Robert Derom

INCREASED MONOZYGOTIC TWINNING RATE AFTER OVULATION INDUCTION

Multiple births after artificial induction of ovulation (AIO) are usually considered to be due to fertilisation of multiple ova. In the East Flanders Prospective Twin Study between 1978 and 1985 the frequency of zygotic splitting after AIO (1.2%) was significantly higher than the expected frequency (0.45%) among spontaneous twins and triplets. Moreover, after AIO the frequency of zygotic division was significantly higher in triplets than in twins. AIO seems to be the first identified biological mechanism influencing the monozygotic twinning rate.

The East Flanders Prospective Twin Survey (Belgium): a population-based register.

The East Flanders Prospective Twin Survey (EFPTS), started in 1964, is unique among the 17 major European twin registers because it is population based, the twins (and higher order births) are ascertained at birth, basic perinatal data are collected, chorion type is established and, when appropriate, genetic markers including DNA fingerprints, are determined. The total number of sets is 5089 twin, 158 triplet and 14 of higher order. Zygosity has been diagnosed on the basis of sex, placental structure and genetic markers in more than 95% of pairs. The EFPTS is the only large register that includes placental data and allows differentiation of three subtypes of monozygotic twins based on the time of the initial zygotic division: the dichorionic-diamnionic pairs (early), the monochorionic-diamnionic pairs (intermediate), and the monochorionic-monoamnionic pairs (late). Methodology and basic results in twins are considered in this article; detailed studies will be reported later. The sex proportion in dizygotic (DZ) twins is the same as in singletons, whereas monozygotic (MZ) twins number more girls than boys. The difference in perinatal mortality between DZ and MZ twins is limited to the monochorionic MZ subgroup. Birth weight is highest in DZ twins and diminishes stepwise in MZ dichorionic and MZ monochorionic twins. Duration of pregnancy follows the same trend but is limited to a few days. Iatrogenic pregnancies are increasing to the point of representing almost 50% of the twin births in 1997.

Validation of a Telephone Zygosity Questionnaire in Twins of Known Zygosity

The aim of this study was to validate a zygosity questionnaire that can be administered over the telephone. Mothers of same-sexed twins of known zygosity and chorionicity between 2 and 31 years of age were interviewed on a nine-item questionnaire. From the answers one unweighted and four weighted indices were computed. As single questions, the mothers opinion and the “two peas in a pod” question differentiated best between monozygotic and dizygotic twins. One independent well-trained observer assessed the zygosity based on the questionnaire and made the correct diagnosis in 96% of the cases. A weighted index of eight similarity questions yielded an accuracy of 98%. This study shows that the zygosity of same-sexed twins more than 2 years old and without gross physical malformation can reliably be determined by a telephone questionnaire with a high accuracy.

Inheritance of physical fitness in 10-yr-old twins and their parents

This study focuses on the quantification of genetic and environmental sources of variation in physical fitness components in 105 10-yr-old twin pairs and their parents. Nine motor tests and six skinfold measures were administered. Motor tests can be divided into those that are performance-related: static strength, explosive strength, running speed, speed of limb movement, and balance; and those that are health-related: trunk strength, functional strength, maximum oxygen uptake, and flexibility. The significance and contribution of genetic and environmental factors to variation in physical fitness were tested with model fitting. Performance-related fitness characteristics were moderately to highly heritable. The heritability estimates were slightly higher for health-related fitness characteristics. For most variables a simple model including genetic and specific environmental factors fitted the observed phenotypic variance well. Common environmental factors explained a significant part of the variation in speed components and flexibility. Assortative mating was significant and positive for speed components, balance, trunk strength, and cardiorespiratory fitness, but negative for adiposity. Static strength, explosive strength, functional strength, and cardiorespiratory fitness showed evidence for reduced genetic transmission or dominance. The hypothesis that performance-related fitness characteristics are more determined by genetic factors than health-related fitness was not supported. At this prepubertal age, genetic factors have the predominant effect on fitness.

The East Flanders Prospective Twin Survey (EFPTS).

The East Flanders Prospective Twin Survey (EFPTS) is a prospective, population-based registry of multiple births in the province of East Flanders, Belgium. EFPTS has several unique features: it is population based and prospective, with the possibility of long-term follow-up; the twins (and higher order multiple births) are ascertained at birth; basic perinatal data recorded; chorion type and zygosity established; and since 1969 placental biopsies have been taken and frozen at -20 degrees C for later determination of genetic markers. The EFPTS is the only large register that includes placental data and allows differentiation of 3 subtypes of monozygotic (MZ) twins based on the time of the initial zygotic division: the dichorionic-diamnionic pairs (early, before the 4th day after fertilization), the monochorionic-diamnionic pairs (intermediate, between the 4th and the 7th day post fertilization), and the monochorionic-monoamnionic pairs (late, after the 8-day post fertilization). This added a new dimension to didymology (the science of twins; didymos is the Greek word for twin): the timing of MZ twinning. Studies can be initiated taking into account primary biases, those originating in utero. Such studies could throw new light on the controversy over the validity of the classic twin method, the consequences of early embryological events (before and just after implantation of the embryo), the origin of congenital malformations, the sex proportion of multiples, the gene-environment interactions as far as intrauterine environment is concerned, to name but a few.

Iatrogenic multiple pregnancies in East Flanders, Belgium*

OBJECTIVE To evaluate the specific contribution of artificial induction of ovulation to the increasing number of multiple gestations in East Flanders and the effects of this treatment on the frequencies of monozygotic and dizygotic twinning. DESIGN Since 1976 the East Flanders Prospective Twin Study has collected data on artificial induction of ovulation for all the multiple births listed in its registry. SETTING East Flanders Prospective Twin Survey. PATIENTS Between 1976 and 1992, 458 twin and 78 triplet pregnancies resulting from artificial induction of ovulation were analyzed. MAIN OUTCOME MEASURES Zygosity and frequency of iatrogenic multiple births. RESULTS Since 1985 there is an explosive increase in twin and triplet births in East Flanders. This increase has been caused mainly by the sole use of fertility-enhancing drugs and in the last few years by resorting to other technologies of assisted reproduction, such as IVF-ET, GIFT, or zygote intrafallopian transfer. CONCLUSION In view of the elevated risk inherent to multiple pregnancies in terms of perinatal mortality and morbidity, the over enthusiastic or improper use of fertility drugs should be curtailed.

The value of twin surveys in the study of malformations

Congenital malformations have been investigated in a consecutive series of 445 monozygotic twin pairs coming from two twin surveys numbering 1,424 pairs. Concordant malformations were found in 6 pairs, discordant in 20 pairs. The significance of these findings is briefly discussed. The methodology of the prospective twin studies is described. The diagnosis of zygosity is based on sex, structure of placental membranes, blood groups and enzyme systems of the blood and placenta.

Length of gestation and birthweight in dizygotic twins

Despite the longer gestation of girls, their birthweight is less than that of boys. Because unlike-sex twins provide a natural situation in which to investigate the influence of sex on gestation, we compared birthweight and gestation of 1929 same-sex and unlike-sex dizygotic pairs. Length of gestation in unlike-sex pairs was similar to that of female same-sex pairs, and significantly (0.4 weeks; p=0.02) longer than that of male same-sex pairs. Birthweight of girls from unlike-sex pairs was similar to that of girls from same-sex pairs, but boys from unlike-sex pairs weighed 78 g more than boys from same-sex pairs (p=0.001). These data show that in unlike-sex pairs it is the girl that prolongs gestation for her brother, resulting in a higher birthweight than that of same-sex boys.

Zygosity determination in newborn twins using DNA variants.

A prerequisite for the optimal use of the twin method in human genetics is an accurate determination of the zygosity at birth. This diagnosis is sometimes hampered by the lack of available specific markers. We report here the use of DNA variants (restriction fragment length polymorphisms) as genetic markers for zygosity determination. We have analysed the placental DNA of 22 twin pairs with known zygosity on Southern blots by hybridisation with polymorphic human DNA probes. We looked at six different polymorphic sites using four restriction enzymes and six DNA probes. Among 10 dizygotic (DZ) pairs, only one was not demonstrably different and seven had at least two discordances. Within each of the 12 monozygotic (MZ) pairs there was complete concordance. Thus, nine of 10 dizygotic and 12 of 12 monozygotic twins were assigned their correct zygosity solely by comparison of six DNA variants. The use of these highly polymorphic DNA probes may have practical importance for antenatal diagnosis and paternity testing.

Preterm birth in twins after subfertility treatment: population based cohort study

Abstract Objectives To assess gestational length and prevalence of preterm birth among medically and naturally conceived twins; to establish the role of zygosity and chorionicity in assessing gestational length in twins born after subfertility treatment. Design Population based cohort study. Setting Collaborative network of 19 maternity facilities in East Flanders, Belgium (East Flanders prospective twin survey). Participants 4368 twin pairs born between 1976 and 2002, including 2915 spontaneous twin pairs, 710 twin pairs born after ovarian stimulation, and 743 twin pairs born after in vitro fertilisation or intracytoplasmic sperm injection. Main outcome measures Gestational length and prevalence of preterm birth. Results Compared with naturally conceived twins, twins resulting from subfertility treatment had on average a slightly decreased gestational age at birth (mean difference 4.0 days, 95% confidence interval 2.7 to 5.2), corresponding to an odds ratio of 1.6 (1.4 to 1.8) for preterm birth, albeit confined to mild preterm birth (34-36 weeks). The adjusted odds ratios of preterm birth after subfertility treatment were 1.3 (1.1 to 1.5) when controlled for birth year, maternal age, and parity and 1.6 (1.3 to 1.8) with additional control for fetal sex, caesarean section, zygosity, and chorionicity. Although an increased risk of preterm birth was therefore seen among twins resulting from subfertility treatment, the risk was largely caused by a first birth effect among subfertile couples; conversely, the risk of prematurity was substantially levelled off by the protective effect of dizygotic twinning. Conclusions Twins resulting from subfertility treatment have an increased risk of preterm birth, but the risk is limited to mild preterm birth, primarily by virtue of dizygotic twinning.