fo und that com bi na ti on of
low se cond tri mes ter EFW with low PAPP-A le v-els in cre a se sen si ti vity and PPV of PAPP-A alo ne, but do es not chan ge the spe ci fi city. The se re sults are si mi lar to tho se of a pre vi o us re port.14But the
pre va len ce of fe tu ses with a low se cond tri mes ter EFW among pa ti ents with low PAPP-A le vels are hig her in our study when com pa red to that of Fox et al.14 In ad di ti on we fo und si mi lar NPV for low
se cond tri mes ter EFW at dif fe rent cut-off le vels for birth we ight, spe ci fi city was the hig hest for birth we ights <5thcen ti le.
Fe tal growth res tric ti on is the re sult of im pa i -red trop hob las tic in va si on of ute ri ne spi ral ar te ri es, the cli ni cal ma ni fes ta ti ons of this can not be de tec -ted un til the se cond tri mes ter.1PAPP-A in cre a ses
the ava i la bi lity of IGF to ac ce le ra te fe tal growth by en han cing trop hob last in va si on to the de ci du a.18
Low PAPP-A le vels act as a mar ker of ab nor mal pla cen ta ti on and dec re a se de li very of nut ri ents to Second trimester ultrasound
Total (n=60) <25% Percentile (n=14) ≥25% Percentile (n=46)
Mean±SD Mean±SD (Median) Mean±SD (Median) p
Age (years) 31.8±4.2 33.7±4.7 (34) 31±3.9 (31.5) 0.073
Gravidity 1.6±0.9 1.8±0.9 (1.5) 1.6±0.9 (1) 0.405
Parity 0.4±0.7 0.6±0.9 0.4±0.6 0.466
Prepregnancy maternal weight (kg) 63±11 66.5±12.5 (62) 61.8±11 (58) 0.191
Weight gain in pregnany (kg) 16±6 13.3±4.8 (13) 17.5±6 (17) 0.078
Maternal weight at birth (kg) 81±11.9 80±11 (77.5) 81±12.4 (81) 0.843
Maternal height (cm) 161±1.6 159±3.6 (158) 166±5.1 (165) 0.002*
Delivery week 38±1.7 38.4±2 (38) 38±1.6 (38.5) 0.504
Birth weight (grams) 3214±571 3038±639 (3120) 3271±543 (3240) 0.235
EFW Percentile 43±32 33±22(37.5) 47±33 (37) 0.194
PAPP-A (MoM) 0.33±0.6 0.34±0.06 (0.36) 0.33±0.06 (0.33) 0.611
TABLE 1: Demographic features of patients.
Mann Whitney U Test; *p<0.01.
Fetal weight in second trimester ultrasound < 25th percentile Sensitivity (%) Specificity (%) PPV (%) NPV (%)
Birth weight (<25thpercentile) 35.7 67.4 26.3 76.3
Birth weight (<5thpercentile) 14.3 90.7 33.3 76.5
Birth weight (<10thpercentile) 28.6 76.7 28.6 76.7
TABLE 2: Sensitivity, specificity, positive (PPV) and negative (NPV) predictive values of second trimester sonographic
cho ri o nic vil li, as a re sult small fe tu ses ha ve smal ler pla cen ta e. Ab nor mal pla cen ta ti on may dec re a se the ge ne ti cally de ter mi ned fe tal growth ra te.19Anot her
con se qu en ce of ab nor mal first tri mes ter pla cen ta ti on is preg nancy in du ced hyper ten si on, which is al -so as -so ci a ted with a low se cond tri mes ter EFW.14,20
When PAPP-A is com bi ned with se cond tri mes ter ute ri ne ar tery Dopp ler fin dings, pre dic ti ve ac cu racy of first tri mes ter PAPP-A for SGA fe tu ses and preg-nancy in du ced hyper ten si on in cre a ses.14,21-23Af ter
this we ek of preg nancy we can not gi ve me di ca ti ons to dec re a se mor bi dity and mor ta lity, we can only pro vi de ef fec ti ve mo ni to ri za ti on of sus pec ted ca ses and ti mely de li very when in di ca ted.
Re cent stu di es fo cu sing on fe tal growth in early preg nancy pro po se a CRL smal ler than 7 days ac cor ding to the ex pec ted da tes as a risk fac tor for a birth we ight be low 2500 g.24,25The se fe tu ses are
al so re por ted to ha ve a hig her mor ta lity ra te.25
Pla-cen ta ti on ta kes pla ce in the first tri mes ter of preg-nancy and spi ral ar te ri es trans form in to low re sis tan ce ar te ri es, the re fo re it is lo gi cal to ex pect fe tal growth ab nor ma li ti es at aro und 11-14 we eks
of ges ta ti on. But stu di es on first tri mes ter fe tal growth ab nor ma li ti es de pend on the last mens tru al pe ri od (LMP) and re mem be ring LMP inac cu ra -tely or ha ving ir re gu lar pe ri ods may cre a te bi a ses. Our study de pends on first tri mes ter CRL and this in cre a ses the strength of the study. The re la ti vely small num ber of pa ti ents and the ret ros pec ti ve na-tu re of the sna-tudy are the li mi ting fac tors.
In conc lu si on com bi na ti on of low se cond tri -mes ter EFW with low PAPP-A le vels in cre a se sen-si ti vity and PPV of PAPP-A. Furt her re se arch to find mar kers that can in cre a se the po si ti ve pre dic -ti ve va lu e of PAPP-A in the first tri mes ter wo uld be a bet ter po licy, but un til then se cond tri mes ter EFW can be used as an ad junct to PAPP-A to iden-tify fe tu ses with growth res tric ti on. We ad vi se to ma ke use of PAPP-A and se cond tri mes ter EFW to de tect SGA fe tu ses, when al re ady per for med for ot -her pur po ses.
A
Acckk nnooww lleedd ggee mmeenntt
Thanks to Ne şat Ku tay for re vi e wing the ar tic le for Eng-lish.
Nilgün GÜDÜCÜ et al. LOW SECOND TRIMESTER ESTIMATED FETAL WEIGHT AS A PREDICTOR...
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