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Newsletter No. 14
  1. Congenital malformations following IVF and ICSI
  2. Treatment of recurrent pelvic pain after conservative surgery for symptomatic endometriosis
  3. Metformin in clomiphene citrate resistant PCOS
  4. Down’s syndrome and reduced ovarian reserve

1. Congenital malformations following IVF and ICSI

Recently, major data were reported from several institution throughout the world concerning the mental and physical health of children born after IVF and ICSI. Here we show the abstracts of the respective publications in the order of the references cited below.

BACKGROUND: It is not known whether infants conceived with use of intracytoplasmic sperm injection or in vitro fertilization have a higher risk of birth defects than infants conceived naturally.

METHODS: We obtained data from three registries in Western Australia on births, births after assisted conception, and major birth defects in infants born between 1993 and 1997. We assessed the prevalence of major birth defects diagnosed by one year of age in infants conceived naturally or with use of intracytoplasmic sperm injection or in vitro fertilization.

RESULTS: Twenty-six of the 301 infants conceived with intracytoplasmic sperm injection (8.6 percent) and 75 of the 837 infants conceived with in vitro fertilization (9.0 percent) had a major birth defect diagnosed by one year of age, as compared with 168 of the 4000 naturally conceived infants (4.2 percent; P<0.001 for the comparison between either type of technology and natural conception). As compared with natural conception, the odds ratio for a major birth defect by one year of age, after adjustment for maternal age and parity, the sex of the infant, and correlation between siblings, was 2.0 (95 percent confidence interval, 1.3 to 3.2) with intracytoplasmic sperm injection, and 2.0 (95 percent confidence interval, 1.5 to 2.9) with in vitro fertilization. Infants conceived with use of assisted reproductive technology were more likely than naturally conceived infants to have multiple major defects and to have chromosomal and musculoskeletal defects.

CONCLUSIONS: Infants conceived with use of intracytoplasmic sperm injection or in vitro fertilization have twice as high a risk of a major birth defect as naturally conceived infants.

BACKGROUND: To evaluate the safety of ICSI, this study compared data of IVF and ICSI children by collecting data on neonatal outcome and congenital malformations during pregnancy and at birth.

METHODS: The follow-up study included agreement to genetic counselling and eventual prenatal diagnosis, followed by a physical examination of the children after 2 months, after 1 year and after 2 years. 2840 ICSI children (1991--1999) and 2955 IVF children (1983--1999) were liveborn after replacement of fresh embryos. ICSI was carried out using ejaculated, epididymal or testicular sperm.

RESULTS: In the two cohorts, similar rates of multiple pregnancies were observed. ICSI and IVF maternal characteristics were comparable for medication taken during pregnancy, pregnancy duration and maternal educational level, whereas maternal age was higher in ICSI and a higher percentage of first pregnancies and first children born was observed in the ICSI mothers. Birthweight, number of neonatal complications, low birthweight, stillbirth rate and perinatal death rate were compared between the ICSI and the IVF groups and were similar for ICSI and IVF. Prematurity was slightly higher in the ICSI children (31.8%) than in the IVF children (29.3%). Very low birthweight was higher in the IVF pregnancies (5.7%) compared with ICSI pregnancies (4.4%). Major malformations (defined as those causing functional impairment or requiring surgical correction), were observed at birth in 3.4% of the ICSI liveborn children and in 3.8% of the IVF children (P = 0.538). Malformation rate in ICSI was not related to sperm origin or sperm quality. The number of stillbirths (born boxline: vertical line20 weeks of pregnancy) was 1.69% in the ICSI group and 1.31% in the IVF group. Total malformation rate taking into account major malformations in stillborns, in terminations and in liveborns was 4.2% in ICSI and 4.6% in IVF (P = 0.482).

CONCLUSIONS: The comparison of ICSI and IVF children taking part in an identical follow-up study did not show any increased risk of major malformations and neonatal complications in the ICSI group.

Since its introduction in 1992, intracytoplasmic sperm injection (ICSI) has become a popular assisted fertilization technique proved very efficient in treating male factor infertility. Many healthy children have been born worldwide from this procedure, and their physical and mental development appears to be within the normal limits. However, because of the peculiarity of the technique and the poor characteristics of the spermatozoa used, concern about the safety of ICSI still exist. In this article, we analyze the in vivo development of embryos conceived after ICSI as well as the obstetric outcome, occurrence of chromosomal abnormalities, and rate of congenital malformations in neonates born as a result of this treatment. A total of 2435 couples were studied in whom the male partners were presumed to be the cause of repeated failed attempts at in vitro fertilization (IVF) or had semen parameters that were unacceptable for conventional IVF treatment. Pregnancies resulting from 3573 ICSI cycles were analyzed; pregnancy outcome data were obtained from the records of obstetrician-gynecologists and/or pediatricians. The overall clinical pregnancy (fetal heartbeat) rate was 44.8% with a resultant delivery rate of 39.2% per ICSI cycle (n = 1388).

In 37 of the 77 miscarriages for which cytogenetic data were available, an autosomal trisomy was found in each and 29 additional pregnancies were terminated because of a chromosomal abnormality revealed by prenatal diagnosis. There was an equal distribution of vaginal deliveries and cesarean sections (n = 682 and n = 658, respectively). Of the 2059 neonates resulting from ICSI treatment, 38 (1.8%) presented with congenital abnormalities (22 major and 16 minor). When the frequency of miscarriages and congenital malformations was analyzed in terms of semen origin, the outcome was no different between ICSI and IVF. The course of pregnancies and occurrence of congenital malformations following treatment by ICSI are within the ranges obtained following conventional IVF.

BACKGROUND: There have been reports suggesting that children born after in-vitro fertilisation by intracytoplasmic sperm injection (ICSI) are at increased risk of neurodevelopmental delay. We have undertaken a case-control study of this issue.

METHODS: We studied 208 singleton children conceived by ICSI and a control group of 221 normally conceived singleton children. Children were recruited from 22 fertility centres and local nurseries throughout the UK. Controls were selected to match cases as closely as possible for social class, maternal educational attainment, region, sex, and race. The primary outcome measure was neurodevelopmental scoring; secondary measures were perinatal outcomes, postnatal health, and congenital abnormalities. A single examiner assessed all the children.

FINDINGS: A follow-up rate of 90% for the ICSI group was achieved at a mean age of 17 months. No difference between the study children and controls was found in mean neurodevelopmental scores (98.08 [SD 10.93] vs 98.69 [9.99]) or any subscales on the Griffiths' scales of mental development. Perinatal outcome was similar apart from a higher rate of caesarean section (73 [35.1%] vs 53 [24.0%], p=0.015) and a lower mean birthweight (3163 [SD 642] vs 3341 [606] g, p=0.013) in the study group. Rates of major congenital abnormality were also similar overall (ten [4.8%] study vs ten [4.5%] control), although there were significantly more congenital anomalies among children born to fathers with oligozoospermia than in other children.

INTERPRETATION: This population study did not show any significant difference between children conceived after ICSI and their naturally conceived peers in terms of physical health and development.

Comment of Ferticonsult:

  1. The ICSI procedure apparently does not expose extra harm to the children born following this procedure in comparison to IVF.
  2. Spontaneously conceived children are no real control because they were obviously born to fertile parents.


Hansen M, Kurinczuk J, Bower C, Webb, S (2002) The risk of major birth defects after intracytoplasmatic sperm injection and in vitro fertilization N. Engl. J.Med. 346: 725-730

Bonduelle M, Liebaers I, Deketelaere V, Derde MP, Camus M, Devroey P, Van Steirteghem A (2002) Neonatal data on a cohort of 2889 infants born after ICI (1991-1999) and of 2995 infants born after IVF (1983-1999). Hum. Reprod. 17: 671-694

Palermo GD, Neri QV, Hariprashad JJ, Davis OK, Veeck LL, Rosenwaks Z (2000) ICSI and its outcome. Semin. Reprod. Med. 18:161-169

Sutcliffe AG, Taylor B, Saunders K, Thornton S, Lieberman BA, Grudzinskas JG (2001) Outcome in the second year of life after in-vitro fertilisation by intracytoplasmic sperm injection: a UK case-control study. Lancet 357:2080-2084

2. Treatment of recurrent pelvic pain after conservative surgery for symptomatic endometriosis

The study was performed as a randomised controlled trial to evaluate the efficacy and safety of cyproterone acetate versus an oral contraceptive in the treatment of endometriosis-associated recurrent pelvic pain. Ninety women were studied with recurrent moderate or severe pelvic pain after conservative surgery for symptomatic endometriosis. The treatment consisted in six months of continuous treatment with oral cyproterone acetate, 12.5 mg/d, or an oral contraceptive containing ethinyl estradiol, 0.02 mg, and desogestrel, 0.15 mg. The degree of satisfaction with the therapy constitutedf the main outcome measure.

Six patients in the cyproterone acetate arm and nine in the oral contraceptive arm withdrew because of side effects (n = 9), treatment inefficacy (n = 4), or loss to follow-up (n = 2). At 6 months, dysmenorrhea, deep dyspareunia, and nonmenstrual pelvic pain scores were substantially reduced, and significant improvements were observed in health-related quality-of-life, psychiatric profile, and sexual satisfaction; no major between-group differences were seen. Subjective and metabolic side effects were limited. According to an intention-to-treat analysis, 33 of 45 (73%) of patients in the cyproterone acetate group and 30 of 45 (67%) in the oral contraceptive group were satisfied with the treatment received. Both cyproterone acetate and a continuous monophasic oral contraceptive were effective, safe, and inexpensive therapy for recurrent pain after conservative surgery for endometriosis.


Vercellini P, De Giorgi O, Mosconi P, Stellato G, Vicentini S, Crosignani PG (2002) Cyproterone acetate versus a continuous monophasic oral contraceptive in the treatment of recurrent pelvic pain after conservative surgery for symptomatic endometriosis. Fertil Steril. 77:52-61

3. Metformin in clomiphene citrate resistant PCOS

The study was performed as a prospective, randomized, double-blind, placebo-controlled study to evaluate the effect of metformin therapy on hyperandrogenism, insulin resistance, cervical scores, ovulation, and pregnancy rates in clomiphene citrate-resistant women with polycystic ovary syndrome (PCOS). Fifty-six women with clomiphene citrate-resistant PCOS entered the study. Interventions: Two cycles of oral metformin therapy (850 mg, twice daily) in group I and placebo therapy (twice daily) in group II. Clomiphene citrate (100 mg/day) on cycle days 3-7 of the second cycle in both groups. Metformin therapy resulted in a significant decrease in total T, LH level, LH/FSH ratio, insulin resistance, and mean BMI. No difference in waist-to-hip ratio, DHEAS level, and fasting insulin level was observed. Clomiphene citrate induction resulted in higher ovulation rates and thicker endometrium in the metformin group than in the placebo group. There was higher cumulative pregnancy rate in the metformin group; however, there was no significant difference in the pregnancy rate between the two groups. Metformin therapy not only decreases hyperandrogenism and insulin resistance but also improves ovulation rates, cervical scores, and pregnancy rates in clomiphene citrate-resistant women with PCOS.


Kocak M, Caliskan E, Simsir C, Haberal A. (2002) Metformin therapy improves ovulatory rates, cervical scores, and pregnancy rates in clomiphene citrate-resistant women with polycystic ovary syndrome. Fertil Steril. 77:101-106

4. Down’s syndrome and reduced ovarian reserve

Parental age is the most important aetiological factor in trisomy formation in humans. Cytogenetic studies on germ cells reviewed here imply that (i) 2-4% sperm are aneuploid and 8.6% oocytes from IVF are hyperploid (ii) a paternal age effect may exist, and (iii) oocytes of aged women contain precociously separated chromatids in metaphase II. Trisomy data suggest that most aneuploidy is generated during meiosis I of oogenesis and is maternal age-dependent. Trisomy 18 is unique, originating mostly from maternal meiosis II errors. The extra gonosome in 47, XXY derives mostly from a paternal meiosis I error.

Trisomy of individual chromosomes may remain low, linearly rise, or exponentially increase with advanced maternal age. Advanced reproductive age is indicated by increased basal FSH levels that represent low ovarian reserve. In a new study basal FSH and inhibin B levels in women with a history of Down’s syndrome (n=118; mean age: 33.8) were compared with those levels of women without this history (n=102; mean age 34.2). In the women with a history of a Down's syndrome pregnancy, there was a significant inverse correlation between basal FSH and inhibin B concentrations (P < 0.0001, 95% CI -0.26 to -0.56). In the control group, this correlation did not reach statistical significance. The data indicate that the elevated basal FSH concentrations observed in women with a history of a Down's syndrome pregnancy are likely to reflect early depletion of the primordial follicle pool. Since there was a large overlap of basal FSH value in these two groups the basal FSH levels have no predictive value concerning the future birth of a child with Down’s syndrome. Further research into the ovarian ageing process could provide more insight in the origination of chromosomal abnormalities during pregnancy.


Eichenlaub-Ritter U (1996) Parental age-related aneuploidy in human germ cells and offspring: a story of past and present. Environ Mol Mutagen. 28:211-236. Review.

Van Montfrans JM, van Hooff MH, Martens F, Lambalk CB. (2002) Basal FSH, estradiol and inhibin B concentrations in women with a previous Down's syndrome affected pregnancy. Hum Reprod. 17:44-47.

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Gerhard Leyendecker