Pregnancies conceived through assisted reproductive technologies (ART) now account for over 1% of all pregnancies in the UK and it is predicted that this proportion will rise further in the next decade. This is largely because women are leaving it till later in life to start a family but find that ART is required because their reproductive potential has diminished with advancing age1.
It has long been recognised that pregnancies conceived through ART have poorer maternal and perinatal outcomes than natural conceptions but debate continues as to the causal factors. The factors that predispose them to adverse outcome may be inherent to the woman (and/or the male partner), including her age at conception, the treatment regimes or to the greater incidence of multiple pregnancy compared with natural conception and this paper will review the outcomes and attempt to put these in context where the evidence exists.
All women undergoing ART should be considered at risk of developing ovarian hyperstimulation syndrome (OHSS) which is characterised by ovarian distension, fluid shift in to the extravascular space and, in the more severe forms, significant activation of the coagulation cascade with increased risk of DVT and pulmonary embolism.
Women with polycystic ovary syndrome, younger women and those using a GnRH-agonist downregulation protocol are at greater risk and that risk is increased further in conception cycles. However, The absolute incidence of OHSS is not known and, because of effective management strategies, maternal death from cardiovascular events is extremely rare2.
In the UK the background rate of ectopic pregnancy is about 1%3 whilst in assisted conceptions it is approximately 2-3%4. Naturally conceived heterotopic pregnancy is rare (1 in 7000) but, because of multiple embryo transfer, may be as high as 1% in ART pregnancies5.
By necessity, the available data on maternal outcomes in ART are retrospective and observational but by using national databases and comparing them with naturally conceived pregnancies, informative data can be derived.
All complications of pregnancy are increased with multiple gestation and include anaemia, pre-eclampsia, polyhydramnios, preterm labour, operative delivery and post partum haemorrhage. There is a ten-fold increase in multiple births in ART compared to spontaneous pregnancies and although most of these are related to replacing more than one embryo, there is also an increased risk of monozygotic multiple pregnancies which may be related to embryo manipulation during in vitro culture6. Undoubtedly many of the maternal complications of ART are related to multiple pregnancy but even amongst singletons the maternal risks are increased.
In a large Swedish study of all women known to have had IVF between 1982 – 2001, logistic regression analysis demonstrated that they had an increased risk of bleeding in early pregnancy (odds ratio = 4.59; 95% CI: 4.08-5.15) and of ovarian torsion (OR = 10.6; CI 5.69-10.7). They were more likely to develop pre-eclampsia (OR = 1.63; 1.53-1.74), placental abruption (OR = 2.17; CI 1.74-2.72), placenta praevia (OR = 3.65; CI 3.15-4.23) and preterm, prelabour rupture of membranes (OR = 2.54; CI 2.34-2.76). Furthermore, induction of labour (OR = 1.37; CI 1.29-1.46) and caesarean sections (OR = 1.38; CI 1.32-1.43) were more frequent7. All pregnancies are “precious” but some of the increase in intervention may be attributable to an inclination by the obstetrician not to “take risks” with ART pregnancies because they are deemed to be “more precious”, whether subconsciously or otherwise, but using different datasets these findings have been confirmed by others8, 9.
The published data on perinatal outcomes in babies born after IVF are conflicting but most studies suggest an increased risk of adverse outcome10,11. It has been suggested that these phenomena may be brought about by the in vitro process12 as animal studies have shown that manipulation of the in vitro embryo culture conditions can influence profoundly subsequent fetal growth and development13.
Multiple gestation is associated with substantially greater perinatal morbidity and mortality because of the higher incidence of preterm labour and delivery and, undoubtedly, the greater incidence of multiple pregnancy in ART conceptions contributes to the poorer perinatal outcomes overall. However, if we consider twin pregnancies, then, compared to naturally conceived twin pregnancies, there doesn’t appear to be a difference in perinatal outcome measures such as birthweight and preterm delivery once other confounding factors such as maternal age and parity are taken in to consideration14.
On the other hand, amongst singleton ART pregnancies, outcomes appear to be poorer compared to spontaneous singleton conceptions. In a meta-analysis, singleton IVF pregnancies were at increased risk of preterm delivery less than 33 weeks’ gestation (OR = 2.99; CI 1.54-5.80), preterm delivery less than 37 weeks’ gestation (OR = 1.93; CI 1.36-2.74), very low birth weight (< 1500 g) (OR = 3.78; CI 4.29-5.75), small for gestational age (OR = 1.59; CI 1.20-2.11), and congenital malformations (OR = 1.41; CI 1.06-1.88). Most studies show a trend towards higher perinatal mortality but as this is a relatively rare event, they are too small to show a statistical effect. However, the advantage of meta-analysis in this case is that it does demonstrate a higher perinatal mortality (OR = 2.40; CI 1.59-3.63)15.
Given the in vitro manipulation of gametes and embryos, long-term follow-up of babies following ART conceptions is also important and again national population data provides a useful source of information.
A Swedish study showed that children up to six years old conceived through ART were more likely to be hospitalised than naturally conceived children but this was partly explained by maternal anxieties. However, diagnoses indicating cerebral damage (such as mental retardation, cerebral palsy, epilepsy and behavioral problems) occurred more frequently but these seemed to be completely explained by the excess of preterm births in the ART cohort. In singleton IVF pregnancies there did not appear to be an excess of neuro-developmental problems and there was no increased risk of cancers although numbers, even with population studies, are inevitably small7.
Most childhood data is from IVF pregnancies because this is the most common form of in vitro ART but now there is increasing data availability from ICSI pregnancies. Compared to natural conceptions, ICSI children were more likely to have a major malformation (OR = 2.77; CI 1.41-5.46) even when adjusted for socio-demographic factors. The higher rate was due partially to an excess of malformations in the boys’ urogenital tract7, 16. Furthermore, recent observational data have suggested an increased prevalence of rare genomic imprinting defects such as Beckwith-Wiedemann syndrome and Angelman syndrome in ICSI pregnancies17. Why this should be the case is unknown and again the numbers in the studies are inevitably small but there is undoubtedly a need for large-scale, long-term studies to clarify the link between genomic imprinting defects and ART as well as to establish the exact biological mechanisms. Importantly, ICSI children do not appear to have greater psychomotor impairment compared with IVF children18.
Why should perinatal outcomes in ART be worse?
Even amongst singletons and controlling for factors such as maternal age, outcomes are poorer and this has been attributed to the in vitro manipulation of gametes and embryos12. It has been shown that singletons conceived to subfertile couples through ovulation induction and intrauterine insemination (OI/IUI) i.e. conceived in vivo, had similar outcomes to IVF singletons19 and these data suggested that it was not the in vitro environment that was responsible.
Furthermore, a subsequent study from the same group demonstrated that whilst OI/IUI conceptions using partner’s sperm had poorer perinatal outcomes than natural conceptions, OI/IUI conceptions using donor sperm (i.e. where the subfertility was related to the male) had similar outcomes to natural conceptions20. This suggests that the stimulation regimes do not impact on subsequent perinatal outcome and it is intrinsic factors (maternal and/or paternal), related to the couple’s subfertility, which plays a role.
Y-chromosome microdeletions are common in men with severe oligospermia and until the advent of ICSI, the only treatment available to such couples was donor sperm. However, these men can now have genetically related children but, if they have a son, these microdeletions will almost inevitably be passed on to the child and this provides some biological plausibility for an excess of urogenital tract malformations in ICSI boys21.
Much needs to be determined about the human genome but it could be that there are subtle genetic variations in women and/or men which predispose them to subfertility and also to adverse perinatal outcome. However, without ART, these couples would never have conceived and so the perinatal outcomes would not have become manifest. With greater success and more widespread adoption of ART, these couples can have children and it is only now that we are appreciating some of the consequences.
Reducing adverse outcomes
Much of the adverse outcomes can be explained by multiple pregnancies and their association with poorer maternal and perinatal outcome7 and, because of this, the ART fraternity should be striving to reduce multiple pregnancy rates.
In the UK most responsible IVF units would only transfer two embryos in women under 40 years old. This does not compromise pregnancy rates but it minimises the risk of triplet pregnancy and its inherent consequences22. However, as above, even twin pregnancies have both higher maternal and perinatal morbidity compared to singletons and the debate is now turning to single versus two-embryo transfer.
Inevitably elective single embryo transfer (eSET) results in lower twin pregnancy rates and hence less chance of preterm delivery and higher birth weight than twin pregnancy. However, interestingly, these advantages were also seen when compared to two-embryo transfer which only resulted in a singleton. This is possibly due to avoidance of “vanishing twin” syndrome but this, at present, is conjecture23.
Cost-benefit analysis, once factors such as additional neonatal care which is more common in twin pregnancies are taken in to consideration, favours eSET in women less than 38 years old, in their first or second ART cycle with good quality embryos24.
Unfortunately, eSET overall results in lower pregnancy rates than two-embryo transfer and in the UK, where most IVF is self-funded, patients may not be prepared to risk compromising the success of their cycle in spite of the potential future and unquantifiable risks of a twin pregnancy. Furthermore, patients often measure the “success” of clinics (public or private) by the clinic’s pregnancy rates and, because of this, individual clinics may be reluctant to move to eSET. As such, it will probably require a change in legislation to effect a policy of eSET and/or additional government funding to allow more couples to receive ART so that they are prepared to undertake eSET.
For women undergoing ART, there is always the risk of OHSS and ectopic pregnancy rates are modestly higher. In later pregnancy the risks of common pregnancy-related problems are also increased but most of this is due to multiple gestation.
However, even amongst singletons, there are additional risks of pre-eclampsia and Caesarean section although some of this may be accounted for by the age of the women.
The additional risks to the baby are more easily demonstrated such that preterm delivery, low birthweight and perinatal morbidity and mortality are increased. Whilst most of this is again due to multiple gestations, this is true of singletons as well. Urogenital tract anomalies are more common amongst ICSI males but this must be taken in the context that they are rare to begin with so even a doubling of the rate still makes it an uncommon occurrence. Furthermore, potential parents can be reassured that there is no evidence that neuro-development in ART pregnancies is any different from natural conceptions.
The mechanisms for the difference in outcomes compared to natural conceptions have yet to be determined but may be due to the in vitro processes, inherent (genetic) characteristics in the woman or man which predispose them to infertility in the first place or even to the numbers of embryos transferred and the goal should be to obtain a singleton, term pregnancy to minimise these risks.
The data presented must be put in to perspective. Most pregnancies conceived through ART will result in a healthy mother and a healthy term singleton and patients can be reassured by this. Nevertheless, like all aspects of obstetrics, management is about anticipating areas of risk and pre-empting those potential problems. As such, the evidence is now substantial and obstetricians should deem ART pregnancies, even in singletons, as “higher” risk and their management should be tailored accordingly20.
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