Multiple Pregnancy: Which Complexities and Risks Should be Taken into Consideration?

The article was designed as a retrospective overview of the basic complexities and risks which are in close correlation with the multifetal pregnancy. With the increased use of fertility drugs and the transfer of multiple embryos, multifetal gestations have increased in number dramatically. As the number of fetuses increases, the probability of risks linked various fetal, neonatal and post–natal complications also dramatically increases, starting with the possibility of spontaneous Gestational Sac loss and concluding with the stillbirth. Complications, interconnected with pregnancy multiplicity were inclusively discussed. The spectrum of issues including a formal comparison of the complexities and risks, which follow the multifetal pregnancies was discussed with the following concepts made. The consensus was established in almost all controversies including the basic recommendations noted for implementation into clinical practice.

Introduction 

At present, multifetal or multiple pregnancies are closely associated with Infertility Treatment therapy outcome. Despite being an efficient and widely used Treatment for infertile couples, In–Vitro Fertilization (IVF) is responsible for an increasing number of multifetal pregnancies and adverse neonatal outcomes. Indisputably, it represents an attractive option to the range of Infertility Treatments available at present. But, the complexities and risks should not be neglected as the negligence of the negative consequences may result into reduced fetal survival or complete fetal loss.

There have always been some naturally, or spontaneously, occurring multiple pregnancies (with twins the most frequent, then triplets and the much rarer quadruplets or even higher), but the frequency has increased enormously since Assisted Procreation has become available [Bortolus et al., 1999]. Most multifetal pregnancies are problematic gestations either because of the high number of fetuses or because of the presence of genetic disease in one fetus. Multiple gestations have become the common occurrence, vividly presenting and reflecting the increasing usage of Assisted Reproductive Technologies for the successful Infertility Treatment. Being the Infertility Treatment’s determinant, multifetal pregnancies are closely associated with adverse neonatal and post–natal complications, what presupposes not only thorough investigations, but transparent interpretation of the results, which should outline: 

1. The status of multifetal pregnancies, 
2. The incidence of multiple births. 

Moreover, perinatal and mortality rates associated with multifetal pregnancies and the problems experienced in the cases of twin and other multifetal (multiple) pregnancies should be evaluated retrospectively through the studying of the issue–related scientific works.

The medical representatives, including scientific elite, experienced researchers and senior clinicians underestimate the negative consequences of multiple pregnancies, because of the absence of inclusive criteria, which can accurately determine both inclusive and exclusive paradigm for considering the hidden complexities and risks in every single case of the multiple gestation. Additionally, what is essential to emphasize is that there are five prime aspects which must not be neglected in case of multiple gestations: the fetal risks, the maternal risks, the feto–maternal risks, the perinatal risks and long–term outcomes of multiple pregnancies.

Multifetal pregnancy, or, in other words, multiple pregnancy, constitutes a common iatrogenic outcome of ovarian stimulation with Fertility Drugs (may occur after ovarian stimulation) and Assisted Reproductive Technology (when more than one embryo is transferred during In Vitro Techniques) [Seoud et al., 1992]. Multiple gestation pregnancy rates are high in Assisted Reproductive Treatment cycles because of the perceived need to stimulate excess follicles and transfer excess embryos in order to achieve reasonable pregnancy rates. The Medical Treatment therapy of infertility is based on replacement of the, naturally occurring, mono–follicular by a, medically induced, poly–follicular ovarian response. The inevitable consequence to the release of multiple oocytes is the dynamic increase in multifetal pregnancies, which has been associated with practically all Infertility Treatments [American Society for Reproductive Medicine, 2012; Fauser et al., 2005].

Multifetal pregnancies (spontaneous twinning/tripling) occur frequently from fertilization of two separate oocytes [1.2% of pregnancies; Dizygotic (DZ) twinning] than from a single fertilized oocyte that subsequently divides into two identical structures [0.4%; Monozygotic (MZ) twinning] [The ESHRE Capri Workshop Group, 2000]. The numerous scientific studies about multiple pregnancies, particularly, twin–pregnancies and triple–pregnancies include the information about the ‘vanishing twin syndrome’: the intricacy of this phenomenal condition can be presented through the percentage: between 10% and 20% of viable twin fetuses disappear. This phenomenon appears to be limited to Dizygotic (DZ) twins [Landy et al., 1986]. The difference between Monozygotic (MZ) twins and Dizygotic (DZ) twins is not simply of academic interest: it is excessively significant for perinatal vitality rates. There are huge differences in perinatal morbidity and mortality, depending on whether the two fetuses share one Gestational Sac.

Multifetal gestations are high risk pregnancies which may be complicated by prematurity, low birthweight, pre–eclampsia, anaemia, postpartum haemorrhage, intrauterine growth restriction, neonatal morbidity and high neonatal and infant mortality. Exemplifying the risk paradigm, it should be highlighted with particular emphasis on perinatal mortality rates, which are, however, 4–fold higher for twins and 6–fold higher for triplets than for singletons [The ESHRE Capri Workshop Group, 2000].

Perinatal health problems after In Vitro Fertilization (IVF) therapy occur primarily because of multiple gestations, but even in In Vitro Fertilization (IVF) singletons low birthweight and prematurity rates are higher than that of spontaneously conceived singletons [Helmerhorst et al., 2004; Jackson et al., 2004].

Being the major complication of Assisted Reproductive Technologies, the high incidence of multiple pregnancies needs inclusive and transparent discussion through which the consensus should be reached because of the higher morbidity and mortality associated with multifetal pregnancy particularly with quadruplets and triplets, every effort should be made to prevent the incidence.

Consequently, it is necessary to note with the special emphasis that an increased number of multifetal pregnancies is an inevitable consequence of ovarian stimulation regimens [Loutradis and Drakakis, 1995]. Transferring multiple embryos into the uterus is excessively controversial theme as it maximizes pregnancy rates, but yields an unacceptably high multiple pregnancy rate [Tummers et al., 2003]. Another challenge for high multifetal pregnancy rate is transferring more than one embryo through IVF Treatment cycle, what may lead to multiple births (of the newborns), associated with adverse outcomes, such as preterm delivery, low birthweight, increased number of neonatal intensive care unit admissions and increased perinatal mortality. Therefore, there is a tendency, nowadays, to transfer a smaller number of embryos (a maximum of three embryos) in order to reduce the incidence of unwanted multifetal pregnancies and such negative consequences as fetal/maternal/feto–maternal/ prenatal/postnatal morbidity and mortality.

Reducing the number of embryos transferred and the use of natural cycle IVF will surely decrease the number of multiple gestations. The option of Single Embryo Transfer (SET) has recently dominated. Undoubtedly, it is essential to note that the elective Single Embryo Transfer prevents all multiples, but results in significantly lower pregnancy rates compared with double Embryo Transfer. If the option of Single Embryo Transfer (SET) would be an absolute imperative in clinical practice, the optimized Cryopreservation programmes will be essential for the additional oocytes and additional embryos which would be used in the future.

Among the preventive measures, implemented into the clinical practice are the reduction procedures in multifetal gestations. Reduction procedures in multifetal gestations are inevitable since it has been established that the obstetric outcome for triplets or a higher number of fetuses is significantly worse than that for singleton or twin gestations [Antsaklis et al., 1999]. The exact number of fetuses that should be left in the uterus is uncertain. Although singletons have longer gestations and lower morbidity compared to twin gestations, the latter are more feasible for the vast majority of multifetal pregnancy reductions since the number of fetuses left should be greater than the final number desired [Dommergues et al., 1991; Evans et al., 1992].

Taken together these emerging concepts suggest that infertility specialists should focus their practical skills almost exclusively on the prevention of the multiple pregnancies through the improvement of multiphasic clinical procedures. Prevention of the multifetal pregnancies should primary be an imperative of the clinical approaches. The spectrum of issues concerning the prevention methods should be discussed in every single case with the following concepts made: cancelling superovulation cycles should be included as necessary and Embryo Transfer techniques in IVF/ICSI cycles should be improved. The consensus should be established in almost all controversies.

2. Multiple pregnancy: which complexities and risks should be taken into consideration?

2.1. Factors determining early embryo loss (early spontaneous miscarriage) in singleton and multiple (multifetal) implantations: embryological potential as an integrative criterion for successful development

In most In–Vitro Fertilization (IVF)/Intracytoplasmic Sperm Injection (ICSI) programmes approximately one ongoing pregnancy in three is multiple. The need to characterize embryos with optimal implantation potential is obvious [Van Royen et al., 1999] for establishing strict top–quality criteria to the Embryo Transfers. Based on retrospective examination, characteristics of these top–quality embryos were revealed and included: 

1. Absence of multinucleated blastomeres, 
2. Four or five blastomeres on day 2, 
3. Seven or more cells on day 3, and 
4. ≤20% anucleated fragments [Van Royen et al., 1999]. 

It must be emphasized that the number of blastomeres (and maybe even the fragmentation) may vary with culture conditions and with timing of evaluation. This means that these criteria are not absolute [Van Royen et al., 1999]. Until now, there has been a controversy between the improvement of the practical aspect of reproduction – to limit multiple pregnancies to two–fetus pregnancies and synchronically with this limitation – to improve the successful pregnancy rates, and, what is more essential, to improve the pregnancy outcomes. This controversial dilemma could be overcome, if it were possible to select embryos with a very high implantation potential [Van Royen et al., 1999].

Still the concept of embryo quality was predominantly based on the results of transfers with a mixture of embryos of different types. Two parameters are mainly involved in this quality notion: cleavage speed and fragmentation [Cummins et al., 1986; Claman et al., 1987]. These parameters were taken into consideration and implemented widely into clinical practice. The exclusively transfers of identical cleavage stage and identical fragmentation embryos resulted into high embryo implantation rates and high embryo survival rates. Ultimately, multivariate analysis revealed that not only cleavage speed and fragmentation parameters are excessively important to quantify the implantation potential of an embryo. Further scientific investigations represented the one more noteworthy criterion: embryos displaying multinucleated blastomeres have a severely impaired implantation potential, what means the appearance of multinucleated blastomeres is another important quality–related parameter [Van Royen et al., 1999].

The spectrum of indicators which are associated with finally achieved pregnancy is far beyond only one of them – perfect morphological parameters, or, in other words, a good embryo quality. The better the embryo quality, the clearer the impact of pregnancy–preventing factors not related to embryo quality, such as lack of endometrial receptivity and shortcomings in the transfer procedure.

The processes of embryo implantation and placentation involve the degradation and remodeling of extracellular matrix, cellular proliferation, apoptosis, and differentiation. Implantation of the developing conceptus in the maternal uterus occurs by the end of the first week of pregnancy. Extra embryonic trophoblast of the blastocyst attaches to the endometrial epithelium at the embryonic pole [Knoth and Larsen, 1972; Lindenberg, 1991]. Upon attachment, the trophoblast proliferates rapidly and invades the uterine epithelium and underlying endometrial stroma. In the first trimester, the embryo attaches to the maternal decidua by intermediate (extravillous) trophoblast that streams off from the anchoring villi [Kurman et al., 1984; Kurman 1991]. The intermediate trophoblast invades maternal endometrial spiral arteries and dilates them in order to achieve a sufficient fetal blood supply. This process peaks during the 12^th week of pregnancy and declines rapidly thereafter.

Successful implantation and further development of implanted embryo(s) absolutely depend on the quality of the embryo, the quality of the implantation site and their interaction, particularly, depends upon synchronized development of the blastocyst to the stage when it is competent to implant and the uterus to the stage when it is receptive to blastocyst growth and implantation, in other words, successful implantation depends upon competent embryo, appropriate intra–uterine conditions and maternal receptive endometrium. Although multiple implantation at 6 weeks is predominantly determined by (morphological) embryo quality, the continuation of pregnancy beyond 6 weeks becomes more dependent on the combination of genetic and developmental potential of the embryo(s) and an optimal uterine milieu [Lambers et al., 2007].

The incidence of spontaneous reduction, or in other words, spontaneous abortion is the highest in the first trimester of pregnancy. Interestingly, but most conceptions are lost very early in gestational life. The risk of spontaneous first trimester abortion is estimated to be between 10 and 20%. Furthermore, the exact percentage of the first trimester abortion is impossible to establish because many abortions occur before pregnancy is clinically proven. The greatest embryo losses appear to occur at the preimplantation stage or during the first week of implantation, what seems that perplexity and mysticism of spontaneous fetus’s (fetuses’) reduction phenomenon are still unknown, the whole pregnancy, being considered as a phenomenon is also incompletely understood and the inclusive spectrum of preventive embryo–loss measures aren’t found. In this regard, it can be concluded, that the subclinical pregnancy loss can also be higher than expected. The arrest of development and subsequent resorption of an embryo may occur at any moment in early gestational life. The paradigm, which was established for spontaneous reduction presents the correlation between high embryo loss rates and multifetal implantation rates: increasing loss of Gestational Sacs correlates to the multiplicity of the pregnancy. It was found that the incidence of loss per Gestational Sac in multiple pregnancies is also much lower compared with singleton pregnancies [Tummers et al., 2003]. It was explicated that embryos of twin pregnancies come from a better cohort and have better intrinsic potential [Tummers et al., 2003]. The inverse correlation between the number of gestations and perinatal outcome has been well documented, and elective Multifetal Pregnancy Reduction (MFPR) has been undertaken in order to reduce the risks in multifetal pregnancies [Boulot et al., 2000].

Nowadays the infertility experts have a limited understanding of the first indicators and causes which result into spontaneous miscarriage. Generally defining, pregnancy is a remarkably inefficient process with a high risk of early fetal loss. Numerous causes for early fetal loss of viable conceptuses can be suggested. It is thought that intrinsic abnormalities within the embryo are the major reason for failed conceptions or early fetal death [Tummers et al., 2003]. Different embryo characteristics (fragmentation of the embryo, presence or absence of any irregular blastomeres, speed of cleavage, etc.) have been reported to influence implantation rates significantly [Van Royen et al., 1999]. Therefore, a better knowledge of embryo characteristics could be vital and could have a large influence on future Embryo Transfer policies, and not only improve pregnancy rates but also decrease early pregnancy loss rates [Tummers et al., 2003].

Following Assisted Reproduction Treatment, the risk of miscarriage may seem a bit higher than in spontaneous pregnancies, but this is thought to be due to earlier pregnancy detection and to older maternal age. Also, it may be assumed that the relative risk of miscarriage in relation to the detection of fetal heart activity and the duration of gestation can be extrapolated to spontaneous pregnancies. It was calculated that the abortion rate (per Gestational Sac separately) in relation to the duration of pregnancy declines once fetal heart activity was positive. Of the 1200 singleton pregnancies, after fetal heart activity was detected on ultrasound, the risk of abortion declined to 12.2%. At 7 weeks this risk decreased to 11.9%, at 9 weeks to 8.2%, at 11 weeks it was 4.2% and at 13 weeks the risk of miscarrying had dropped to 2.2%. Of the 397 twin pregnancies, once fetal heart activity was positive, the risk of abortion was 7.3%. At 9 weeks gestational age the abortion risk had declined to 4.9%, at 11 weeks this risk was 2.2% and at 13 weeks it was 2.0%. The observation that miscarriage rates per fetal sac are lower in twin than in singleton pregnancies, therefore, may suggest that embryos in twin pregnancies have a better intrinsic potential than in singleton pregnancies. It would seem that these embryos are part of a better cohort of embryos, not only possessing a higher implantation potential, but also a higher potential for successful further development [Tummers et al., 2003].

When the complete pregnancy loss in twins (5.1%) was compared with the pregnancy loss in singletons (21.1%) the difference is very significant. This means that the embryological potential for successful development is not the same [Tummers et al., 2003].

The alterations observed in the Embryo Transfer policy after establishment of the concept that multiple pregnancies are associated with a significantly higher risk of complications for both mother and fetus/newborn than singleton pregnancies, Tummers et al. (2003) noted that the results of their study should not be interpreted as a plea for twin pregnancies and double Embryo Transfer. On the contrary, this study provides additional proof that Single Embryo Transfer (SET) is a logical strategy to consider. Indeed, in pregnancies occurring after Single Embryo Transfer (SET), the embryo which was selected for transfer would have implanted if a double Embryo Transfer had been performed. This implies that this single embryo leading to pregnancy after Single Embryo Transfer (SET) has the same developmental potential as when it would have been part of a twin pregnancy following a double transfer [Tummers et al., 2003].

Comparative multivariate statistical analysis of the data, presented in studies has shown that the incidence of first trimester pregnancy loss is much lower in IVF twin pregnancies than in IVF singleton pregnancies.

Notably, abortion should be registered as having occurred on the day that an empty Gestational Sac or fetal demise was recorded by transvaginal ultrasound, irrespective of the time of expulsion or evacuation by curettage [Tummers et al., 2003].

In conclusion, after fetal heart activity is established, the risk of abortion in IVF pregnancies is halved. The potential for survival is significantly higher in twin pregnancies at all stages of the first trimester, pointing to a cohort phenomenon [Tummers et al., 2003].

2. Complexities and risks, which closely correlate with multiple pregnancy: twin and triplet (multifetal) pregnancies with a ‘vanished’ embryo in close focus

Multiple pregnancies imply a higher rate of maternal as well as perinatal complications [Bernasko and Lynch, 1997]. Multiple gestations after Infertility Treatment cycles are documented to have a high incidence of spontaneous reduction, when the pregnancy begins with twins or higher gestations, but concludes with a lower number of newborns being born alive. This is commonly referred to as the ‘vanishing embryo syndrome’, which is associated with pregnancy complexities and potential risks. Interestingly, spontaneous pregnancy loss mainly occurs between 8 and 9 weeks of gestation. The occurrence of the vanishing twin phenomenon is dependent on the rate of twin gestations, and as a consequence closely related to the use of Assisted Reproductive Technology.

Vanishing embryo is a phenomenon, which occurs before the ninth gestational week. Embryo vanishing phenomenon was defined as the spontaneous loss of one or more embryos after identifying heart activity [Rodríguez–González et al., 2002]. Attempting to minimize interpretative error Rodríguez–González et al. (2002) identified a true intrauterine Gestational Sac using several sonographic characteristics. These included: a double contour, identification of a yolk sac within the Gestational Sac, and recognition of an embryonic heart after 6 weeks of gestation [Blumenfeld et al., 1992]. Little is known about the pathophysiology of this ‘embryo vanishing’ process. Due to the difficulties and limitations in its definition and diagnosis, the reported frequency of vanishing phenomenon has ranged from 3.7–100% [Dickey et al., 1990; Legro et al., 1995]. Spontaneous embryo reduction (spontaneous embryo loss), defined as the vanishing of embryos during early gestational life, has long been an area of close scientific interest which turned to be the mainstream of the reproductive endocrinology’s investigations nowadays.

To confirm that Fertility Treatment has been successful, an early ultrasound scan (around pregnancy Week 8) is an obligatory procedure at all Fertility Clinics in order to demonstrate the presence of a live fetus: fetal heart activity should be established to prove the presence of a live fetus in utero. In spontaneously conceived pregnancies, an early ultrasound scan is not usually mandatory, thus the vanishing twin phenomenon is less frequent diagnosed in early pregnancy, and, therefore, in such cases there is the potential risk of underestimation of early vanishing twins, as an empty Gestational Sac can be over–looked by the clinicians or misinterpreted as an intrauterine hematoma.

The increasing use of high–quality ultrasound in early pregnancy has vividly demonstrated that spontaneous reduction of a twin pregnancy to a singleton pregnancy, the so–extensionally defined ‘vanishing twin phenomenon’, is a rather frequent incident, in percentage it can be presented as 10–40% of all multifetal pregnancies [Landy and Keith, 1998; Dickey et al., 2002]. Despite the transvaginal ultrasound is advanced nowadays, what allows to screen the embryo’s development and detect the various malformations, it was shown that ‘vanishing embryo’ is not an infrequent event in medical practice, the information, concerning this pathophysiological process is still limited.

Vanishing embryos may be observed in 21% of dichorionic twins and in up to 50% of monochorionic twins [Benson et al., 1993]. In triplet pregnancies, vanishing embryos of one of the embryos may be observed in 90% of the cases during the first 7 gestational weeks [Manzur et al., 1995].

Multiple embryo implantation can’t guarantee that absolutely all embryos would develop normally into fetuses. On the contrary, discovering more than one Gestational Sac before the eighth week should not be considered as definitive because vanishing embryo phenomenon may occur [Mansour et al., 1999].

To verify and confirm the conventional paradigm outlined above, the additional statistical data can be represented: the scientific group under the management of Pinborg A. (2007) presented the statistical information for the concerned couples with a viable fetus and an empty Gestational Sac or a non–viable fetus in early pregnancy that more than 93% are likely to deliver a live born baby [Pinborg et al., 2007], what provides evidence that vanishing twins from multiple Embryo Transfer is one of the reasons for the poorer outcome in IVF singletons [Pinborg et al., 2007]. Careful early ultrasound monitoring is highly recommended to precisely identify the occurrence of a vanished embryo and the time when the vanishing occurred.

3. Stillbirth and neonatal mortality as the most negative consequence of multifetal pregnancy

Although multifetal pregnancy is associated with increased risk of early fetal loss, perinatal mortality and morbidity, the pathophysiology of early fetal loss has not been completely elucidated. Basically, identification of determinants of pregnancy outcome is complex and it is difficult to disentangle the effects of related factors. Maternal, fetal and iatrogenic factors may play a significant role in spontaneous multiple pregnancy reduction (spontaneous abortion). Improvement in ultrasound technique has allowed better visualization of embryonic and extra–embryonic structures in the early stages of pregnancy, which has led in turn to more frequent reporting of this phenomenon.

Intrauterine death or stillbirth was defined as the birth of a dead fetus at 24 or more completed weeks of gestation. Even two–fetuses’ pregnancies are well known to carry a higher risk of adverse birth outcomes compared with singleton pregnancies. Late intrauterine death of one twin in naturally conceived twin pregnancies is associated with a considerably increased morbidity and mortality risk in the surviving co–twin [Pharoah and Adi, 2000; Scher et al., 2002]. Thus, the stillbirth rate in twins is four times and neonatal mortality is five to seven times higher than in singletons [Doyle, 1996; Bell et al., 2004].

There is no inclusively represented factors with potential influence on the risk of stillbirth. In the most cases, stillbirth is unpreventable, as it may happen at any gestational age. For assessing the risk of stillbirth by gestational age, it has been suggested that fetuses at risk (in all ongoing pregnancies) is a more appropriate denominator than fetuses delivered at that gestational age [Yudkin et al., 1987; Kramer et al., 2002].

There are further methodological inconsistencies between the twin studies that complicate comparison. While in singleton pregnancies date of delivery is normally close to date of fetal death, in twin pregnancies with a single fetal death gestational age at death may differ from that at delivery by many weeks. Similarly to studies of singletons, studies of twins using gestational age at delivery as a proxy for gestational age of fetal death reported that stillbirth risk increases with advancing gestational age. Studies using gestational age at death, as in the current study, have in contrast found the highest risk of death at earlier gestational weeks (24–25 weeks), with the risk decreasing with advancing gestation and then usually, but not always rising again near term for twins (36–37 weeks) [Glinianaia et al., 2011].

Ultimately, the scientific group Glinianaia et al. (2011) presented two different approaches for the calculation of the gestational age-specific risk of antepartum stillbirth in twins. The first approach (including only stillbirths at a given gestational age) is useful for determining the risk of antepartum stillbirth within that gestational age, which may have an etiologic association with that gestational period, while the second approach (including stillbirths at or beyond the given gestation) predicts the overall risk of antepartum stillbirth from any gestation in continuing pregnancies and is therefore more clinically useful. Both approaches demonstrated a much higher risk of antepartum stillbirth for Monochorionic (MC) twins at any gestation, but the first one showed the highest risk for Monochorionic (MC) at 24–27 weeks increasing again at 32–36 weeks, while for Dichorionic (DC) twins the risk was lowest at 35–36 weeks, increasing at 37–38 weeks [Glinianaia et al., 2011].

Placental angioarchitecture is a major factor for inter–twin birthweight discordance and selective Intrauterine Growth Restriction (IUGR), and consequently, for poor perinatal outcomes in Monochorionic (MC) twin pregnancies. The higher risk of fetal death in Monochorionic (MC) compared with Dichorionic (DC) twin results from the presence of placental vascular anastomoses in the vast majority of Monochorionic (MC) twin pregnancies, unequal placental sharing and abnormalities in umbilical cord insertion that may cause Twin–Twin Transfusion Syndrome (TTTS), birthweight discordance or acute feto–fetal haemorrhage after intrauterine demise of one twin. Unequal placental sharing (defined as one twin receiving blood from >60% of the placenta) has been found to be a significant risk factor for birthweight discordance in MCDA twins even after controlling for gestational age and vascular anastomoses [Glinianaia et al., 2011].

There is still much to learn about factors that affect pregnancy outcome and the way in which they interact. In addition to recognized risk factors for fetal death, it is important to assess the impact of past reproductive experience.

Conclusion

At present, multifetal or multiple pregnancies are closely associated with Infertility Treatment therapy outcome. Despite being an efficient and widely used Treatment for infertile couples, In–Vitro Fertilization (IVF) is responsible for an increasing number of multifetal pregnancies and adverse neonatal outcomes. It has been suggested that in case of double implantation, continuation of pregnancy is more likely, because embryos were selected from a better cohort of embryos [Tummers et al., 2003]. Lambers et al. (2007) multiple logistic regression analysis indeed indicates good morphological embryo quality as the strongest factor determining the chance of double implantation [Lambers et al., 2007]. Undisputedly, it represents an attractive option to the range of Infertility Treatments available at present. But, the complexities and risks should not be neglected as the negligence of the negative consequences may result into reduced fetal survival or complete fetal loss.

Controversies, correlate with morphological parameters should also be outlined. An embryo that is morphologically optimal, even has perfect morphologic features, may have high potential of further development and subsequent implantation. But there still is a good possibility of chromosomal abnormality, as not all chromosomal alterations can be detected and therefore, there still is a good possibility of spontaneous abortion, because approximately 50% of all first trimester abortions are associated with cytogenic abnormalities [Lambers et al., 2007].

Multifetal pregnancies are recognized as an adverse outcome and are responsible for feto–maternal morbidity and mortality as well as maternal/newborn/maternal and newborn morbidity and mortality, in case if it has happened in the postnatal period. Perinatal mortality and morbidity and maternal mortality and morbidity are increased in multiple pregnancies as compared with singleton pregnancies because of a higher rate of prematurity and low birth weights in the newborn babies, and because of pregnancy complications in the mothers. Obstetric complications associated with multiple pregnancy include prenatal screening problems and increased incidence of pregnancy–induced hypertension, antepartum haemorrhage, preterm labour and assisted or surgical delivery. Neonatal problems include low birthweight and increased prevalence of congenital malformations.

Therefore, it is important not only to be able to provide the couple evidence–based information but also to bring into focus potentially preventable adverse outcomes. Additionally, it is necessary to emphasize one extremely vital concept for the successful pregnancy outcome: any kind of multiple pregnancy, even the one, which does not have any complications and seems to be ‘perfect’ needs to be guided and monitored by the experienced clinicians in order to prevent or limit the possibilities of the negative consequences’ occurrence.

References:

[1] American Society for Reproductive Medicine. Multiple Pregnancy Associated with Infertility [The document, which replaces the 2006 ASRM Practice Committee document]. Fertil. Steril., 2012; 97: 825–834.

[2] Antsaklis A.J., Drakakis P., Vlazakis G.P., Michalas S. Reduction of multifetal pregnancies to twins does not increase obstetric or perinatal risks. Hum. Reprod., 1999; 14(5): 1338–1340.

[3] Bell R., Glinianaia S.V., Rankin J., Wright C., Pearce M.S., Parker L. Changing patterns of perinatal death, 1982–2000: a retrospective cohort study. Arch. Dis. Child Fetal Neonatal Ed., 2004; 89: F531–F536; https://doi.org/10.1136/adc.2003.038414

[4] Benson C.B., Doubilet P.M., Laks M.P. Outcome of twin gestations following sonographic demonstration of two heart beats in the first trimester. Ulltrasound Obstet. Gynecol., 1993; 3: 343–345.

[5] Bergh C., Moller A., Nilsson L., Wikland M. Obstetric outcome and psychological follow-up of pregnancies after embryo reduction. Hum. Reprod., 1999; 14(8) 2170–2175.

[6] Bernasko J., Lynch L. Twin pregnancies conceived by assisted reproductive techniques: maternal and neonatal outcomes. Obstet. Gynecol., 1997; 89: 368–372.

[7] Blumenfeld Z., Dirnfeld M., Abramovici H. et al. Spontaneous fetal reduction in multiple gestations assessed by transvaginal ultrasound. Brit. J. Obstet. Gynaecol., 1992; 99: 333–337.

[8] Bortolus R., Parazzini F., Chatenoud L., Benzi G., Bianchi M.M., Marini A. The epidemiology of multiple births. Hum. Reprod. Update, 1999; 5: 179–187.

[9] Boulot P., Vignal J., Vergnes C., Dechaud H., Faure J.M., Hedon B. Multifetal reduction of triplets to twins: a prospective comparison of pregnancy outcome. Hum. Reprod., 2000; 15(7): 1619–1623.

[10] Claman P., Armant D.R., Seibel M.M. et al. The impact of embryo quality and quantity on implantation and the establishment of viable pregnancies. J. In vitro Fert. Embryo Transfer, 1987; 4: 218–222.

[11] Coffler M.S., Kol S., Drugan A., Itskovitz–Eldor J. Early transvaginal embryo aspiration: a safer method for selective reduction in high order multiple gestations. Hum. Reprod., 1999; 14(7): 1875–1878.

[12] Cummins J.M., Breen T.M., Harrison K.L. et al. A formula for scoring human embryo growth rates in in vitro fertilisation: its value in predicting pregnancy and in comparison with visual estimates of embryo quality. J. In vitro Fert. Embryo Transfer, 1986; 3: 284–295.

[13] Dickey R.P., Olar T.T., Curole D.N., Taylor S.N., Rye P.H., Matulich E.M. The probability of multiple births when multiple gestational sacs or viable embryos are diagnosed at first trimester ultrasound. Hum. Reprod., 1990; 5(7): 63–64.

[14] Dommergues M., Nisand I., Mandelbrot L. et al. (1991) Embryo reduction in multifetal pregnancies after infertility therapy: obstetrical risks and perinatal benefits are related to operative strategy. Fertil. Steril., 55, 805–811.

[15] Doyle P. The outcome of multiple pregnancy. Hum. Reprod., 1996; 11 (4): 110–117.

[16] Evans I.M., Littmann L., King M., Fletcher J.R. Multiple gestation: The role of multifetal pregnancy reduction and selective termination. Clin. Perinatol., 1992; 19: 345–357.

[17] Fauser BCJM, Devroy P and Macklow NS (2005) Multiple births resulting from ovarian stimulation for subfertility treatment. Lancet, 365:1807–1816.

[18] Glinianaia S.V., Obeysekera A.M., Stephen Sturgiss S., Bell R. Stillbirth and neonatal mortality in monochorionic and dichorionic twins: a population–based study. Hum. Reprod., 2011; 26(9): 2549–2557.

[19] Helmerhorst F.M., Perquin D.A.M., Donker D., Keirse M.J.N.C. Perinatal outcome of singletons and twins after assisted conception: a systematic review of controlled studies. Br. Med. J., 2004; 328: 261–265.

[20] Jackson R.A., Gibson K.A., Wu Y.W., Croughan M.S. Perinatal outcomes in singletons following in vitro fertilization: a meta–analysis. Obstet. Gynecol., 2004; 103 (3): 551–563.

[21] Knoth M., Larsen J.F. Ultrastructure of a human implantation site. Acta. Obstet. Gynecol. Scand., 1972; 51: 385–393.

[22] Kramer M.S., Liu S., Luo Z., Yuan H., Platt R.W., Joseph K.S. Analysis of perinatal mortality and its components: time for a change? Am. J. Epidemiol., 2002; 156: 493–497.

[23] Kurman R.J., Main C.S., Chen H.–C. Intermediate trophoblast: distinctive form of trophoblast with specific morphological, biochemical and functional features. Placenta, 1984; 5: 349–370.

[24] Kurman RJ. The morphology, biology, and pathology of intermediate trophoblast: a look back to the present. Hum. Pathol., 1991; 22: 847–855.

[25] Lambers M.J., Mager E., Goutbeek J., McDonnell J., Homburg R., Schats R., Hompes P.G.A., Lambalk C.B. Factors determining early pregnancy loss in singleton and multiple implantations. Hum. Reprod., 2007; 22(1): 275–279.

[26] Landy H.J., Keith L.G. The vanishing twin: a review. Hum. Reprod. Update, 1998; 4(2): 177–183.

[27] Legro R.S., Wong I.L., Paulson R.J. et al. Multiple implantation after oocyte donation: a frequent but inefficient event. Fertil. Steril., 1995; 63: 849–853.

[28] Lindenberg S. Ultrastructure in human implantation: transmission and scanning electron–microscopy. Baillieres Clin. Obstet. Gynaecol., 1991; 5: 1–14.

[29] Loutradis D., Drakakis, P. Multiple pregnancies after assisted reproductive techologies (ART). Syllabus of the 3^rd ESHRE Campus Symposium, [November], 1995; 10–11.

[30] Mansour R.T., Aboulghar M.A., Serour G.I. et al. Multifetal pregnancy reduction: modification of the technique and analysis of the outcome. Fertil. Steril., 1999; 71: 380–384.

[31] Manzur A., Goldsman M.P., Stone S.C. et al. Outcome of triplet pregnancies after assisted reproductive techniques: how frequent are the vanishing embryos? Fertil. Steril., 1995; 48: 86–93.

[32] Pharoah P.O.D., Adi Y. Consequences of in-utero death in a twin pregnancy, Lancet, 2000; 355: 1597–1602.

[33] Pinborg A., Lidegaard Ø., la Cour Freiesleben N., Andersen A.N. Vanishing twins: a predictor of small-for-gestational age in IVF singletons. Hum. Reprod., 2007; 22(10): 2707–2714.

[34] Rodríguez–González M., Serra V., Garcia–Velasco J.A., Pellicer A., Remohí J. The ‘vanishing embryo’ phenomenon in an oocyte donation programme. Hum. Reprod., 2002; 17(3): 798–802.

[35] Scher A.I., Petterson B., Blair E., Ellenberg J.H., Grether J.K., Haan E., Reddihough D.S., Yeargin–Allsopp M., Nelson K.B. The risk of mortality or cerebral palsy in twins: a collaborative population–based study. Pediatr. Res., 2002; 52: 671–681.

[36] Seoud M.A.–F., Toner J.P., Kruithoff C. et al. Outcome of twin, triplet and quadruplet in vitro fertilization pregnancies: the Norfolk Experience. Fertil. Steril., 1992; 57: 825–834.

[37] The ESHRE Capri Workshop Group. Multiple gestation pregnancy. Hum. Reprod., 2000; 15(8): 1856–1864.

[38] Torok O., Lapinski R., Salafia C.M. et al. Multifetal pregnancy reduction is not associated with an increased risk of intrauterine growth restriction, except for very–high order multiples. Am. J. Obstet. Gynecol., 1998; 179: 221–225.

[39] Tummers P., De Sutter P., Dhont M. Risk of spontaneous abortion in singleton and twin pregnancies after IVF/ICSI. Hum. Reprod., 2003; 18(8): 1720–1723.

[40] Van Royen E., Mangelschots K., Neubourg D.D., Valkenburg M., Van de Meerssche M., Ryckaert G., Eestermans W., Gerris J. Characterization of a top–quality embryo, a step towards single–embryo transfer. Hum. Reprod., 1999; 14(9): 2345–2349.

[41] Yaron T., Johnson K.D., Bryant–Greenwood P.K., Kramer R.L., Johnson M.P., Evans M.I. Selective termination and elective reduction in twin pregnancies: 10 years–experience at a single centre. Hum. Reprod., 1998; 13(8): 2301–2304.

[42] Yudkin P.L., Wood L., Redman C.W. Risk of unexplained stillbirth at different gestational ages. Lancet 1987; 1: 1192–1194.

[43] World Health Organization, International Statistical Classification of Disease and Related Health Problems, 1993; 10^th revision, Geneva WHO