Editing In vitro fertilisation (section)

== Complications and health effects ==

===Multiple births===
The major complication of IVF is the risk of [[multiple birth]]s. This is directly related to the practice of transferring multiple embryos at embryo transfer. Multiple births are related to increased risk of pregnancy loss, [[obstetrical complications]], [[preterm birth|prematurity]], and neonatal morbidity with the potential for long term damage. Strict limits on the number of embryos that may be transferred have been enacted in some countries (e.g. Britain, Belgium) to reduce the risk of high-order multiples (triplets or more), but are not universally followed or accepted. Spontaneous splitting of embryos in the uterus after transfer can occur, but this is rare and would lead to identical twins. A double blind, randomised study followed IVF pregnancies that resulted in 73 infants, and reported that 8.7% of singleton infants and 54.2% of twins had a birth weight of less than {{convert|2500|g|lb}}.<ref>{{cite journal |vauthors=Olivennes F, Mannaerts B, Struijs M, Bonduelle M, Devroey P |date=August 2001 |title=Perinatal outcome of pregnancy after GnRH antagonist (ganirelix) treatment during ovarian stimulation for conventional IVF or ICSI: a preliminary report |journal=Human Reproduction |volume=16 |issue=8 |pages=1588–1591 |doi=10.1093/humrep/16.8.1588 |pmid=11473947 |doi-access=free}}</ref> There is some evidence that making a double embryo transfer during one cycle achieves a higher live birth rate than a single embryo transfer; but making two single embryo transfers in two cycles has the same live birth rate and would avoid multiple pregnancies.<ref>{{cite journal |vauthors=Kamath MS, Mascarenhas M, Kirubakaran R, Bhattacharya S |date=August 2020 |title=Number of embryos for transfer following in vitro fertilisation or intra-cytoplasmic sperm injection |journal=The Cochrane Database of Systematic Reviews |publisher=Cochrane Database Syst Rev. |publication-date=21 August 2020 |volume=2020 |issue=8 |pages=CD003416 |doi=10.1002/14651858.CD003416.pub5 |pmc=8094586 |pmid=32827168}}</ref>

===Sex ratio distortions===

Certain kinds of IVF have been shown to lead to distortions in the [[sex ratio]] at birth. [[Intracytoplasmic sperm injection]] (ICSI), which was first applied in 1991, leads to slightly more female births (51.3% female). [[Blastocyst transfer]], which was first applied in 1984, leads to significantly more male births (56.1% male). Standard IVF done at the second or third day leads to a normal sex ratio.{{Citation needed|date=April 2023}}

[[Epigenetic modifications]] caused by extended culture leading to the death of more female embryos has been theorised as the reason why blastocyst transfer leads to a higher male sex ratio; however, adding retinoic acid to the culture can bring this ratio back to normal.<ref>{{cite journal |display-authors=6 |vauthors=Tan K, An L, Miao K, Ren L, Hou Z, Tao L, Zhang Z, Wang X, Xia W, Liu J, Wang Z, Xi G, Gao S, Sui L, Zhu DS, Wang S, Wu Z, Bach I, Chen DB, Tian J |date=March 2016 |title=Impaired imprinted X chromosome inactivation is responsible for the skewed sex ratio following in vitro fertilization |journal=Proceedings of the National Academy of Sciences of the United States of America |volume=113 |issue=12 |pages=3197–3202 |bibcode=2016PNAS..113.3197T |doi=10.1073/pnas.1523538113 |pmc=4812732 |pmid=26951653 |doi-access=free}}</ref> A second theory is that the male-biased sex ratio may due to a higher rate of selection of male embryos. Male embryos develop faster in vitro, and thus may appear more viable for transfer.<ref>{{cite journal |vauthors=Lou H, Li N, Zhang X, Sun L, Wang X, Hao D, Cui S |date=July 2020 |title=Does the sex ratio of singleton births after frozen single blastocyst transfer differ in relation to blastocyst development? |journal=Reproductive Biology and Endocrinology |volume=18 |issue=1 |pages=72 |doi=10.1186/s12958-020-00623-x |pmc=7362517 |pmid=32669110 |doi-access=free }}</ref>

===Spread of infectious disease===
By [[sperm washing]], the risk that a chronic disease in the individual providing the sperm would infect the birthing parent or offspring can be brought to negligible levels.

If the sperm donor has [[hepatitis B]], The Practice Committee of the American Society for Reproductive Medicine advises that sperm washing is not necessary in IVF to prevent transmission, unless the birthing partner has not been effectively vaccinated.<ref>{{cite journal |author1=Practice Committee of American Society for Reproductive Medicine |date=November 2008 |title=Hepatitis and reproduction |journal=Fertility and Sterility |volume=90 |issue=5 Suppl |pages=S226–S235 |doi=10.1016/j.fertnstert.2008.08.040 |pmid=19007636 |doi-access=free}}</ref><ref name="Lutgens2009">{{cite journal |vauthors=Lutgens SP, Nelissen EC, van Loo IH, Koek GH, Derhaag JG, Dunselman GA |date=November 2009 |title=To do or not to do: IVF and ICSI in chronic hepatitis B virus carriers |journal=Human Reproduction |volume=24 |issue=11 |pages=2676–2678 |doi=10.1093/humrep/dep258 |pmid=19625309 |doi-access=free}}</ref> In women with hepatitis B, the risk of [[vertical transmission]] during IVF is no different from the risk in spontaneous conception.<ref name="Lutgens2009" /> However, there is not enough evidence to say that [[Intracytoplasmic sperm injection|ICSI]] procedures are safe in women with hepatitis B in regard to vertical transmission to the offspring.<ref name="Lutgens2009" />

Regarding potential spread of [[HIV/AIDS]], Japan's government prohibited the use of IVF procedures in which both partners are infected with HIV. Despite the fact that the ethics committees previously allowed the [[Ogikubo, Tokyo]] Hospital, located in Tokyo, to use IVF for couples with HIV, the [[Ministry of Health, Labour and Welfare (Japan)|Ministry of Health, Labour and Welfare]] of Japan decided to block the practice. Hideji Hanabusa, the vice president of the Ogikubo Hospital, states that together with his colleagues, he managed to develop a method through which scientists are able to remove HIV from sperm.<ref>{{cite web |date=21 July 2008 |title=Japan Bans in Vitro Fertilisation for HIV Couples |url=http://www.infoniac.com/health-fitness/japan-bans-in-vitro-fertilization-for-hiv-couples.html |publisher=Infoniac.com |access-date=3 August 2013 |archive-date=19 September 2013 |archive-url=https://web.archive.org/web/20130919204101/http://www.infoniac.com/health-fitness/japan-bans-in-vitro-fertilization-for-hiv-couples.html |url-status=dead }}</ref>

In the United States, people seeking to be an embryo recipient undergo infectious disease screening required by the [[Food and Drug Administration (United States)|Food and Drug Administration]] (FDA), and reproductive tests to determine the best placement location and cycle timing before the actual embryo transfer occurs. The amount of screening the embryo has already undergone is largely dependent on the genetic parents' own IVF clinic and process. The embryo recipient may elect to have their own [[embryologist]] conduct further testing.

===Other risks to the egg provider/retriever===
A risk of ovarian stimulation is the development of [[ovarian hyperstimulation syndrome]], particularly if hCG is used for [[Final maturation (IVF)|inducing final oocyte maturation.]] This results in swollen, painful ovaries. It occurs in 30% of patients. Mild cases can be treated with over the counter medications and cases can be resolved in the absence of pregnancy. In moderate cases, ovaries swell and fluid accumulated in the abdominal cavities and may have symptoms of heartburn, gas, nausea or loss of appetite. In severe cases, patients have sudden excess abdominal pain, nausea, vomiting and will result in hospitalisation.

During egg retrieval, there exists a small chance of bleeding, infection, and damage to surrounding structures such as bowel and bladder (transvaginal ultrasound aspiration) as well as difficulty in breathing, chest infection, allergic reactions to medication, or nerve damage (laparoscopy).

[[Ectopic pregnancy]] may also occur if a fertilised egg develops outside the uterus, usually in the fallopian tubes and requires immediate destruction of the foetus.

IVF does not seem to be associated with an elevated risk of [[cervical cancer]], nor with [[ovarian cancer]] or [[endometrial cancer]] when neutralising the [[confounder]] of infertility itself.<ref>{{cite journal |display-authors=6 |vauthors=Siristatidis C, Sergentanis TN, Kanavidis P, Trivella M, Sotiraki M, Mavromatis I, Psaltopoulou T, Skalkidou A, Petridou ET |year=2012 |title=Controlled ovarian hyperstimulation for IVF: impact on ovarian, endometrial and cervical cancer—a systematic review and meta-analysis |journal=Human Reproduction Update |volume=19 |issue=2 |pages=105–123 |doi=10.1093/humupd/dms051 |pmid=23255514 |s2cid=10086076|doi-access=free }}</ref> Nor does it seem to impart any increased risk for [[breast cancer]].<ref>{{cite journal |vauthors=Sergentanis TN, Diamantaras AA, Perlepe C, Kanavidis P, Skalkidou A, Petridou ET |year=2013 |title=IVF and breast cancer: a systematic review and meta-analysis |journal=Human Reproduction Update |volume=20 |issue=1 |pages=106–123 |doi=10.1093/humupd/dmt034 |pmid=23884897 |doi-access=free}}</ref>

Regardless of pregnancy result, IVF treatment is usually stressful for patients.<ref name="RockliffLightman2014">{{cite journal |vauthors=Rockliff HE, Lightman SL, Rhidian E, Buchanan H, Gordon U, Vedhara K |year=2014 |title=A systematic review of psychosocial factors associated with emotional adjustment in in vitro fertilization patients |journal=Human Reproduction Update |volume=20 |issue=4 |pages=594–613 |doi=10.1093/humupd/dmu010 |pmid=24676468 |doi-access=free}}</ref> [[Neuroticism]] and the use of [[Escapism|escapist]] coping strategies are associated with a higher degree of distress, while the presence of social support has a relieving effect.<ref name="RockliffLightman2014" /> A negative pregnancy test after IVF is associated with an increased risk for [[Depression (mood)|depression]], but not with any increased risk of developing [[anxiety disorders]].<ref name="volgsten">{{cite journal |vauthors=Volgsten H, Skoog Svanberg A, Ekselius L, Lundkvist O, Sundström Poromaa I |date=March 2010 |title=Risk factors for psychiatric disorders in infertile women and men undergoing in vitro fertilization treatment |journal=Fertility and Sterility |volume=93 |issue=4 |pages=1088–1096 |doi=10.1016/j.fertnstert.2008.11.008 |pmid=19118826 |doi-access=free}}</ref> Pregnancy test results do not seem to be a risk factor for depression or anxiety among men in the case of relationships between two cisgender, heterosexual people.<ref name="volgsten" /> [[Hormone therapy|Hormonal agents]] such as [[gonadotropin-releasing hormone agonist]] (GnRH agonist) are associated with [[Major depressive disorder|depression]].<ref>{{cite book|vauthors=Botts S, Ryan M|title=Drug-Induced Diseases Section IV: Drug-Induced Psychiatric Diseases Chapter 18: Depression|url=https://www.ashp.org/DocLibrary/Policy/Suicidality/DID-Chapter18.aspx|archive-url=https://web.archive.org/web/20101223035009/http://www.ashp.org/DocLibrary/Policy/Suicidality/DID-Chapter18.aspx|url-status=dead|archive-date=23 December 2010|pages=1–23}}</ref>

Studies show that there is an increased risk of [[venous thrombosis]] or [[pulmonary embolism]] during the first trimester of IVF.<ref>{{cite journal |vauthors=Henriksson P, Westerlund E, Wallén H, Brandt L, Hovatta O, Ekbom A |date=January 2013 |title=Incidence of pulmonary and venous thromboembolism in pregnancies after in vitro fertilisation: cross sectional study |journal=BMJ |volume=346 |issue=3 |pages=e8632 |doi=10.1136/bmj.e8632 |pmc=3546085 |pmid=23321489}}</ref>  When looking at long-term studies comparing patients who received or did not receive IVF, there seems to be no correlation with increased risk of cardiac events. There are more ongoing studies to solidify this.<ref>{{cite journal |display-authors=6 |vauthors=Dayan N, Filion KB, Okano M, Kilmartin C, Reinblatt S, Landry T, Basso O, Udell JA |date=September 2017 |title=Cardiovascular Risk Following Fertility Therapy: Systematic Review and Meta-Analysis |journal=Journal of the American College of Cardiology |volume=70 |issue=10 |pages=1203–1213 |doi=10.1016/j.jacc.2017.07.753 |pmid=28859782 |doi-access=free}}</ref>

[[Spontaneous pregnancy]] has occurred after successful and unsuccessful IVF treatments.<ref>{{cite journal |vauthors=Hunault CC, Habbema JD, Eijkemans MJ, Collins JA, Evers JL, te Velde ER |date=September 2004 |title=Two new prediction rules for spontaneous pregnancy leading to live birth among subfertile couples, based on the synthesis of three previous models |journal=Human Reproduction |volume=19 |issue=9 |pages=2019–2026 |doi=10.1093/humrep/deh365 |pmid=15192070 |doi-access=free}}</ref> Within 2 years of delivering an infant conceived through IVF, subfertile patients had a conception rate of 18%.<ref>{{cite journal |vauthors=Shimizu Y, Kodama H, Fukuda J, Murata M, Kumagai J, Tanaka T |date=January 1999 |title=Spontaneous conception after the birth of infants conceived through in vitro fertilization treatment |journal=Fertility and Sterility |volume=71 |issue=1 |pages=35–39 |doi=10.1016/S0015-0282(98)00417-8 |pmid=9935113 |doi-access=free}}</ref>

===Birth defects===
A review in 2013 came to the result that infants resulting from IVF (with or without ICSI) have a [[relative risk]] of birth defects of 1.32 (95% [[confidence interval]] 1.24–1.42) compared to naturally conceived infants.<ref name="pmid23449641">{{cite journal |vauthors=Hansen M, Kurinczuk JJ, Milne E, de Klerk N, Bower C |year=2013 |title=Assisted reproductive technology and birth defects: a systematic review and meta-analysis |journal=Human Reproduction Update |volume=19 |issue=4 |pages=330–353 |doi=10.1093/humupd/dmt006 |pmid=23449641 |doi-access=free}}</ref> In 2008, an analysis of the data of the National Birth Defects Study in the US found that certain birth defects were significantly more common in infants conceived through IVF, notably [[septal heart defect]]s, [[cleft lip]] with or without [[cleft palate]], [[esophageal atresia]], and [[anorectal atresia]]; the mechanism of causality is unclear.<ref>{{cite journal |vauthors=Reefhuis J, Honein MA, Schieve LA, Correa A, Hobbs CA, Rasmussen SA |date=February 2009 |title=Assisted reproductive technology and major structural birth defects in the United States |journal=Human Reproduction |volume=24 |issue=2 |pages=360–366 |doi=10.1093/humrep/den387 |pmid=19010807 |doi-access=free}}</ref> However, in a population-wide cohort study of 308,974 births (with 6,163 using assisted reproductive technology and following children from birth to age five) researchers found: "The increased risk of birth defects associated with IVF was no longer significant after adjustment for parental factors."<ref name="Davies">{{cite journal |display-authors=6 |vauthors=Davies MJ, Moore VM, Willson KJ, Van Essen P, Priest K, Scott H, Haan EA, Chan A |date=May 2012 |title=Reproductive technologies and the risk of birth defects |journal=The New England Journal of Medicine |volume=366 |issue=19 |pages=1803–1813 |doi=10.1056/NEJMoa1008095 |pmid=22559061 |s2cid=12552533 |doi-access=free}}</ref> Parental factors included known independent risks for birth defects such as maternal age, smoking status, etc. Multivariate correction did not remove the significance of the association of birth defects and ICSI (corrected odds ratio 1.57), although the authors speculate that underlying male infertility factors (which would be associated with the use of ICSI) may contribute to this observation and were not able to correct for these confounders. The authors also found that a history of infertility elevated risk itself in the absence of any treatment (odds ratio 1.29), consistent with a Danish national registry study<ref name="Zhu">{{cite journal |vauthors=Zhu JL, Basso O, Obel C, Bille C, Olsen J |date=September 2006 |title=Infertility, infertility treatment, and congenital malformations: Danish national birth cohort |journal=BMJ |volume=333 |issue=7570 |pages=679 |doi=10.1136/bmj.38919.495718.AE |pmc=1584372 |pmid=16893903}}</ref> and "implicates patient factors in this increased risk."<ref name="Davies"/> The authors of the Danish national registry study speculate: "our results suggest that the reported increased prevalence of congenital malformations seen in singletons born after assisted reproductive technology is partly due to the underlying infertility or its determinants."<ref name="Zhu"/>

{| class="wikitable" style="float:right;"
|+ Risk in singleton pregnancies resulting from IVF (with or without [[intracytoplasmic sperm injection|ICSI]])<ref name="Pandey2012">{{cite journal |vauthors=Pandey S, Shetty A, Hamilton M, Bhattacharya S, Maheshwari A |year=2012 |title=Obstetric and perinatal outcomes in singleton pregnancies resulting from IVF/ICSI: a systematic review and meta-analysis |journal=Human Reproduction Update |volume=18 |issue=5 |pages=485–503 |doi=10.1093/humupd/dms018 |pmid=22611174 |doi-access=free}}</ref>
|-
! Condition !! [[Relative risk|Relative<br /> risk]] !! 95% [[confidence interval|confidence<br /> interval]]
|-
| [[Beckwith–Wiedemann syndrome]] || 3-4 ||
|-
| [[congenital anomalies]] || 1.67 || 1.33–2.09
|-
| [[ante-partum haemorrhage]] || 2.49 || 2.30–2.69
|-
| [[hypertensive disorders of pregnancy]] || 1.49 || 1.39–1.59
|-
| [[preterm rupture of membranes]] || 1.16 || 1.07–1.26
|-
| [[Caesarean section]] || 1.56 || 1.51–1.60
|-
| [[gestational diabetes]] || 1.48 || 1.33–1.66
|-
| [[induction of labour]] || 1.18 || 1.10–1.28
|-
| [[small for gestational age]] || 1.39 || 1.27–1.53
|-
| [[preterm birth]] || 1.54 || 1.47–1.62
|-
| [[low birthweight]] || 1.65 || 1.56–1.75
|-
| [[perinatal mortality]] || 1.87 || 1.48–2.37
|}

===Other risks to the offspring===
If the underlying infertility is related to abnormalities in [[spermatogenesis]], male offspring will have a higher risk for sperm abnormalities. In some cases genetic testing may be recommended to help assess the risk of transmission of defects to progeny and to consider whether treatment is desirable.<ref>{{cite book |last1=Leslie |first1=Stephen W. |last2=Soon-Sutton |first2=Taylor L. |last3=Khan |first3=Moien AB |title=Male Infertility |date=February 25, 2024 |publisher=StatPearls Publishing |location=Treasure Island (FL) |pmid=32965929 |url=https://www.ncbi.nlm.nih.gov/books/NBK562258/}}</ref>

IVF does not seem to confer any risks regarding cognitive development, school performance, social functioning, and behaviour.<ref name="Hart2-2013">{{cite journal |vauthors=Hart R, Norman RJ |year=2013 |title=The longer-term health outcomes for children born as a result of IVF treatment. Part II—Mental health and development outcomes |journal=Human Reproduction Update |volume=19 |issue=3 |pages=244–250 |doi=10.1093/humupd/dmt002 |pmid=23449643 |doi-access=free}}</ref> Also, IVF infants are known to be as securely attached to their parents as those who were naturally conceived, and IVF adolescents are as well-adjusted as those who have been naturally conceived.<ref>{{cite book |title=Infants, Children, and Adolescents |vauthors=Berk LE |date=December 2010 |publisher=Pearson Learning Solutions |isbn=978-0-205-77541-5 |edition=7th |page=67 |via=VitalBook}}</ref>

Limited long-term follow-up data suggest that IVF may be associated with an increased incidence of [[hypertension]], [[impaired fasting glucose]], increase in total [[body fat]] composition, advancement of [[bone age]], subclinical [[thyroid disorder]], early adulthood [[clinical depression]] and [[binge drinking]] in the offspring.<ref name="Hart2-2013" /><ref name="Hart1-2013">{{cite journal |vauthors=Hart R, Norman RJ |year=2013 |title=The longer-term health outcomes for children born as a result of IVF treatment: Part I—General health outcomes |journal=Human Reproduction Update |volume=19 |issue=3 |pages=232–243 |doi=10.1093/humupd/dms062 |pmid=23449642 |doi-access=free}}</ref> It is not known, however, whether these potential associations are caused by the IVF procedure in itself, by adverse obstetric outcomes associated with IVF, by the genetic origin of the children or by yet unknown IVF-associated causes.<ref name="Hart2-2013" /><ref name="Hart1-2013" /> Increases in embryo manipulation during IVF result in more deviant fetal growth curves, but birth weight does not seem to be a reliable marker of fetal stress.<ref name="BloiseFeuer2014">{{cite journal |vauthors=Bloise E, Feuer SK, Rinaudo PF |year=2014 |title=Comparative intrauterine development and placental function of ART concepti: implications for human reproductive medicine and animal breeding |journal=Human Reproduction Update |volume=20 |issue=6 |pages=822–839 |doi=10.1093/humupd/dmu032 |pmc=4196686 |pmid=24947475}}</ref>

IVF, including [[Intracytoplasmic sperm injection|ICSI]], is associated with an increased risk of [[imprinting disorder]]s (including [[Prader–Willi syndrome]] and [[Angelman syndrome]]), with an [[odds ratio]] of 3.7 (95% [[confidence interval]] 1.4 to 9.7).<ref name="LazaraviciuteKauser2014">{{cite journal |vauthors=Lazaraviciute G, Kauser M, Bhattacharya S, Haggarty P, Bhattacharya S |year=2014 |title=A systematic review and meta-analysis of DNA methylation levels and imprinting disorders in children conceived by IVF/ICSI compared with children conceived spontaneously |journal=Human Reproduction Update |volume=20 |issue=6 |pages=840–852 |doi=10.1093/humupd/dmu033 |pmid=24961233 |doi-access=free}}</ref>

An IVF-associated incidence of [[cerebral palsy]] and [[neurodevelopmental delay]] are believed to be related to the [[confounder]]s of prematurity and low birthweight.<ref name="Hart2-2013" /> Similarly, an IVF-associated incidence of [[autism]] and [[attention-deficit disorder]] are believed to be related to confounders of maternal and obstetric factors.<ref name="Hart2-2013" />

Overall, IVF does not cause an increased risk of [[childhood cancer]].<ref name="Williams2013">{{cite journal |display-authors=6 |vauthors=Williams CL, Bunch KJ, Stiller CA, Murphy MF, Botting BJ, Wallace WH, Davies M, Sutcliffe AG |date=November 2013 |title=Cancer risk among children born after assisted conception |journal=The New England Journal of Medicine |volume=369 |issue=19 |pages=1819–1827 |doi=10.1056/NEJMoa1301675 |pmid=24195549|doi-access=free }}</ref> Studies have shown a decrease in the risk of certain cancers and an increased risks of certain others including [[retinoblastoma]],<ref name="pmid19783550">{{cite journal |vauthors=Marees T, Dommering CJ, Imhof SM, Kors WA, Ringens PJ, van Leeuwen FE, Moll AC |date=December 2009 |title=Incidence of retinoblastoma in Dutch children conceived by IVF: an expanded study |journal=Human Reproduction |volume=24 |issue=12 |pages=3220–3224 |doi=10.1093/humrep/dep335 |pmid=19783550 |doi-access=free}}</ref> [[hepatoblastoma]]<ref name="Williams2013" /> and [[rhabdomyosarcoma]].<ref name="Williams2013" />