Multiple pregnancies following assisted reproductive technologies – A happy consequence or double trouble?

doi:10.1016/j.siny.2014.03.001

Seminars in Fetal and Neonatal Medicine

Volume 19, Issue 4, August 2014, Pages 222-227

https://doi.org/10.1016/j.siny.2014.03.001 Get rights and content

Summary

The association between assisted reproduction technologies (ART) and multiple pregnancy is well-established, with a multiple birth rate of 24% in ART pregnancies. Multiple pregnancy is associated with significantly increased maternal and perinatal morbidity and mortality, as well as increased costs to the National Health Service. Evidence relating to the obstetric outcomes of ART twins versus naturally conceived twins is discussed in this review. Methods to reduce the risk of multiple births including elective single embryo transfer and multifetal pregnancy reduction are also discussed.

Introduction

The incidence of multiple births has risen steadily over the last 30 years, mainly due to the increasing use of assisted reproduction technologies (ART) and the increase in average maternal age at conception. ART is defined as any procedure that entails the handling of both eggs and sperm, or of embryos, for the purpose of establishing a pregnancy [gamete intrafallopian transfer (GIFT); in-vitro fertilisation (IVF); intracytoplasmatic sperm injection (ICSI)] [1]. In 2009, 16 women per 1000 had multiple births accounting for 3% of all live births [2]. The current rate of multiple births in ART is 24% [2]. Although multiple pregnancy is associated with adverse pregnancy outcomes, a significant proportion of infertility patients considers multiple pregnancy to be an ideal treatment outcome [3].

Multiple pregnancy is associated with significantly higher risk than singleton pregnancies for both the mother and the babies. Maternal antepartum, intrapartum and postpartum complications are more frequent, as are perinatal sequelae. Multiple pregnancies therefore require more monitoring and increased contact with healthcare professionals, resulting in an increased financial burden to the National Health Service (NHS). Indeed the maternal care for twin pregnancies appears to be twice as costly as the care for mothers with singleton pregnancy, because of the increased caesarean section rate and the need for specialist obstetric care [4]. Increased rates of prematurity will increase costs of caring for the neonate, as well as the costs of prematurity-induced lifelong disability. This paper aims to review the maternal and perinatal consequences of multiple pregnancy. The outcome of ART twins versus naturally conceived twins is also discussed. Current best practice advice on minimising the risk of multiple pregnancy in ART will also be outlined.

Section snippets

Maternal consequences of multiple pregnancy

Multiple pregnancy is associated with increased maternal morbidity compared with singleton pregnancy [2]. There is good evidence that the incidence of pregnancy-induced hypertension is increased with multiple pregnancy. A cohort study reporting on 34,374 pregnancies with one to four fetuses published in 2005 found the incidence of pregnancy-related hypertensive disease to be 6.5% for singletons versus 12.7–19.7% for multifetal pregnancies (P < 0.001) [5]. Sibai et al. undertook a prospective

Perinatal consequences of multiple pregnancies

The most frequently reported perinatal consequence of multiple pregnancy is the risk of preterm labour. Approximately 94% of multiple gestations are twins [16]. Recent US national statistics published in 2011 found that in 137,217 twin pregnancies 58.8% delivered preterm (<37 weeks) and 11.4% were delivered very preterm (<32 weeks of gestation) [17]. In the same report of 5095 triplet pregnancies, 94.4% delivered preterm (<37 weeks of gestation) and 36.8% delivered very preterm (<32 weeks of

Outcomes of ART versus naturally conceived twins

The number of women having ART (IVF/ICSI) pregnancies is increasing worldwide, and the rate of multiple pregnancy is higher with ART. It has been suggested that obstetric outcomes in pregnancies after IVF/ICSI are poorer when compared with those after natural conception, and this affects the counselling of patients and the guidance of clinical practice [28]. Apart from the overall complications of a twin pregnancy per se, ART twin pregnancies usually have additional obstetric risk factors

Strategies for minimising risk

Due to the increased perinatal and maternal risks of multiple pregnancy it is paramount to identify ways of preventing iatrogenic multiple pregnancies. Multiple pregnancy remains the single biggest risk to the health and welfare of children born after IVF [42]. The National Institute for Health and Care Excellence (NICE) fertility guideline published in February 2013, aimed at maximising outcome and minimising risk, provides an authoritative and carefully researched body of evidence [43]. A

Conclusion

Multiple pregnancy rates in the context of ART remain high. Twins and higher-order multiples carry increased maternal and perinatal risks as well as an increased cost to the NHS. Although most of the current research states that obstetric outcomes of ART twins are similar to naturally conceived twins, twin pregnancy per se significantly increases the risk of obstetric complications and perinatal mortality and morbidity. For the above reasons centres performing ART should strive to prevent

Conflict of interest statement

None declared.

Funding sources

None.

References (62)

B. Sibai et al.
Hypertensive disorders in twin versus singleton gestations
Am J Obstet Gynecol
(2000)
E. Norwitz et al.
Maternal physiology and complications of multiple pregnancy
Semin Perinatal
(2005)
D. Schwartz et al.
Gestational diabetes mellitus: metabolic and blood glucose parameters in singleton versus twin pregnancies
Am J Obstet Gynaecol
(1999)
E. Simpson et al.
Venous thromboembolism in pregnancy and the puerperium: incidence and additional risk factors from a London perinatal database
Br J Obstet Gynaecol
(2001)
M. Collins et al.
Seventy-one quadruplet pregnancies: management and outcome
Am J Obstet Gynecol
(1990)
J.P. Elliott
High-order multiple gestations
Semin Perinatol
(2005)
A. Sutcliffe et al.
Follow-up of twins: health, behaviour, speech, language outcomes and implications for parents
Early Hum Dev
(2006)
S. McDonald et al.
Perinatal outcomes of in vitro fertilization twins: a systematic review and meta-analyses
Am J Obstet Gynecol
(2005)
P. McGovern et al.
Increased risk of preterm birth in singleton pregnancies resulting from in vitro fertilization–embryo transfer or gamete intrafallopian transfer: a meta-analysis
Fertil Steril
(2004)
B. Fitzsimmons et al.
Perinatal and neonatal outcomes in multiple gestations: assisted reproduction versus spontaneous conception
Am J Obstet Gynecol
(1998)

F. Olivennes et al.

Perinatal outcome of twin pregnancies obtained after in vitro fertilization: comparison with twin pregnancies obtained spontaneously or after ovarian stimulation

Fertil Steril

(1996)

T. Gelbaya et al.

The likelihood of live birth and multiple birth after single versus double embryo transfer at the cleavage stage: a systematic review and meta-analysis

Fertil Steril

(2010)

A. Gremeau et al.

Outcome and feasibility of elective single embryo transfer (eSET) policy for the first and second IVF/ICSI attempts

Eur J Obstet Gynecol Reprod Biol

(2012)

D. De Neubourg et al.

Impact of a restriction in the number of embryo transferred on the multiple pregnancy rate

Eur J Obstet Gynaecol Reprod Biol

(2006)

M. Evans et al.

Fetal reduction

Semin Perinatol

(2005)

R. Wimalasundera

Selective reduction and termination of multiple pregnancies

Semin Fetal Neonat Med

(2010)

M. Evans et al.

Improvement in outcomes of multifetal pregnancy reduction with increased experience

Am J Obstet Gynaecol

(2001)

A. Zuppa et al.

Neonatal outcomes in triplet pregnancies: assisted reproduction versus spontaneous conception

J Perinat Med

(2007)

Clinical guideline 129. Multiple pregnancy – the management of twin and triplet pregnancies in the antenatal period

(2011)

T.J. Child et al.

The desire for multiple pregnancy in male and female infertility patients

Hum Reprod

(2004)

H. Mistry et al.

Costs of NHS maternity care for women with multiple pregnancy compared with high-risk and low-risk singleton pregnancy

Br J Obstet Gynaecol

(2007)

C. Misty et al.

The effect of fetal number on the development of hypertensive conditions of pregnancy

Obstet Gynecol

(2005)

K. Duckitt et al.

Risk factors for pre-eclampsia at antenatal booking: a systematic review of controlled studies

BMJ

(2005)

C. Little

One consequence of infertility treatment: multifetal pregnancy

Am J Maternal/Child Nurs

(2010)

G. Chamberlain

Multiple pregnancy

BMJ

(1991)

J. Rauh-Hain et al.

Risk for developing gestational diabetes in women with twin pregnancies

J Maternal–Fetal Neonat Med

(2009)

Clinical guideline 132. Caesarean section

(2011)

N. Rizwan et al.

Maternal morbidity and perinatal outcome with twin pregnancy

J Ayub Coll Abbottabad

(2010)

J. Martin et al.

Births: final data for 2009

Natl Vital Stat Rep

(2011)

Perinatal Mortality 2007: United Kingdom

(2009)

Human Fertilisation and Embryology Authority

Multiple pregnancies and birth: considering the risks

(2006)

Cited by (46)

Utility of cervical pessary in the prevention of preterm birth in triplet pregnancies: A single-center observational retrospective study of 165 triplet pregnancies
2024, European Journal of Obstetrics and Gynecology and Reproductive Biology
Premature births are a health problem arising in triplet pregnancies, resulting in high levels of morbidity and mortality. The objective of this study is to evaluate the utility of cervical pessaries in reducing prematurity (<34 weeks) in triplet pregnancies.
This is a single-center, retrospective case-control study regarding triplet pregnancies with follow-up at the La Paz University Hospital between 2000 and 2023. Maternal characteristics, obstetric and perinatal outcomes, and the use of cervical pessaries were examined.
165 triplet pregnancies were analyzed: 87 (52.7 %) in the case group (premature triplet pregnancies) and 78 in the control group (non-premature triplet pregnancies). A cervical pessary was inserted in 15 (17.2 %) triplet pregnancies in the case group and in 12 (16.7 %) triplet pregnancies in the control group (p = 0.92; OR = 1.04 (0.46–2.35)). A pessary was later inserted in the non-premature group (p = 0.01). The risk of preterm labor and the use of tocolytics ± glucocorticoids were found to be significantly more frequent in the premature group, with p = 0.01; OR = 2.30 (1.21–4.36) and p < 0.01; OR = 2.36 (1.23–4.44), respectively. Protocol-based cesarean sections were more frequent in the non-premature group (p < 0.01), while cesarean sections due to maternal complications (p < 0.01) and premature membrane rupture (p < 0.01) were more frequent in the premature group.
The cervical pessary is not useful in preventing preterm births (< 34 weeks) in triplet pregnancies. It is likely that being pregnant with triplets is a powerful independent factor associated with prematurity, despite other pregnancy conditions. Women who are pregnant with triplets and at risk of preterm labor and those taking tocolytics ± glucocorticoids may benefit from pessary insertion.
Comparison of maternal, fetal, obstetric and neonatal outcomes for 234 triplet pregnancies conceived in vivo versus IVF and ICSI conceptions
2024, Reproductive BioMedicine Online
Is there a difference in maternal, fetal, obstetric and neonatal outcomes for triplet pregnancies when comparing in vivo conceptions with those conceived by assisted reproductive technology (ART)?
This single-centre, retrospective cohort study included all triplet pregnancies followed up at La Paz University Hospital, Madrid between 2000 and 2022. The characteristics of the pregnant women, and maternal, fetal, obstetric and perinatal outcomes were examined. Univariate and multivariate statistical analyses were performed.
In total, 234 triplet pregnancies were analysed: 92 in the natural and assisted insemination conception group (in-vivo conception) and 142 in the in vitro fertilization and intracytoplasmic sperm injection conception group (ART conception). ART triplet pregnancies were more common between 2000 and 2010 (P = 0.003). The percentage of monochorionic triamniotic pregnancies was significantly higher (P = 0.02) in the in-vivo conception group, and the percentage of dichorionic triamniotic pregnancies was significantly higher (P = 0.003) in the ART conception group. After adjusting for confounders, intrauterine growth restriction (IUGR) remained significantly more common in the ART conception group (adjusted odds ratio 8.65, 95% CI 1.66–45.03; P = 0.01). Differences in maternal age (P = 0.61), threatened preterm labour (P = 0.10), Apgar score ≤5 at 5 min (P = 0.99), umbilical cord pH <7.20 (P = 0.99) and fetal death (P = 0.99) disappeared after adjustment for confounders.
ART triplet pregnancies had a higher rate of IUGR than in vivo triplet pregnancies. This could be related to higher maternal age, and higher rates of Apgar score ≤5 at 5 min and umbilical cord pH <7.20 in these pregnancies. In these cases, placental examination could provide valuable information.
Cardiovascular mortality risk a decade after twin and singleton pregnancies complicated by hypertensive disorders of pregnancy
2022, Pregnancy Hypertension
Citation Excerpt :
In other words, the pregnancy acts as a “stress test” for the already susceptible maternal cardiovascular system [17]. Compared to singleton pregnancies, the incidence of PE in twin pregnancies is two to three times higher [21–23]. This might be explained by a greater placental mass in twin pregnancies, posing greater stress to the maternal cardiovascular system [24–28].
To describe the cardiovascular mortality (CVM) risk in women after twin versus singleton pregnancies complicated by hypertensive disorders of pregnancy (HDP).
Retrospective cohort study of nulliparous women with a twin or singleton pregnancy who delivered in the Netherlands between 1995 and 2015. We used data of the Perinatal Registry of the Netherlands and data of the National Death Registry to determine baseline data, the occurrence of HDP and CVM. In the two main analyses we compared twin pregnancies complicated by HDP to 1) singleton pregnancies complicated by HDP and 2) uncomplicated twin pregnancies (i.e. without HDP) of women who delivered within a hospital setting.
CVM risk using cox-proportional hazard models, adjusted for maternal age (aHR).
1,243,231 nulliparous women were included, of which 30,623 (2.5%) had a twin and 1,212,608 (97.5%) had a singleton pregnancy. A total of 9,853 (32.2%) twin pregnancies were complicated by HDP, versus 249,141 (20.6%) singleton pregnancies (p < 0.0001). Within the HDP twin cohort, 14/73 (19.2%) maternal deaths were due to cardiovascular causes, versus 335/1,788 (18.7%) in the HDP singleton cohort and 10/117 (8.6%) in the uncomplicated twin cohort. The corresponding aHR was 2.85 (95% CI 1.26–6.41; p = 0.01) for the HDP twin versus the uncomplicated twin cohort, and 1.05 (95% CI 0.62–1.80; p = 0.85) for the HDP twin versus the HDP singleton cohort.
Women after both twin and singleton pregnancies complicated by HDP are at a similarly increased risk of CVM later in life.
Obstetric and perinatal complications in infertile women who become pregnant
2021, Revista Medica Clinica Las Condes
Las pacientes infértiles tienen un riesgo aumentado de resultados obstétricos y perinatales adversos que dependen de los factores de infertilidad subyacentes previos y de factores inherentes a los tratamientos recibidos para lograr el embarazo. La edad materna, las patologías previas ginecológicas, hormonales, endocrinológicas, metabólicas y anatomo funcionales son reconocidas como factores de riesgo para resultados adversos obstétricos y perinatales. Los tratamientos como la hiperestimulación ovárica y los tratamientos de reproducción asistida condicionan riesgos adicionales, especialmente por el aumento de embarazos múltiples que se generan con estas terapias. El aumento de la edad materna de pacientes tratadas por infertilidad y la necesidad creciente de tratamientos de reproducción asistida determinan probablemente, un mayor riesgo futuro de complicaciones obstétricas y perinatales. Muchos de estos factores de riesgo pueden ser modificados y manejados antes de iniciar los tratamientos con la finalidad de mejorar el pronóstico para la madre y el recién nacido. La consideración de estos factores de riesgo y sus consecuencias en el embarazo son parte esencial del consejo reproductivo que debiera recibir toda paciente que se somete a tratamientos por infertilidad.
El objetivo de esta revisión es mostrar la relación existente entre las pacientes que consultan por infertilidad, los tratamientos usados y los potenciales riesgos obstétricos y perinatales cuando se produce el embarazo.
Infertile patients have an increased risk of adverse obstetric and perinatal outcomes that depend on underlying infertility factors and on those treatments recieved to become pregnant. Maternal age, hormonal, endocrinologial, metabolic and anatomic/functional gynecological diseases are widely recognized risk factors for adverse obstetric and perinatal outcomes. Infertility treatments like controlled ovarian hyperstimulation and assisted reproductive technologies add aditional risks, specially related to multiple pregnancies that are associated to. The higher maternal age of patients seeking for infertility treatment and the increasing need of assisted reproductive technologies probably determines a higher and increasing risk of obstetric and perinatal adverse outcomes. In many cases risk factors can be adequately modified and controlled before treatments are initiated thus improving maternal and neonatal prognosis. This risk factors and their consequences in pregnancy have to be strongly considered in reproductive counselling that should recieve every patient treated for infertility.
The aim of this article is to show the relation between infertile patients seeking for treatment and their potential risks of obstetric and perinatal adverse outcomes when they get pregnant.
Second-generation preimplantation genetic testing for aneuploidy in assisted reproduction: a SWOT analysis
2019, Reproductive BioMedicine Online
Second-generation preimplantation genetic testing for aneuploidy (PGT-A 2.0) in patients with an unfavourable reproductive and IVF prognosis is becoming common practice, with the aim of improving reproductive outcomes. However, there is still no clear evidence on the possible advantages and drawbacks with regard to this procedure. In this discussion paper, based on a SWOT (strengths, weaknesses, opportunities, threats) analysis, the different aspects of this strategy are evaluated. Current evidence suggests that PGT-A 2.0 should not at present have an indiscriminate application, but it might be indicated in cases in which the risk of aneuploidy is increased.
Clinical outcomes of multifetal pregnancy reduction in trichorionic and dichorionic triplet pregnancies: A retrospective observational study
2019, Taiwanese Journal of Obstetrics and Gynecology
Citation Excerpt :
Besides, multiple embryos transferring in ART treatment cycles are applied to maximize pregnancy rate [3–5]. Meanwhile, the complications and risks for both women and infants in multifetal pregnancies are well recognized, including the increased rates of abortion, preterm birth, cesarean section, and postpartum hemorrhage [6]. In addition, neonatal morbidity and mortality rates may also increase due to malformation and intrauterine growth retardation in multifetal pregnancy [7].
To observe the pregnancy and perinatal outcomes of trichorionic triplet (TCT) and dichorionic triplet (DCT) pregnancies with or without multifetal pregnancy reduction (MFPR).
This was a retrospective study of 732 TCT and 118 DCT pregnancies after IVF/ICSI cycles between October 1999 and May 2014 at the Reproductive & Genetic Hospital of CITIC-Xiangya. The TCT and DCT groups were subdivided into three subgroups: MFPR to single fetus group, MFPR to twins group and expectant group. Pregnancy and perinatal outcomes were compared between different subgroups.
The resulting subgroups were TCT-Expectant (n = 40), TCT to twin (n = 610), TCT to single (n = 22), DCT-Expectant (n = 17), DCT to twin (n = 50), and DCT to single (n = 22). The groups with MFPR had the better pregnancy and perinatal outcomes. Meanwhile, the significantly higher abortion rates but lower live birth and take home baby rates were found in TCT-Expectant group and DCT-Expectant group (all P < 0.05). Besides, the abortion rate of DCT-Expectant group was much higher than TCT-Expectant group (41% verse 15%, P = 0.032). As for the perinatal outcomes, retaining single fetus group showed the advantage of higher birth weight, and elder gestational age in both DCT and TCT pregnancies (all P < 0.05).
For DCT and TCT pregnancies, MFPR application could reduce the miscarriage rate, while improving live birth and take home baby rates compared to the expectant groups. Especially, when reduced to a single fetus, MFPR could provide the better perinatal outcomes.

View all citing articles on Scopus

View full text

ReviewMultiple pregnancies following assisted reproductive technologies – A happy consequence or double trouble?

Summary

Introduction

Section snippets

Maternal consequences of multiple pregnancy

Perinatal consequences of multiple pregnancies

Outcomes of ART versus naturally conceived twins

Strategies for minimising risk

Conclusion

Conflict of interest statement

Funding sources

Am J Obstet Gynecol

Semin Perinatal

Am J Obstet Gynaecol

Br J Obstet Gynaecol

Am J Obstet Gynecol

Semin Perinatol

Early Hum Dev

Am J Obstet Gynecol

Fertil Steril

Am J Obstet Gynecol

Fertil Steril

Fertil Steril

Eur J Obstet Gynecol Reprod Biol

Eur J Obstet Gynaecol Reprod Biol

Semin Perinatol

Semin Fetal Neonat Med

Am J Obstet Gynaecol

Neonatal outcomes in triplet pregnancies: assisted reproduction versus spontaneous conception

J Perinat Med

Clinical guideline 129. Multiple pregnancy – the management of twin and triplet pregnancies in the antenatal period

The desire for multiple pregnancy in male and female infertility patients

Hum Reprod

Costs of NHS maternity care for women with multiple pregnancy compared with high-risk and low-risk singleton pregnancy

Br J Obstet Gynaecol

The effect of fetal number on the development of hypertensive conditions of pregnancy

Obstet Gynecol

Risk factors for pre-eclampsia at antenatal booking: a systematic review of controlled studies

BMJ

One consequence of infertility treatment: multifetal pregnancy

Am J Maternal/Child Nurs

Multiple pregnancy

BMJ

Risk for developing gestational diabetes in women with twin pregnancies

J Maternal–Fetal Neonat Med

Clinical guideline 132. Caesarean section

Maternal morbidity and perinatal outcome with twin pregnancy

J Ayub Coll Abbottabad

Births: final data for 2009

Natl Vital Stat Rep

Perinatal Mortality 2007: United Kingdom

Multiple pregnancies and birth: considering the risks

Review
Multiple pregnancies following assisted reproductive technologies – A happy consequence or double trouble?