Renal and Hepatic Functions after A Week of Controlled Ovarian Hyperstimulation during In Vitro Fertilization Cycles

Renal and Hepatic Functions after A Week of Controlled

Ovarian Hyperstimulation during

In Vitro

Fertilization Cycles

Ilaria Romito, M.D.1_{, Ferdinando Antonio Gulino, M.D.}1_{, Antonio Simone Laganà, M.D.}2*_,

Salvatore Giovanni Vitale, M.D.2_{, Attilio Tuscano, M.D.}1_{, Gianluca Leanza, M.D.}1_{, Giulia Musmeci, Ph.D.}3_,

Vito Leanza, M.D.1_{, Agnese Maria Chiara Rapisarda, M.D.}1_{, Marco Antonio Palumbo, M.D.}1

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Abstract

%DFNJURXQGOne the main aspects of in vitroIHUWLOL]DWLRQ,9)F\FOHLVWRDYRLGDQ\ possible systemic damage on women undergoing a controlled ovarian hyperstimulation (COH). The aim of this work is to evaluate renal and hepatic function blood tests in pa-tients undergoing controlled ovarian hyperstimulation during IVF cycles.

0DWHULDOVDQG0HWKRGV We performed a prospective cohort analysis. All patients

re-ceived a long stimulation protocol with gonadotropin-releasing hormone (GnRH) ana-ORJXHVE\GDLO\DGPLQLVWUDWLRQVLQFHWKHWZHQW\¿UVWGD\RIWKHSUHYLRXVRYDULDQF\FOH followed by COH with recombinant follicle-stimulating hormone (FSH). The daily dose RIH[RJHQRXVJRQDGRWURSLQVIRUHYHU\VLQJOHSDWLHQWZDVPRGL¿HGDFFRUGLQJWRKHUIRO-OLFXODUJURZWK7KHRRF\WHVZHUHUHWULHYHGGXULQJWKHRRF\WHSLFNXSDQGIHUWLOL]HGE\ VWDQGDUGSURFHGXUHVRILQWUDF\WRSODVPLFVSHUPLQMHFWLRQ,&6,7KHEORRGVDPSOHVWR evaluate renal and hepatic functions were taken at the 7th _{day of ovarian stimulation.}

5HVXOWVWe enrolled 426 women aged between 19 and 44 years, with a mean body mass LQGH[%0,RI.JP2_{7KHPHDQYDOXHRIEORRGXUHDQLWURJHQZDV“PJ}

GOFUHDWLQLQH“PJGOXULFDFLG“PJGOWRWDOSURWHLQV“PJGO DVSDUWDWHDPLQRWUDQVIHUDVH“P8PODODQLQHDPLQRWUDQVIHUDVH“P8 PODONDOLQHSKRVSKDWDVH“P8POWRWDOELOLUXELQ“PJG/$OORIWKH UHVXOWVZHUHFRQVLGHUHGDVDQRUPDOUDQJHIROORZLQJWKH0HGLFDO&RXQFLORI&DQDGD

&RQFOXVLRQOur data suggest that, unlike ovarian hyperstimulation syndrome (OHSS), COH patients did not show any alteration to renal and hepatic functions.

Keywords:,QIHUWLOLW\2YDULDQ+\SHUVWLPXODWLRQ,QWUDF\WRSODVPLF6SHUP,QMHFWLRQIn

Vitro)HUWLOL]DWLRQ

Citation: Romito I, Gulino FA, Laganà AS, Vitale SG, Tuscano A, Leanza G, Musmeci G, Leanza V, Rapisarda AM, Palumbo MA. Renal and hepatic functions after a week of controlled ovarian hyperstimulation during in vitro fertiliza-tion cycles. Int J Fertil Steril. 2017; 11(1): 15-19.

Received: 27 Jan 2016, Accepted: 24 Jul 2016

Unit of Gynecology and Obstetrics, Department of Human Pa-thology in Adulthood and Childhood “G. Barresi”, University of

Messina. Via C. Valeria 1, 98125 Messina, Italy _{Royan Institute}

Introduction

The correlation between renal and hepatic dam-ages and ovarian stimulation is not well under-stood, and so far data about ovarian hyperstimu-lation syndrome (OHSS) are not enough robust. As widely evidenced, OHSS is a rare iatrogenic complication of ovarian stimulation, that

usu-ally happens during an in vitroIHUWLOL]DWLRQ,9) cycle, luteal phase or early pregnancy. OHSS KDV EHHQ NQRZQ VLQFH  ZKHQ UHFRPELQDQW gonadotrophins recombinant follicle-stimulating KRUPRQH U)6+ DQG UHFRPELQDQW OXWHLQL]LQJ KRUPRQH U/+ ZHUH XVHG IRU WKH ¿UVW WLPH WR induce ovulation (1, 2). OHSS generally occurs

only after exposure to human chorionic gonado-tropin (hCG) and its mortality rate is between 1 LQDQGLQDQGLWKDVDPRU-bidity even higher though not accurately quanti-¿HG %DVHG RQ WKH FOLQLFDO SUHVHQWDWLRQ ODERUD-WRU\DQGXOWUDVRXQG¿QGLQJV2+66LVFODVVL¿HG into three categories (mild, moderate and severe) DQG¿YHJUDGHV“RIVHYHULW\7KHLQLWLDO symptoms are abdominal bloating and pain; the RYDULDQVL]HXVXDOO\LVFP,QVHYHUHFOLQLFDO presentations, the patients suffer from ascites, oliguria and haemoconcentration; in these cases, RYDULDQVL]HLVXVXDOO\!FP7KHPLOGIRUPKDV rather high incidence considering that it affects XSWRRIZRPDQXQGHUJRLQJWR,9)F\FOHV while the moderate or severe OHSS complicates  RI ,9) F\FOHV  $OWHUHG OLYHU IXQFWLRQ tests have been considered to be a rare expres-sion of the severe form of OHSS, because it may induce microvascular thrombosis and liver tissue ischemia leading to hepatic dysfunction (6).

An accurate evaluation of the patient before an IVF technique includes an hysteroscopy for di-agnostic as well as therapeutic purpose (7-9), but also the study of any thrombophilic genetic nu-cleotide polymorphisms (10); it is mandatory to study male partner, evaluating accurately semen parameters (11).

The main risk of a stimulation protocol for an IVF cycle could be considered OHSS, so to date it is recommended to accurately check renal and hepatic functions through blood tests, in order to suspect this condition as early as possible. Con-sidering also that most of the women try repeated cycles of IVF, due to the common failure of the technique, it is important to know whether the nor-mal stimulation protocol (which does not hesitate LQWR2+66FRXOGGHWHUPLQHUHQDODQGRUKHSDWLF damages. To the best of our knowledge, no study has yet investigated this point, since most of the available data were focused on OHSS. In the light of this evidence, we think that it is extremely im-portant to know if even normal stimulation pro-tocols with controlled ovarian hyperstimulation &2+ PD\ OHDG WR UHQDO DQGRU KHSDWLF DOWHUHG functions, also taking into account the “basal risk” before the start of another IVF cycle. Thus, the aim of this work is to evaluate renal and hepatic func-tion blood tests in patients undergoing COH dur-ing IVF cycles.

Materials and Methods

We performed this single-center prospective co-KRUWVWXG\DWWKH'HSDUWPHQWRI*HQHUDO6XUJHU\ DQG 0HGLFDO 6XUJLFDO 6SHFLDOWLHV RI WKH 8QLYHU-sity of Catania (Italy), between July 2012 and Au-gust 2015. We enrolled women IVF for primary or secondary infertility, considering the develop-PHQWRI2+66DVH[FOXVLRQFULWHULD(DFKSDWLHQW was informed about the procedures and signed an informed consent allowing data collection for re-search purposes.

All patients received a long stimulation proto-FRO ZKLFK LQYROYHG WKH SLWXLWDU\ GHVHQVLWL]DWLRQ with gonadotropin-releasing hormone (GnRH) analogues by daily administration since the twen-W\¿UVW GD\ RI WKH SUHYLRXV RYDULDQ F\FOH :KHQ ZHUHDFKHGSLWXLWDU\GHVHQVLWL]DWLRQLQGLFDWHGE\

VHUXPHVWUDGLRO(₂

OHYHOSJPODQGIROOLFX-lar diameter <10 mm, we started ovarian stimula-WLRQZLWKU)6+*21$/I0HUFN6HURQR(XURSH 8. :H PRGL¿HG WKH GDLO\ GRVH RI H[RJHQRXV gonadotropins for every single patient according to her follicular growth.

We administrated 10000 UI of hCG (Gonasi +3,%6$)DUPDFHXWLFL,WDOLD,WDO\ZKHQWKHWZR largest follicles reached a minimum diameter of 16

PP ZLWK D SHDN RI (₂ RI DERXW  SJPO:H

SHUIRUPHGRRF\WHSLFNXSDERXWDIWHUKRXUVE\ transvaginal ultrasound-guided needle aspiration of the follicles.

7KH RRF\WHV ZHUH IHUWLOL]HG E\ VWDQGDUG SURFH-GXUHVRILQWUDF\WRSODVPLFVSHUPLQMHFWLRQ,&6, After 72 hours embryos were transferred into the uterus. All patients underwent luteal phase support with progesterone and low-dose of acetylsalicylic acid. The pregnacy test was performed after 12 days.

We evaluated renal and hepatic function blood tests (creatinine, blood urea nitrogen, total protein, uric acid, transaminases, total bilirubin, alkaline

phosphatase) at the day 7th_{, since ovarian}

stimula-tion with rFSH.

The study was designed in accordance with the +HOVLQNL 'HFODUDWLRQ FRQ¿UPLQJ WKH &RPPLWWHH RQ 3XEOLFDWLRQ (WKLFV &23( JXLGHOLQHV DQG LW ZDV DSSURYHG E\ WKH ,QVWLWXWLRQDO 5HYLHZ %RDUG ,5%RIWKHXQLYHUVLW\KRVSLWDOZKHUHWKLVZRUN was performed. All designs, analyses,

interpreta-tion of data, drafting and revisions followed the Strengthening the Reporting of Observational 6WXGLHV LQ (SLGHPLRORJ\ 6752%( 6WDWHPHQW guidelines for reporting observational studies, DYDLODEOHWKURXJKWKH(48$725(QKDQFLQJWKH 48$OLW\ DQG 7UDQVSDUHQF\ 2I KHDOWK 5HVHDUFK network. All the results were considered as nor-PDO UDQJH IROORZLQJ WKH VWDQGDUG YDOXHV GH¿QHG E\0HGLFDO&RXQFLORI&DQDGD

Results

We recruited 426 women aged between 19 and \HDUVPHDQDJH\HDUVWKDWPHWLQFOX-sion and exclu\HDUVPHDQDJH\HDUVWKDWPHWLQFOX-sion criteria. We excluded from the study four patients that have developed OHSS GXULQJ ,9) SURFHGXUHV 0HDQ ERG\ PDVV LQGH[

%0,RIWKHFRKRUWZDV.JP2_{. As reported}

in Table 1, we measured aspartate aminotrasferase $67LQSDWLHQWVDODQLQHDPLQRWUDV-IHUDVH $/7 LQ  SDWLHQWV  DONDOLQH SKRVSKDWDVHLQSDWLHQWVWRWDOELOLUX-ELQ LQ  SDWLHQWV  EORRG XUHD QLWURJHQ LQSDWLHQWVFUHDWLQLQHLQSDWLHQWV  XULF DFLG LQ  SDWLHQWV  WRWDO SURWHLQVLQSDWLHQWV Table 1: ZĞŶĂůĂŶĚŚĞƉĂƟĐďůŽŽĚƚĞƐƚƐ͘^ƚĂŶĚĂƌĚǀĂůƵĞƐƌĞĨĞƌƚŽDĞĚŝͲ ĐĂůŽƵŶĐŝůŽĨĂŶĂĚĂ͕ƉƉĞŶĚŝdžͲůŝŶŝĐĂů>ĂďŽƌĂƚŽƌLJdĞƐƚƐ;ϮϬϭϬͿ 9DULDEOHV 0HDQ“6' 6WDQGDUG YDOXHV %ORRGXUHDQLWURJHQ PJG/ “ 7.0-22.0 Creatinine PJG/ “ 0.57-1.02 Uric acid PJG/ “  Total protein PJG/ “  Aspartate aminotrasferase P8P/ “  Alanine aminotrasferase P8P/ 19.06 ± 10.41  3KRVSKDWDVHDONDOLQH P8P/ “  Total bilirubin PJG/ “ <1.5 Discussion 3UHJQDQF\ LV D SK\VLRORJLFDO FRQGLWLRQ WKDW may predispose itself to abnormal renal and KHSDWLF IXQFWLRQV  'XULQJ SUHJQDQF\ WKH

increased blood flow in the liver should re-duce transaminases (14), but there are several pathologic conditions such as chronic intrahe- SDWLFFKROHVWDVLVDQG+(//3+HPRO\VLVLV(O-HYDWHG/LYHU HQ]\PH OHYHOV DQG /RZ 3ODWHOHW syndrome in which there is an increase in AST and ALT (15, 16). Although several studies al-ready investigated renal and hepatic alterations in women who developed OHSS, to the best of our knowledge this is the first report of liver and kidney function during COH. As previously HYLGHQFHGE\.RS\ORYHWDO,9)SUHJQDQ-cies had more elevated AST values compared to spontaneous ones. Generally, liver blood WHVWVDUHHOHYDWHGLQDERXWRIDOOSUHJQDQ-FLHV*LXJOLDQRHWDOUHSRUWHGDFDVH of liver failure after four cycles of COH and subsequent intrauterine insemination (IUI): in WKLVFDVHWKHSDWLHQWVGHYHORSHGVHYHUH+(//3 syndrome during the third trimester, allowing DXWKRUV WR K\SRWKHVL]H D FRUUHODWLRQ EHWZHHQ &2+ DQG OLYHU IDLOXUH &RQVLGHULQJ +(//3 syndrome, hepatic damage could be due (at least in part) by endothelial dysfunction, since it was already demonstrated that increased an-giotensin and pro-inflammatory cytokines may lead to hepatic ischemia (20). Furthermore, as GRFXPHQWHG E\ 2EU]XW HW DO  OLYHU GDP-age severity could be foretold by high value of estradiol during ovarian stimulation, in di-rect proportion with risk of developing OHSS. %DVHG RQ WKHVH GDWD ZH FRXOG K\SRWKHVL]H D link between high estradiol values during ovar-ian hyperstimulation and histopathological liver changes in woman with severe OHSS, similar to those already determined during oral contraceptive therapy (22-24).

Recent data (25, 26) demonstrated that the trends in liver and renal function tests could be affected by single- or double-dose methotrexate in case of ectopic pregnancy after fresh IVF em-bryo transfer cycles; for this reason, liver and re-nal function tests have to be carefully evaluated in these patients.

$QRWKHUVSHFL¿FFRQGLWLRQLVUHSUHVHQWHGE\FDV-es of IVF treatment in renal transplanted patients (who have already altered renal function) and ne-phrotic syndrome: these patients have higher risk to develop OHSS (27), so they have to be moni-tored strictly to avoid it.

Conclusion

The ovarian hyperstimulation, even if controlled, GHWHUPLQHVSK\VLRORJLFDOPRGL¿FDWLRQVDQGFRXOG lead to hemodynamic changes in kidney and liver. %DVHGRQWKDWLQRXUVWXG\ZHH[SHFWHGFKDQJHV on the parameters of liver and kidney function in women undergoing COH. Our data demonstrated WKDW QR SDWLHQW GHYHORSHG KHSDWLF DQGRU UHQDO GDPDJHVXJJHVWLQJDJRRGVDIHW\SUR¿OHIRU&2+ Nevertheless, several limitations of this study VKRXOGEHWDNHQLQWRDFFRXQW¿UVWRIDOOZHGLGQRW measure all parameters in every patients, although UDWHRIHYDOXDWLRQZDVDERYHLQRIWKHP VHFRQGZHPRGL¿HGWKHGDLO\GRVHRIH[RJHQRXV gonadotropins for every single patient according WRKHUIROOLFXODUJURZWK¿QDOO\RXUFRKRUWLQFOXG-ed patients with different ages (between 19 and 44 years) and different types of infertility (primary or secondary). For these reasons, it is required to fur-ther study on larger cohorts, with greater statistical SRZHUWRDFFXUDWHO\FODULI\WKHULVNRIKHSDWLFDQG or renal damage during COH.

Acknowledgements

$OO$XWKRUVKDYHQRSURSULHWDU\¿QDQFLDOSUR-fessional or other personal interest of any nature in any product, service or company.

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