INTRODUCTION
Over the past few decades, incidence of multiple gestations has increased steadily not only in developed countries but also in developing and underdeveloped countries. Apart from reasons related to increased use of ART, other reasons are also responsible for these changes. Since 1980, world witnessed sharp increase in incidence of twin as well as higher order pregnancy. This was probably because of increased use of ART technique, higher number embryo transfer, and also changes in the age distribution of women at child birth, with more women giving birth at older ages. Multiple births have huge impact on health care. Though with the medical and technological advances outcome of preterm and low-birth weight babies has improved, multiple gestations are still associated with increased risk of maternal and perinatal complications. Fortunately, since the last one decade, with more rational embryo transfer practices, though twin pregnancy incidence has remained high, incidence of higher order pregnancy has started declining.
The epidemiology of twinning is complex and, though not fully understood, there are certain factors which have definite bearing with occurrence of multiple gestations.
It is important to understand the changing epidemiology of multiple births, especially for women with advanced maternal age. Twin pregnancies are the result of a complex interaction of genetic and environmental factors. Twinning rate rose by 76% from 18.8 to 32.1 per 1000 live births in 2009. Since then, however, evolving infertility management has resulted in decreased rates of higher order multifetal births to its lowest level. Especially, rates of triplets are decreased by 10% from 153 per 100,000 births to 138 per 100,000 births in 2010.1 Frequency of monozygotic twin birth is relatively constant worldwide approximately one set per 250 births, incidence is generally independent of race, heredity, age, and parity. One exception is that zygotic splitting is increased following ART.2
RACIAL AND GEOGRAPHICAL FACTORS
Twin pregnancy incidence varies from country to country. Highest reported is in Nigeria and the lowest in Japan.3 In general, the dizygotic twinning rate is about 8/1000 in Caucasians, about twice as large in Negroes and less than half in mongoloids. The factors which influence the racial differences in dizygotic twinning incidence include genetic 2predisposition, levels of follicle-stimulating hormone (FSH) and undernourishment.4
Mothers of dizygotic twins have significantly higher basal FSH concentrations and FSH pulse frequency with consequent elevation of follicular phase estradiol, inhibin and luteinizing hormone (LH) concentrations. In the study by Martin et al., it was found that basal FSH concentration in women is significantly higher in populations with high twinning rates (e.g. Western Nigeria: 50/1000 maternities) compared to that in women from populations with low twinning rates.5
MATERNAL AGE
Dizygotic twinning frequency increases almost 4-fold between ages of 15 and 37 years,6 monozygotic rates being fairly constant. It is in this age range that maximal FSH stimulation increases the rate of multiple follicles developing.7 Rate of twinning increases dramatically with advancing maternal age because the use of ART is more likely in older women.8 Although paternal age has been linked to frequency of twinning, its affect is felt to be small.9 Bulmer et el. reported that if parity is held constant, rate of twinning is increased by 4-fold, or by 300%, between the ages 15 and 37 years.10
SOCIAL, CONSTITUTIONAL AND MATERNAL LIFESTYLE FACTORS
In women of lower social class in Nigeria,11 higher rates of twinning were observed, and this could be attributed to the different dietary habits. No consistent association between education and risk of twin pregnancies emerged from case-control study.12 Some association was found between greater maternal height and risk of dizygotic twins. Higher incidence of twins was seen in overweight women.13 Taller-heavier women had a twinning rate of 25–30% greater than short, nutritionally deprived women.14 Higher folate intake and plasma folate concentrations were associated with an increased rate of twinning in women undergoing in-vitro fertilization techniques.15 Nylander14 showed a definite increase gradient in the twinning rate related to greater nutritional status as reflected by maternal size. Ericson,16 Haggarty,17 Hasbargen18 have reported 40% increase in prevalence of twinning among women who have taken supplementary folic acid.
In two case-control studies conducted in Greece and Italy,12,19 authors reported that there is increased tendency of multiple gestations, both monzygotic and dizygotic, in women who are heavy smokers, but this finding was not statistically significant. Also the risk of multiple gestations tended to be higher in alcoholic women, consuming 15 or more alcoholic drinks per week.
FIRST-DEGREE RELATIVES AND PARENTAL CONSANGUINITY
While consanguinity showed, though insignificant, yet positive association with dizygotic twins in Indian population, total and monozygotic twinning rate declined with closeness of consanguinity.20 In a study by Lichtenstein et al., they reported an increased risk of giving birth to twins in women who were themselves twins.21
It was also reported in that study that dizygotic mothers had an increased risk of giving birth to dizygotic twins, while monozygotic mothers had an increased risk of having monozygotic twins. Parisi et al. analyzed the incidence of twinning in the families of twins, and indicated that a propensity to monozygotic twinning, as well as to dizygotic twinning, may be inherited through the maternal line.22 They also found a paternal role in dizygotic, but not in monozygotic twinning. As a determinant of twinning, the family history of mother is more important than that of the father. White and Wyshak23 found that women who themselves were a dizygotic twins gave birth to twins at a rate of 1 set per 58 births. Women who were not a twin but whose husbands were a dizygotic twins, gave birth to twins at a rate of 1 set per 116 pregnancies. Painter et al.6 found potential linkage peaks with the long arm of chromosome 6 and also on chromosomes 7, 9 and 16.
REPRODUCTIVE HISTORY
A positive relationship has been seen between parity and frequency of dizygotic twinning.20 Conversely, Rao et al.20 in their study reported a negative corelation between monozygotic pregnancies and multiparity, while Olusanya24 found an 8-fold increase in multiple gestations 3when parity was 4 or less and 20-fold increase when parity was 5 or more compared with primiparas.
USE OF ORAL CONTRACEPTIVES
Several studies have been published on the relationship between use of oral contraceptives (OCs) and subsequent risk of multiple gestations after their discontinuation. Different studies in literature have shown conflicting results regarding relationship of the use of oral contraceptives and multiple gestations. Though some studies have shown decrease in risk of multiple gestations, particularly, in those women using pills for short duration, many more studies have quoted 3- to 6- fold increase in risk. This increase in risk is only for short period after discontinuation of OC due to rebound increase of pituitary gonadotropins. Hemon et al.25 reported lower fertility with higher incidence of chromosomal abnormalities among spontaneous abortions after OC discontinuation. Increased fecundity and higher rate of dizygotic twinning was reported in women who conceive within 1 month after stopping oral contraception but not during subsequent months.26 Paradox of declining fertility but increasing twinning with advancing maternal age can be explained by an exaggerated pituitary release of FSH in response to decreases negative feedback from impending ovarian failure.8
INFERTILITY THERAPY
Ovulation induction with clomiphene or FSH with chorionic gonadotropins remarkably enhances likelihood of multiple ovulations. Incidence of multifetal gestations in assisted reproductive technology is 14%. With clomiphene citrate treatment, it is 6.8–17%, and with gonadotropins, 18–53%. Risk of multiple gestations is 50% and 32% when gonadotropins were used for ovulation induction in hypogonadotropic women and normogonadotropic women respectively, while in oligomenorrhic women, chance is 18% as reported by Assessment of Multiple Intrauterine Gstations from Ovarian Stimulation (AMIGOS) and Pregnancy in Polycystic Ovary Syndrome (PPCOS II).27
CONCLUSION
Epidemiological observations show us that the causes of monozygotic and dizygotic twins are multi-factorial. Monozygotic twins are largely determined by genetic mechanisms as the frequency of monozygotic pregnancies over the time and in different areas are constant, and the trends in dizygotic pregnancies suggest that environmental factors play a role here. Maternal age and the hereditary components are the best-defined determinants of risk of multiple births, other determinants being race, parity and nutrition. Higher rates of neonatal problems and greater risk of complications of pregnancy and delivery are associated with multiple births.28 Thus, it is important to clarify the causes of this condition.
REFERENCES
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- Painter JN, Willemsen G, Nyholt D, et al. A genome wide linkage scan for dizygotic twinning in 525 families of mothers of dizygotic twins. Human Reprod. 2010;25(6):1569.
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- Kapidaki M, Roupa Z, Sparos L, et al. Coffee intake and other factors in relation to multiple deliveries: a study in Greece. Epidemiology. 1995;6:294-8.
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- Haggarty P, McCallum H, McBain H, et al. Effects of B vitamins and genetics on success of in-vitro fertilization—prospective cohort study. Lancet. 2006:367:1513.
- Ericson A, Kallen B, Alberg A. Use of multivitamin and folic acid in early pregnancy and multiple births in Sweden. Twin Res. 2001;4(2):63.
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- Hasbargen U, Lohse P, Thaler CJ. The number of dichorionic twin pregnancies is reduced by the common MTHFR 677C → T mutation. Hum Reprod. 2000;15(12):2659.
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- Parisi P, Gatti M, Prinzi G, et al. Familial incidence of twinning. Nature. 1983;304:626-8.
- White C, Wyshak G. Inheritance in human dizygotic twinning: N Engl J Med. 1964:271:1003.
- Olusanya BO, Solanke OA. Perinatal correlates of delayed childbearing in a developing country. Arch Gynecol Obstet. 2012;285(4):951.
- Hemon D, Berger C, Lazar P. Twinning following oral contraceptive discontinuation. Int J Epidemiol. 1981;10:319-28.
- Rothman KJ. Fetal loss, twinning and birthweight after oral contraceptive use. N Engl J Med. 1977: 297:468.
- Legro RS, Kunselman AR, Brzyski RG, et al. The pregnancy in polycystic ovarian syndrome ii trial: rationale and design of a double blind randomised trial of clomiphene citrate and letrozole for the treatment of infertility in women with polycystic ovarian syndrome. Contemp Clin Trials. 2012: 33:470.
- MacGillivray I. Twin pregnancy. In: Phillip EE, Barnes J, Newton M (eds). Obstetrics and Gynaecology. William Heinemann Medical Books, London; 1986. pp. 248-53.