Rapid Responses to:
|
|
Rapid Responses: Rapid Responses published:
-
![[Read Rapid Response]](/icons/misc/sectionDOWN.gif)
Zygosity does matter
- Peter O Pharoah (30 January 2004)
-
multiple embryo transfer and risk of adverse outcomes in singleton
- Jim X. Wang (4 February 2004)
-
Infertility itself may be a confounding variable
- William M. Buckett (10 February 2004)
-
"Appropriate control groups from the same population"?
- Bryony M Willis (10 February 2004)
-
perinatal death rate
- carlo v bellieni (11 February 2004)
-
Genetics of Infertility
- Maj A Hulten, Hazel Baker, Erik Iwarsson (12 February 2004)
-
Cumulative meta-analysis demonstrates evidence of poor perinatal outcome for singletons after assisted conception has been evident for at least nine years.
- Inez E Cooke, Michael Stevenson, Neil McClure (25 February 2004)
-
Lower Mortality Rates for Assisted Mutiple Births
- Ashley M. Wilson (20 January 2005)
|
|
|||
|
Peter O Pharoah, Emeritus Professor of Public Health Department of Public Health, University of Liverpool, Liverpool L69 3GB
Send response to journal:
|
The observation that, in twin pregnancies, perinatal mortality is about 40% lower after assisted conception compared with natural conception, needs to be tempered with caution. The authors accept that chorionicity plays a part because dichorionic fare better than monochorionic pregnancies and monochorionic comprise 5-7% of assisted compared with 30% of natural twin pregnancies. However, the effect of chorionicity is dismissed because of the lack of effect in studies that controlled for zygosity. That zygosity does not matter needs to be better documented. In an analysis of national England and Wales data for 1993-5, the relative risk (RR) for monozygous (MZ) compared with dizygous (DZ) twins for both twins to be stillbirths was 10.9 (95% confidence interval (CI) 6.9 to 17.1; p<0.00001), for stillbirth/infant death twins the RR was 3.8 (95% CI 2.4 to 6.1; p<0.00001), for one stillbirth/one survivor the RR was 1.3 (95% CI 1.1 to 1.5; p=0.005) and for both to be livebirths and both to die in infancy the RR was 2.3 (95% CI 1.9 to 2.8; p<0.0001). Reference 1. An additional bias associated with zygosity is that there is a highly significant inverse trend in proportion of MZ twins with decreasing birthweight. MZ comprise about 50% of twins of birthweight less than 500g but only about 25% of those with birthweight >=3000g. Reference 2. As a partial proxy for excluding MZ, and therefore, monochorionic twins, so as to compare like with like, it may be worth comparing perinatal mortality in assisted conceptions with unlike sex twins in spontaneous conceptions. The very high risk of intra-uterine death, early (and late) infant death and serious morbidity in survivors that is associated with monochorionicity must be adequately accounted for in a comparison of assisted and spontaneous conceptions. P.O.D.Pharoah References 1. Pharoah POD. Neurological outcome in twins. Seminars in Neonatology 2002;7:223-230. 2. Pharoah POD. Cerebral palsy in the surviving twin associated with infant death of the co-twin. Archives of Disease in Childhood Fetal and Neonatal Edition 2001;84:F111-F116. Competing interests: None declared |
|||
|
|
|||
|
Jim X. Wang, Research Officer Reprodutive Medicine Unit, Dept. Obst. & Gyn. University of Adelaide, The Queen Elizabeth Hospital
Send response to journal:
|
The significant "worse" outcomes in singletons following in vitro fertilization (IVF) treatment compared with naturally conceived babies as reported in this study may be attributable partly to that many singleton births started in early pregnancy as twins due to the common practice of multiple embryo transfer in IVF. The death/disappearance of one of the early implanting foetuses has been reported in more than 10% of IVF multiple pregnancies (ref 1 2). It has been shown that the risk of cerebral palsy is increased in such pregnancies (ref 3). Schevil et al have reported that the birth weight of singleton babies progressively reduces with the number of foetuses observed in early ultrasound scan in IVF pregnancies (ref 4). The authors noted this although they had no data to assess this effect. If this effect can be established then it again highlights the need to promote the practice of single embryo transfer in ART in order to reduce the risk of multiple implantation and multiple pregnancy. 1. 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- 3. 2. Manzur A, Goldsman MP, Stone SC, Frederick JL, Balmaceda JP, Asch RH. Outcome of triplet pregnancies after assisted reproductive techniques: how frequent are the vanishing embryos? Fertil Steril 1995;63(2):252-7. 3. Pharoah PO, Adi Y. Consequences of in-utero death in a twin pregnancy. Lancet 2000;355(9215):1597-602. 4. Schieve LA, Meikle SF, Ferre C, Peterson HB, Jeng G, Wilcox LS. Low and very low birth weight in infants conceived with use of assisted reproductive technology. N Engl J Med 2002;346(10):731-7. Competing interests: None declared |
|||
|
|
|||
|
William M. Buckett, Assistant professor McGill University, Montreal, Canada H3A 1A1
Send response to journal:
|
Editor, Helmerhorst and colleagues (1) have shown that singleton pregnancies from assisted reproduction have a worse perinatal outcome than non- assisted singleton pregnancies. However, the differences between assisted and non-assisted twin pregnancies were less marked - even when controlled for chorionicity - and the authors were at a loss to explain the lower twin perinatal mortality following assisted reproduction. Infertility itself, whether followed by spontaneous conception (2) or conception following non-assisted reproductive treatment (3), has been associated with poorer perinatal outcomes when compared with non-infertile controls. As many infertility treatments (such as ovulation induction, intra-uterine insemination (IUI), and gamete intrafallopian transfer (GIFT)) are also associated with an increased incidence of twin pregnancy, the presence of couples with infertility amongst the control groups could mask any difference in perinatal outcome in twin pregnancies. Most of the studies in their meta-analysis of twin outcomes matched controls from national or regional registries. In only one of the studies (4), were controls with any other infertility treatment excluded - and this accounted for only 192 (6.1%) of the 3128 cases studied. Further research in this important area should seek to match pregnancy outcomes following assisted reproduction with women with infertility (without assisted reproduction) as well as fertile controls - for both single and multiple gestations. Until these studies are performed and data is made available from pregnancy outcomes following assisted reproduction in women without infertility (for example surrogacy), will any effect of assisted reproduction itself on perinatal outcome be known. Yours sincerely WILLIAM BUCKETT , MB ChB MD MRCOG Assistant Professor Division of Reproductive Endocrinology and Infertility Department of Obstetrics and Gynecology McGill University Montréal, Canada William.buckett@muhc.mcgill.ca References 1. Helmerhorst FM, Perquin DAM, Donker D, Keirse MJNC. Perinatal outcome of singletons and twins after assisted conception: a systematic review of controlled studies. Br Med J 2004;328:261-265. 2. Draper ES, Kurinczuk jj, Abrams KR, Clarke M. Assessment of separate contributions to perinatal mortality of infertility history and treatment: a case control analysis. Lancet 1999;353:1746-1749. 3. Gaudoin M, Dobbie R, Finlayson A, Chalmers J, Cameron IT, Fleming R. Ovulation induction/intra-uterine insemination in infertile couples is associated with low birth weight infants. Am J Obstet Gynecol 2003;188:611 -616. 4. Koudstaal J, Bruinse IIW, Helmerhorst FM, Vermeiden JP, Willemsen WN, Visser GIL. Obstetric outcome of twin pregnancies after in-vitro fertilization: a matched controlled study in four Dutch university hospitals. Hum Reprod 2000;15:935-940. Competing interests: None declared |
|||
|
|
|||
|
Bryony M Willis, Clinical Assistant in Fertility Royal Berkshire Hospital, RG1 5AN
Send response to journal:
|
To demonstrate that pregnancy outcome is worse after assisted conception, it is necessary to control for any confounding effect of subfertility itself. Thus, control populations should be drawn from subfertile patients, not the general population. I have had the opportunity to study the full text of 13 out of the 14 matched studies included in the singletons data (I had no access to the full text of reference [18] and the abstract did not specify a subfertile control group). References [1][4][8][9][19]&[21] clearly did not use subfertile controls. In references [6][7][12]& [20] the controls are not clearly stated but appear to be drawn from the general population. Reference [10] included a control group of all patients undergoing IVF but not of non-assisted conception pregnancies in subfertile patients. This leaves only two studies that explicitly used a subfertile population -- [5] & [22]-- contributing only 425 patients of the 5,680 patients in the total matched studies consdiered -- 7.5%. These two studies are evidence that assisted conception per se has an association with adverse pregnancy outcome in singletons. In contrast, Helmerhorst et al's systematic review is simply evidence that assisted conception in subfertile patients is associated with adverse pregnancy outcome in singletons that may be linked to the assisted conception, the subfertility or a combination of the two. Competing interests: None declared |
|||
|
|
|||
|
carlo v bellieni, md Neonatologia Policlinico di Siena, 53100 Siena, Italy
Send response to journal:
|
Sir, in the discussion of the paper “Perinatal outcome of singletons and twins after assisted conception: a systematic review of controlled studies” (1), the Authors found lower perinatal death rate in assisted than in natural twin pregnancies, but could not find a definitive explanation for this datum. Don’t they think that a possible explanation may be the different attitude of caregivers towards so desired babies? Is it possible that in the case of assisted conception withholding or withdrawing therapy may be rarer? If so, this may help to reconsider delivery rooms choices, as all lives are equally worth to be lived, and not only those “particularly” desired. 1) Helmerhorst FM: Perinatal outcome of singletons and twins after assisted conception: a systematic review of controlled studies. BMJ 2004;328:261 Competing interests: None declared |
|||
|
|
|||
|
Maj A Hulten, Professor of Medical Genetics Department of Biological Sciences, University of Warwick, Coventry CV4 7AL, Hazel Baker, Erik Iwarsson
Send response to journal:
|
Helmerhorst et al1 have in a meta-analysis of reproductive performance in IVF patients found that singleton pregnancies are more likely to result in perinatal death, preterm delivery and growth restricted babies than controls.
We feel it is exceedingly important to stress that this effect may be that expected due to the genetics of infertility; infertile couples are predisposed to this type of reproductive problems, due to a number of confounding genetic conditions. Historically this has more often been recognized in the male than female partner. Chromosome analysis using blood samples (karyotyping) documented that there is an increasing risk of a man being a carrier of a constitutional chromosome abnormality the lower his sperm count2. Structural chromosome rearrangements such as translocations, inversions and insertions, for example, often run in families. They may be associated with reduced fertility in males but subfertility in females, leading to miscarriage, intrauterine- or perinatal deaths as well as live born multiply handicapped children. One other concern is the existence of genetic conditions specifically affecting spermatogenesis such as recombination deficiency, leading to spermatogenetic arrest and increased non-disjunction with aberrant chromosome number (aneuploidy) in the few sperm produced. Any conceptions are likely to abort early but may also produce live born children with conditions such as Down’s syndrome. Meiotic recombination deficiency (which may well constitute the first meiotic mutant in humans) discovered in the early 1970s by investigation of testicular biopsy samples3 is not uncommon2. These examples illustrate the point that it is indeed important to recognize that genetic conditions have an inherent impact on the reproductive performance in assisted conception of couples, of particular concern when the underlying cause for their infertility is unknown, a situation not uncommon in most IVF clinics. One of the worst scenarios here is successful assisted conception but the birth of a more or less severely handicapped child. How can this unfortunate situation be improved? Ideally a thorough family history should be taken and karyotyping be performed on both partners. Questions should be asked not only on previous reproductive performance in relatives, but also whether or not the parents of either partner are biologically related, for instance being first cousins (which could point to a recessive genetic condition). Karyotyping should obviously include novel molecular technology to disentangle the occurrence of more subtle carrier status of chromosome rearrangements4 that may have equally disastrous effects with respect to treatment outcome. Any failed conceptions should also be investigated in detail, a minimum requirement being storage of DNA for rapidly developing molecular technologies. Is this programme realistic? Most people would probably think not. It is simply too expensive. The most common practice is to undertake karyotyping only in the situation when the sperm count of the male partner is substantially reduced (from the normal lower limit of 60 million per ml to less than 5 million); and to our knowledge molecular (subtelomeric) screens4 have not been introduced anywhere. The costs involved in monetary terms vary substantially between countries. Standard karyotyping in the UK may cost £100 and molecular screening £150. The cost implications of failed IVF treatment, including the psychological impact on couples and their families, are more difficult to assess but are likely to be substantial. Moreover, people who have not experienced the psychological burden of unexplained reproductive problems may not appreciate the immense relief, once a diagnostic explanation is provided. Also, appropriate prenatal diagnosis may then be offered. This likely will become more acceptable in future if performed early in pregnancy and non-invasively, using foetal cells/DNA in maternal blood samples e.g. see5 rather than through invasive procedures such as CVS or amniocentesis (associated with procedure-related foetal loss in around 1 per 100 cases). Perhaps the expense for diagnostic accuracy of genetic predisposition to infertility and subfertility is not too high a price to pay after all? 1. Helmerhorst, F.M., et al., Perinatal outcome of singletons and twins after assisted conception: a systematic review of controlled studies. BMJ, 2004. 328: 261-264. 2. Van Assche, E., et al., Cytogenetics of infertile men. Hum Reprod, 1996. 11 Suppl 4: 1-24. 3. Hultén, M., R. Eliasson, and K.G. Tillinger, Low chiasma count and other meiotic irregularities in two infertile 46, XY men with spermatogenic arrest. Hereditas, 1970. 65: 285-290. 4. Knight, S.J. and J. Flint, Perfect endings: a review of subtelomeric probes and their use in clinical diagnosis. J Med Genet, 2000. 37: 401-409. 5. Chen, C.P., S.R. Chern, and W. Wang, Fetal DNA analyzed in plasma from a mother's three consecutive pregnancies to detect paternally inherited aneuploidy. Clin Chem, 2001. 47: 937-939. Competing interests: None declared |
|||
|
|
|||
|
Inez E Cooke, Senior Lecturer / Consultant in Obstetrics and Gynaecology School of Medicine, Dept of Obstetrics and Gynaecology, Queens University Belfast, Belfast BT12 6BJ, Michael Stevenson, Neil McClure
Send response to journal:
|
We very much appreciate the meta-analysis of case controlled studies reporting the obstetric outcome of pregnancies following assisted conception (ART) that highlighted the increased risk of preterm delivery, small for dates and lower birthweight amongst singleton pregnancies. However, we would suggest that this difference in obstetric outcome for singletons has been evident for some time. The majority of studies , case- controlled or not, published since the MRC Working Party (1990)(1) have indicated a poorer obstetric outcome for children born after ART which could not simply be explained by the increased rate of multiple births, or older age of these mothers. Indeed only one of the 12 case-matched studies included within the meta-analysis is at variance with the other 11 (2). If the 12 case-matched studies included in this meta-analysis are analyzed in chronological order the cumulative data shows that a systematic review published 9 years ago would have reached the same conclusion. With the exception of Dhont et al, (2), the seven studies included within the review, and published since 1995, have only continued to narrow the confidence limits of these findings (Table 1). It is disappointing that a problem highlighted by Cochrane 30 years ago continues to dog clinical practice - namely, that both the effectiveness of new treatments and concerns of possible harmful effects of long-used treatments, (ART has now been in practice 25 years), are not identified sooner, when the evidence is present. Since 1999 there have been two large case-matched studies indicating that an increased risk of prematurity and low birthweight is present in pregnancies associated with a history of infertility itself where no infertility intervention was performed (3,4). Hence, in this instance, the underlying causal factors of the infertility itself, rather than the assisted conception treatments involved, may be the root cause of the poor obstetric outcome. References 1. Beryl V, Doyle P. MRC working party on children conceived by in vitro fertilization; births in Great Britain resulting from assisted conception 1978-1987. BMJ 1990; 300: 1229-1233. 2. Dhont M, De Neubourg P, Van der Elst J, De Sutter P. Perinatal outcome of pregnancies after assisted reproduction: a case-control study. J Assist Reprod Genet 1997; 14: 575-580. 3. Draper ES, Kurinczuk JJ, Abrams KR, Clarke M. Assessment of separate contributions to perinatal mortality of infertility history and treatment: a case-control analysis. Lancet 1999; 353: 1746 - 1749 4. Basso O, Baird DD. Infertility and preterm delivery, birthweight, and Caesaean Section: a study within the Danish National Birth Cohort. Hum Reprod 2003; 18: 2478-2484 Table 1. Cumulative meta-analysis of the risk of preterm birth in singleton pregnancies after assisted conception compared with matched controls (natural conception). Point of meta analysis No of Studies RR (95% CIs) End 1995 5 1.68 (1.07 – 2.63) End 1997 7 1.53 (0.92 – 2.54) End 1999 9 2.02 (1.51 – 2.70) End 2000 10 2.05 (1.56 – 2.69) End 2002 12 1.99 (1.50 – 2.63) Competing interests: None declared |
|||
|
|
|||
|
Ashley M. Wilson, Private Sydney 2216
Send response to journal:
|
In response to this article (and I don't know why no one else picked this up) the reason assisted (IVF, GIFT, Clomid, etc) multiple births had a lower mortality rate is not so much that they are monitored more but that the majority of assisted multiple pregnancies are DZ (fraternal). DZ multiples no not share an amnion or chorion and have separate placentas (in most cases, unless they are fused, which can happen in MZ's too), therefore, they get equal nourishment during gestation. MZ's are not the usual result of assisted pregnancies, and if looking at them alone, and comparing them to naturally concieved MZ's there is unlikely to be much difference. However, only late-splitting MZ's share a chorion, and even later splitting both amnion and chorion giving them a single placenta. That causes TTTS (Twin To Twin Transfusion Syndrome) where one twin becomes a donor and the other reciever of unequal gestational nourishment, therefore endagering one or both of their lives. So, because DZ's don't have the danger of TTTS or sharing of amnions and chorions, DZ's fare better than MZ's. And, as I said above, the majority of multiples born through assisted pregnancies are DZ. This is like asking if naturally concieved DZ's have a better chance than MZ's. Of course they do. Competing interests: None declared |
|||