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Ali so pri otrocih rojenih po postopku oploditve z biomedicinsko pomocjo kromosomske nepravilnosti pogostejše?
Avtor: Sara Korošec, Petra Kaplan
Mentor: prof. dr. Tomaž Tomaževic, dr. med
Somentor: asist. dr. Tanja Premru Sršen, dr. med.; Tanja Talan , dr. med.; Brigita Valentincic, dipl. biol.; doc. dr. Borut Peterlin, dr. med
Izhodišce. Kljub dvomom o varnosti postopka oploditve v epruveti s prenosom zarodka (IVF-ET), postopka oploditve z vbrizganjem spermija v citoplazmo (ICSI) in uporabi zamrznjenih zarodkov, raziskave kažejo, da tveganje za prirojene nepravilnosti ni bistveno povecano. Izkazalo se je le, da so pri novorojenckih, rojenih po oploditvi s postopkom ICSI, pogostejše nepravilnosti spolnih kromosomov. Dejavniki tveganja neplodnih parov so njihova višja starost, neplodnost in pogostejše mnogoplodne nosecnosti. Ocena pojavnosti kromosomskih, pa tudi strukturnih prirojenih nepravilnosti pri nas bi bila uporabna pri obravnavi neplodnih parov v prihodnosti.
Namen in hipoteze raziskave. V naši raziskavi želimo ugotoviti, ali so prirojene nepravilnosti pri novorojenckih, rojenih po postopkih oploditve z biomedicinsko pomocjo, pogostejše kot pri novorojenckih, rojenih po spontani zanositvi. Hipoteza 1. Kromosomske, strukturne in letalne nepravilnosti pri novorojenckih, rojenih po postopkih oploditve z biomedicinsko pomocjo niso pogostejše kot pri novorojenckih, rojenih po spontani zanositvi.
Hipoteza 2. Kromosomske, strukturne in letalne nepravilnosti pri novorojenckih, rojenih po postopkih oploditve z biomedicinsko pomocjo niso pogostejše kot pri novorojenckih, rojenih po spontani zanositvi, katerih matere smo po starosti, pariteti, mnogoplodnosti in letu poroda izenacili z materami študijske skupine. Hipoteza 3. Deleži prirojenih nepravilnosti v skupini novorojenckov s prirojenimi nepravilnostmi, rojenih po postopkih oploditve z biomedicinsko pomocjo, se ne razlikujejo od deležev prirojenih nepravilnosti v skupini novorojenckov s prirojenimi nepravilnostmi, rojenih po spontani zanositvi.
Hipoteza 4. Starost, pariteta, mnogoplodnost in oploditev po postopku ICSI niso dejavniki tveganja za rojstvo novorojencka s prirojeno nepravilnostjo pri materah, zdravljenih s postopki oploditve z biomedicinsko pomocjo.
Preiskovanke in metode dela. V retrospektivno raziskavo smo vkljucili 242164 novorojenckov, ki so se rodili 241607 materam od aprila 1987 do decembra 1997 v Sloveniji ter jo razdelili na 3 kohortne in 1 kontrolirano študijo. V prvih dveh študijah smo primerjali pojavnost kromosomskih, strukturnih in letalnih prirojenih nepravilnosti. Pri prvi študiji smo primerjali 1404 novorojenckov rojenih po oploditvi s postopkom IVF-ET z novorojencki, rojenimi po spontani zanositvi. Pri drugi, kontrolirani študiji, smo primerjali 1270 novorojenckov rojenih po oploditvi mater s postopkom IVF-ET s 1270 novorojencki, rojenimi materam po spontani zanositvi ob tem, da smo matere po starosti, številu plodov, pariteti in letu poroda izenacili. Pri tretji študiji smo ugotavljali pojavnost kromosomskih, strukturnih in letalnih prirojenih nepravilnosti glede na nacin oploditve. 73 novorojenckov s prirojenimi nepravilnostmi, rojenih po oploditvi s postopkom IVF-ET smo primerjali s 9685 novorojencki s prirojenimi nepravilnostmi, rojenimi po spontani zanositvi. V cetrti študiji smo ugotavljali možne dejavnike tveganja (starost, mnogoplodnost, pariteta in izvedba postopka ICSI) pri materah, udeleženih v postopku IVF-ET. Primerjali smo 54 mater novorojenckov rojenih po oploditvi s postopkom IVF-ET, ki imajo prirojene nepravilnosti s 1048 materami novorojenckov, rojenih po oploditvi s postopkom IVF-ET, ki nimajo prirojenih nepravilnosti. Opisali smo potek in izid nosecnosti in poroda novorojencka, rojenega po prenosu odmrznjenih zarodkov. Rezultate smo ovrednotili s testom hi-kvadrat za neparametricne in t-testom za parametricne spremenljivke. Razlike med vzorci smo imeli za statisticno znacilne, kadar je bila stopnja tveganja (vrednost p) manjša od 0,05 (p < 0,05).
Rezultati. Pri novorojenckih, rojenih po postopku oploditve z biomedicinsko pomocjo, smo ugotovili vec vseh prirojenih nepravilnosti skupaj, vec letalnih nepravilnosti, vec malformacij dihal, srca in obtocil ter manj malformacij mišicno skeletnega sistema kot pri novorojenckih, rojenih po spontani zanositvi. Po izenacitvi mater po starosti, pariteti, mnogoplodnosti in letu poroda nismo pri primerjavi novorojenckov našli nobenih znacilnih razlik. Pri novorojenckih s prirojenimi nepravilnostmi, rojenih po postopku oploditve z biomedicinsko pomocjo smo našli vecji delež letalnih nepravilnosti, malformacij srca in obtocil ter manjši delež malformacij mišicno skeletnega sistema kot pri novorojenckih s prirojenimi nepravilnostmi, rojenih po spontani zanositvi. Pri materah, zdravljenih s postopki oploditve z biomedicinsko pomocjo, ki so rodile otroke s prirojenimi nepravilnostmi, nismo ugotovili nic vec dejavnikov tveganja kot pri materah, zdravljenih s postopki oploditve z biomedicinsko pomocjo, ki so rodile neprizadete otroke. Pri novorojenckih, rojenih po postopku oploditve ICSI, smo našli štiri manjše nepravilnosti.
Zakljucki. Prvo hipotezo smo ovrgli in ugotovili, da so prirojene nepravilnosti pri novorojenckih, rojenih po postopkih oploditve z biomedicinsko pomocjo, pogostejše kot pri novorojenckih, rojenih po spontani zanositvi. Drugo hipotezo smo potrdili in s tem pokazali, da se po izenacitvi starosti in paritete matere, števila plodov ter leta poroda razlike med skupinama novorojenckov iznicijo. Tretjo hipotezo smo ovrgli in ugotovili, da imajo novorojencki s prirojenimi nepravilnostmi, rojeni po postopkih oploditve z biomedicinsko pomocjo, pomembno vecji delež malformacij srca in obtocil ter letalnih nepravilnosti v primerjavi z novorojencki s prirojenimi nepravilnostmi, rojenimi po spontani zanositvi. Cetrto hipotezo smo potrdili in pokazali, da se starost, pariteta, mnogoplodnost in oploditev po postopku ICSI niso izkazali kot dejavnik tveganja za rojstvo novorojencka s prirojeno nepravilnostjo pri materah, zdravljenih s postopki oploditve z biomedicinsko pomocjo.
[Abstract / English version]
Are rates of chromosomal anomalies higher in children conceived after assisted reproductive techniqes?
Author: Sara Korošec, Petra Kaplan
Mentor: prof. dr. Tomaž Tomaževic, dr. med
Co-mentor: asist. dr. Tanja Premru Sršen, dr. med.; Tanja Talan , dr. med.; Brigita Valentincic, dipl. biol.; doc. dr. Borut Peterlin, dr. med
Background. Despite doubts about safety of in vitro fertilisation-embryo transfer (IVF-ET), intracytoplasmic sperm injection (ICSI) and use of frozen embryos, statistical analyses up to date have shown that risk of congenital malfomations is not essentially different from the risk in case of natural conception. The only fact that was shown is that in neonates born after ICSI procedure, abnormalities of sex chromosomes were present more often. Risk factors of sterile couples are: their age, sterility and frequent multiple pregnancies. An assessment of prevalence and distribution of chromosomal and structural malformations in our country would be useful in treating the sterile couples in the future.
Aim and hypothesis. The aim of the survey is to determine whether rates of congenital malformations in neonates born after assisted reproductive techniques are higher than in neonates born after a spontaneous conception.
Hypothesis 1. Chromosomal, structural and lethal abnormality rates in neonates born after are not higher than in general population.
Hypothesis 2. Chromosomal, structural and lethal abnormality rates in neonates born after assisted reproductive techniques are not higher than in neonates born after sponataneus conception whose mothers were matched according to their age, number of fetuses, parity and year of birth to mothers of the study group.
Hypothesis 3. Shares of congenital abnormality rates in neonates born with congenital abnormalities after assisted reproductive techniques does not differ from shares of congenital abnormality rates in group of neonates with congenital abnormalities born after natural conception.
Hypothesis 4. Age, parity, multiplicity and conception with help of ICSI procedure are not risk factors for congenital abnormality occurrence in neonates born to mothers treated with assisted reproductive techniques.
Patients and methods. 242164 neonates born to 241607 mothers from April 1987 to December 1997 in Slovenia, were included in retrospective survey. The survey was divided into 3 cohort and 1 case-controlled studies. In first two studies prevalence of chromosomal, structural and lethal abnormalities were observed. In first study we compared 1404 neonates born after IVF-ET procedure with neonates born after spontaneous conception. In second controlled study we compared 1270 neonates born after IVF-ET procedure with 1270 neonates born after spontaneous conception, whose mothers were matched according to their age, multiplicity, parity and year of birth. In third study we observing the shares of congenital abnormality rates according to a form of fertilisation. We compared 73 neonates with congenital abnormalities, born after IVF-ET procedure with 9685 neonates with congenital abnormalities, born after spontaneous conception. In the fourth study we were assessing possible risk factors (age, multiplicity, parity and ICSI procedure). We compared 54 mothers of neonates with congenital malformations with 1048 mothers of neonates without congenital malformations born after IVF-ET procedure. Data of neonate born after frozen embryo transfer was analysed in descriptive manner. Results were statistically evaluated by chi-square test for non-parametrical variables and t-test for parametrical variables.
Results: More lethal, respiratory, cardiovascular malformations and less locomotor system malformations were found in neonates conceived after assisted reproductive techniques than in neonates of general population. No differences between the two groups of neonates were found after matching their mothers according to age, multiplicity, parity and year of birth. In the group of neonates with congenital abnormalities we found bigger share of lethal and cardiovascular malformations and smaller share of locomotor malformation in the group of neonates conceived after assisted reproductive techniques than in the group of neonates born after spontaneous conception. In comparison of mothers treated with assisted reprodutive techniques whose neonates were born with congenital abnormalities and those treated mothers whose neonates had any congenital abnormalities we found no significant risk factors. In neonates born after ICSI we found only four minor abnormalities.
Conclusions: We established that congenital abnormality rates were higher in group of neonates born after assisted reproductive techniques than in neonates of general population, but neonate abnormality rate differences dissapered after matching mothers according to age, parity, multiplicity and year of birth. We failed to confirm our first hypothesis and confirmed our second hypothesis. We established higher share of cardiovascular and lethal abnormalities in group of neonates with congenital abnormalities born after assisted reproductive techniques than in group of neonates with congenital abnormalities born after spontaneous conception. We failed to confirm our third hypothesis. We confirmed our forth hypothesis by demonstrating that age, parity, multiplicity and ICSI procedure are not risk factors for birth of abnormal neonate to mothers treated with assisted reproductive techniques.