Viveca Söderström-Anttila

Why do singletons conceived after assisted reproduction technology have adverse perinatal outcome? Systematic review and meta-analysis

BACKGROUNDnAssisted reproduction technology (ART) is used worldwide, at increasing rates, and data show that some adverse outcomes occur more frequently than following spontaneous conception (SC). Possible explanatory factors for the well-known adverse perinatal outcome in ART singletons were evaluated.nnnMETHODSnPubMed and Cochrane databases from 1982 to 2012 were searched. Studies using donor or frozen oocytes were excluded, as well as those with no control group or including <100 children. The main outcome measure was preterm birth (PTB defined as delivery <37 weeks of gestation), and a random effects model was used for meta-analyses of PTB. Other outcomes were very PTB, low-birthweight (LBW), very LBW, small for gestational age and perinatal mortality.nnnRESULTSnThe search returned 1255 articles and 65 of these met the inclusion criteria. The following were identified as predictors for PTB in singletons: SC in couples with time to pregnancy (TTP) > 1 year versus SC singletons in couples with TTP ≤ 1 year [adjusted odds ratio (AOR) 1.35, 95% confidence interval (CI) 1.22, 1.50]; IVF/ICSI versus SC singletons from subfertile couples (TTP > 1 year; AOR 1.55, 95% CI 1.30, 1.85); conception after ovulation induction and/or intrauterine insemination versus SC singletons where TTP ≤ 1 year (AOR 1.45, 95% CI 1.21, 1.74); IVF/ICSI singletons versus their non-ART singleton siblings (AOR 1.27, 95% CI 1.08, 1.49). The risk of PTB in singletons with a vanishing co-twin versus from a single gestation was AOR of 1.73 (95% CI 1.54, 1.94) in the narrative data. ICSI versus IVF (AOR 0.80, 95% CI 0.69-0.93), and frozen embryo transfer versus fresh embryo transfer (AOR 0.85, 95% CI 0.76, 0.94) were associated with a lower risk of PTB.nnnCONCLUSIONSnSubfertility is a major risk factor for adverse perinatal outcome in ART singletons, however, even in the same mother an ART singleton has a poorer outcome than the non-ART sibling; hence, factors related to the hormone stimulation and/or IVF methods per se also may play a part. Further research is required into mechanisms of epigenetic modification in human embryos and the effects of cryopreservation on this, whether milder ovarian stimulation regimens can improve embryo quality and endometrial conditions, and whether longer culture times for embryos has a negative influence on the perinatal outcome.

Children born after cryopreservation of embryos or oocytes: a systematic review of outcome data

BACKGROUNDnAn estimated 3.5 million children have been born to date using assisted reproduction technologies. We reviewed the data in order to evaluate current knowledge of medical outcome for IVF/ICSI children born after cryopreservation, slow freezing and vitrification of early cleavage stage embryos, blastocysts and oocytes.nnnMETHODSnA systematic review was performed. We searched the PubMed, Cochrane and Embase databases from 1984 to September 2008. Inclusion criteria for slow freezing of early cleavage stage embryos were controlled studies reporting perinatal or child outcomes. For slow freezing and vitrification of blastocysts and oocytes, and vitrification of early cleavage stage embryos, case reports on perinatal or child outcomes were also included. Three reviewers independently read and evaluated all selected studies.nnnRESULTSnFor early cleavage embryos, data from controlled studies indicated a better or at least as good obstetric outcome, measured as preterm birth and low birthweight for children born after cryopreservation, as compared with children born after fresh cycles. Most studies found comparable malformation rates between frozen and fresh IVF/ICSI. For slow freezing of blastocysts and for vitrification of early cleavage stage embryos, blastocysts and oocytes, limited neonatal data was reported. We found no long-term child follow-up data for any cryopreservation technique.nnnCONCLUSIONnData concerning infant outcome after slow freezing of embryos was reassuring. Properly controlled follow-up studies of neonatal outcome are needed after slow freezing of blastocysts and after vitrification of early cleavage stage embryos, blastocysts and oocytes. In addition, child long-term follow-up studies for all cryopreservation techniques are essential.

Obstetric and neonatal outcome after oocyte donation in 106 women with Turner syndrome: a Nordic cohort study

STUDY QUESTIONnWhat are the obstetric and neonatal outcomes of deliveries after oocyte donation (OD) in women with Turner syndrome (TS)?nnnSUMMARY ANSWERnPregnancies among women with TS carry a substantial risk, particularly for hypertensive disorders. Potentially life-threatening complications occurred in 3.3% of pregnancies. The neonatal outcomes were generally reassuring, with similar rates of preterm birth and low birthweight (LBW) as after conventional IVF and better than previously reported in deliveries after OD in women with TS.nnnWHAT IS KNOWN ALREADYnOD pregnancies in women with TS are known to be high-risk pregnancies.nnnSTUDY DESIGN, SIZE, DURATIONnThis retrospective cohort study included 106 women with TS who delivered after OD (n = 122 deliveries, n = 131 newborns) in three Nordic countries (Finland, Denmark, Sweden) between 1992 and 2011.nnnPARTICIPANTS, SETTING AND METHODSnWomen with TS who delivered after OD in three Nordic countries were identified (n = 110). Four women declined to participate or were lost to follow-up, thus 106 women were included in the study. The medical data from fertility clinics, antenatal clinics and the hospitals where the women had been treated and/or delivered were scrutinized.nnnMAIN RESULTS AND THE ROLE OF CHANCEnIn this cohort, the karyotype was 45,X in 44% of the women with TS. Ten women (9.4%) had a known cardiac defect before pregnancy. Single embryo transfer was performed in 70.3% of the cases and the multiple birth rate was 7.4%. In total, 35.0% of the pregnancies were associated with a hypertensive disorder including pre-eclampsia in 20.5%. Potentially life-threatening complications occurred in four pregnancies (3.3%), including one woman with aortic dissection, one with mild regurgitation of the tricuspid and mitral valve, one with a mechanical heart valve who developed HELLP syndrome (haemolysis, elevated liver enzymes, low platelets) and one who underwent a post-partum hysterectomy due to severe haemorrhaging. Neonatal outcomes were reassuring, with a preterm birth rate of 8.0% and LBW rate of 8.8% in singletons. Major birth defects were found in 3.8% of the children. The perinatal mortality was 2.3% (3/131), including a set of extremely preterm twins.nnnLIMITATIONS, REASONS FOR CAUTIONnAlthough this study was performed over a period of almost 20 years in three different countries, with a low drop-out rate and little missing data, much larger series are needed to assess rare events. This study also lacks an appropriate control group.nnnWIDER IMPLICATIONS OF THE FINDINGSnThis study suggests that cardiovascular evaluation before and during pregnancy may contribute to favourable obstetric outcomes in many cases. Maternal outcomes were in agreement with the literature while neonatal outcomes were generally better than previously reported. The outcomes were consistent across the three countries, supporting generalizability to similar populations.

Surrogacy: outcomes for surrogate mothers, children and the resulting families—a systematic review

BACKGROUNDnSurrogacy is a highly debated method mainly used for treating women with infertility caused by uterine factors. This systematic review summarizes current levels of knowledge of the obstetric, medical and psychological outcomes for the surrogate mothers, the intended parents and children born as a result of surrogacy.nnnMETHODSnPubMed, Cochrane and Embase databases up to February 2015 were searched. Cohort studies and case series were included. Original studies published in English and the Scandinavian languages were included. In case of double publications, the latest study was included. Abstracts only and case reports were excluded. Studies with a control group and case series (more than three cases) were included. Cohort studies, but not case series, were assessed for methodological quality, in terms of risk of bias. We examined a variety of main outcomes for the surrogate mothers, children and intended mothers, including obstetric outcome, relationship between surrogate mother and intended couple, surrogates experiences after relinquishing the child, preterm birth, low birthweight, birth defects, perinatal mortality, child psychological development, parent-child relationship, and disclosure to the child.nnnRESULTSnThe search returned 1795 articles of which 55 met the inclusion criteria. The medical outcome for the children was satisfactory and comparable to previous results for children conceived after fresh IVF and oocyte donation. The rate of multiple pregnancies was 2.6-75.0%. Preterm birth rate in singletons varied between 0 and 11.5% and low birthweight occurred in between 0 and 11.1% of cases. At the age of 10 years there were no major psychological differences between children born after surrogacy and children born after other types of assisted reproductive technology (ART) or after natural conception. The obstetric outcomes for the surrogate mothers were mainly reported from case series. Hypertensive disorders in pregnancy were reported in between 3.2 and 10% of cases and placenta praevia/placental abruption in 4.9%. Cases with hysterectomies have also been reported. Most surrogate mothers scored within the normal range on personality tests. Most psychosocial variables were satisfactory, although difficulties related to handing over the child did occur. The psychological well-being of children whose mother had been a surrogate mother between 5 and 15 years earlier was found to be good. No major differences in psychological state were found between intended mothers, mothers who conceived after other types of ART and mothers whose pregnancies were the result of natural conception.nnnCONCLUSIONSnMost studies reporting on surrogacy have serious methodological limitations. According to these studies, most surrogacy arrangements are successfully implemented and most surrogate mothers are well-motivated and have little difficulty separating from the children born as a result of the arrangement. The perinatal outcome of the children is comparable to standard IVF and oocyte donation and there is no evidence of harm to the children born as a result of surrogacy. However, these conclusions should be interpreted with caution. To date, there are no studies on children born after cross-border surrogacy or growing up with gay fathers.

Obstetric and neonatal complications in pregnancies conceived after oocyte donation – a systematic review and meta‐analysis

Approximately 50 000 oocyte donation (OD) treatment cycles are now performed annually in Europe and the US.

Epigenetics and assisted reproductive technologies.

Epigenetic modification controls gene activity without changes in the DNA sequence. The genome undergoes several phases of epigenetic programming during gametogenesis and early embryo development, coinciding with assisted reproductive technologies (ART) treatments. Imprinting disorders have been associated with ART techniques, but disentangling the influence of the ART procedures per se from the effect of the reproductive disease of the parents is a challenge. Epidemiological human studies have shown altered birthweight profiles in ART compared with spontaneously conceived singletons. Conception with cryopreserved/thawed embryos results in a higher risk of large‐for‐gestational‐age babies, which may be due to epigenetic modification. Further animal studies have shown altered gene expression profiles in offspring conceived by ART related to altered glucose metabolism. It is controversial whether human adolescents conceived by ART have altered lipid and glucose profiles and thereby a higher long‐term risk of cardiovascular disease and diabetes. This commentary describes the basic concepts of epigenetics and gives a short overview of the existing literature on the association between imprinting disorders, epigenetic modification and ART.

An oocyte donation program with goserelin down-regulation of voluntary donors

Background. In ovum donation programs oocytes can be requested from infertile women going through an in vitro fertilization cycle. Currently, when embryos can be cryopreserved, these donors have virtually disappeared. Instead, most donors have been healthy fertile volunteers willing to go through an IVF attempt solely for the purpose of donating all oocytes.

Attitudes towards and management of single embryo transfer among Nordic IVF doctors

Background. The objective of this study was to investigate the attitudes towards and management of single embryo transfer (SET) among Nordic in vitro fertilisation (IVF) doctors, and to present the rate of SET and multiple pregnancies in the different countries. Methods. A questionnaire was sent to all IVF doctors in the Nordic countries (n = 198, 78.5% responded). Pregnancy rates, SET and multiple births rates were extracted from registries. Main outcome measure was attitudes and management of SET. Results. Almost all doctors thought that a twin pregnancy compared unfavourably to a singleton. A twin rate >10% was acceptable for 5% of Swedish doctors. Corresponding figures for Finnish, Danish and Norwegian doctors were 21, 35 and 35%, respectively. For a woman <36 years, performing her first cycle and with two good quality embryos, almost all doctors would recommend SET. For a woman ≥36 years in a similar situation, SET would be recommended only in Sweden and Finland. The pregnancy rate per embryo transfer (ET), the SET rate 2003, the multiple birth rate, and the estimated SET rate 2004 were 33.3, 21.5, 22.7 and 25% (Denmark), 31.3, 43.4, 14 and 51% (Finland), 40.5, 10.5, 26.5 and 16% (Iceland), 30.6, 18, 25.2 and 26% (Norway), and 35.3, 55.1, 11.8 and 71% (Sweden). Conclusions. The SET and multiple birth rates reflect the attitudes of Nordic IVF doctors to SET and multiple births well. When introducing SET, the attitude of the IVF doctor seems to be important.

Genetics and assisted reproduction technology

In the past 20u2003years, a significant improvement has been shown in the treatment for infertility in both women and men through the development of in vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI). Only donated sperm could be previously used for treatment; now oocytes can also be donated. Furthermore, the combination of IVF and ICSI with advanced genetic methods has made preimplantation genetic diagnosis possible for many genetic conditions. These methods enable genetic testing of the early human embryo by using only a single cell, one blastomere biopsied from the embryo, as the sample from which the diagnosis of many chromosome rearrangements and other inherited diseases can be made. It has also been established that a considerable proportion of infertility is caused by genetic defects, which have several implications for infertility treatment. The purpose of this review is to give a concise introduction on how genetics is involved in assisted reproduction technology to specialists who may not be working in this particular field of gynecology, but who would need some knowledge of this for proper care of their patients.

The effect of paternal factors on perinatal and paediatric outcomes: a systematic review and meta-analysis

BACKGROUNDnMaternal factors, including increasing childbearing age and various life-style factors, are associated with poorer short- and long-term outcomes for children, whereas knowledge of paternal parameters is limited. Recently, increasing paternal age has been associated with adverse obstetric outcomes, birth defects, autism spectrum disorders and schizophrenia in children.nnnOBJECTIVE AND RATIONALEnThe aim of this systematic review is to describe the influence of paternal factors on adverse short- and long-term child outcomes.nnnSEARCH METHODSnPubMed, Embase and Cochrane databases up to January 2017 were searched. Paternal factors examined included paternal age and life-style factors such as body mass index (BMI), adiposity and cigarette smoking. The outcome variables assessed were short-term outcomes such as preterm birth, low birth weight, small for gestational age (SGA), stillbirth, birth defects and chromosomal anomalies. Long-term outcome variables included mortality, cancers, psychiatric diseases/disorders and metabolic diseases. The systematic review follows PRISMA guidelines. Relevant meta-analyses were performed.nnnOUTCOMESnThe search included 14 371 articles out of which 238 met the inclusion criteria, and 81 were included in quantitative synthesis (meta-analyses). Paternal age and paternal life-style factors have an association with adverse outcome in offspring. This is particularly evident for psychiatric disorders such as autism, autism spectrum disorders and schizophrenia, but an association is also found with stillbirth, any birth defects, orofacial clefts and trisomy 21. Paternal height, but not BMI, is associated with birth weight in offspring while paternal BMI is associated with BMI, weight and/or body fat in childhood. Paternal smoking is found to be associated with an increase in SGA, birth defects such as congenital heart defects, and orofacial clefts, cancers, brain tumours and acute lymphoblastic leukaemia. These associations are significant although moderate in size, with most pooled estimates between 1.05 and 1.5, and none exceeding 2.0.nnnWIDER IMPLICATIONSnAlthough the increased risks of adverse outcome in offspring associated with paternal factors and identified in this report represent serious health effects, the magnitude of these effects seems modest.