Twins may arise from one of two mechanisms: division of a single fertilized ovum into two embryos (“identical” or monozygotic twins) or fertilization of two separate ova (“fraternal” or dizygotic twins). Either or both processes may be involved in the generation of higher numbers of fetuses. Triplets could develop from one, two or three ova; quadruplets from one, two, three or four and so on. It is exceedingly rare for a zygote to divide more than once.
The two twinning processes have very distinct origins and implications for pregnancy outcome. While all multiple gestations carry a risk of preterm delivery from early labor, monozygotic twin pregnancies carry an additional risk of placental problems, chromosomal abnormalities and fetal malformations. These can dramatically influence pregnancy outcomes.
Biology of monozygotic twinning
It is not known exactly what causes an embryo to divide to produce monozygotic twins. However, it is clear that division of the fertilized ovum at specific early stages of development is responsible for the spectrum of clinical presentations with monozygotic twinning. These stages are depicted in Fig. 35.1. Basically, the earlier the fertilized ovum divides, the more separate the twins. Cleavage prior to development of an inner cell mass will result in two placentas, two sets of membranes and two fetuses, whereas division after the embryonic disc has formed results in conjoined twins.
The most common type of monozygotic twinning arises from division during days 3–8 after fertilization. As division occurs after inner cell mass development, but before amnion or embryonic disk formation, this produces a pregnancy with two amniotic sacs and a single placenta (diamniotic monochorionic twins). The second most common type of monozygotic twinning results from a division of the embryo within the first 72h after fertilization and produces a pregnancy with two amniotic sacs and two placentas (diamniotic dichorionic twins). Twins resulting from divisions later than day 8 after fertilization are rare. If the division occurs on or after the amnion forms on day 8 post-fertilization, both fetuses will be in the same amniotic sac (monoamniotic monochorionic twins). Siamese or conjoined twins are the rarest and arise from cleavage of the differentiating embryonic disc 13–16 days post-conception. Fraternal twins are always diamniotic dichorionic. Therefore, it is necessary to perform zygosity testing on twins with separate placentas who are suspected of being monozygous.
Most of the spontaneously conceived multifetal pregnancies are twin gestations. The incidence of conception of twins is at least twice the rate of liveborn twins. In many cases, one of a pair of diamniotic dichorionic twins just disappears. Less often, the whole pregnancy miscarries. The frequency of monozygotic twinning is about 1 set in every 250 births and is relatively fixed in most populations. In contrast to monozygotic twinning, the incidence of dizygotic twinning varies dramatically among different populations. Dizygotic twinning is highly influenced by race and heredity. Maternal age over 40, increasing parity and infertility treatment are positively linked to dizygotic twinning.
The racial differences in dizygotic twinning are quite marked. Twinning among Asians is least common, with a rate of only 1.3 dizygotic twin births per 1000 total births in Japan. White women in the USA and the UK have rates of about 8 dizygotic twin sets per 1000 births. Black women have the highest rates of all. They range from a rate of 11 per 1000 births in the USA to 49 per 1000 in some tribes in Nigeria, or 1 in every 20 births. The influence of heredity on dizygotic twinning is carried largely through maternal lineages, with about a 2% chance of delivering twins if the mother herself is a dizygotic twin. When the father of the baby is a dizygotic twin, the rate of twinning is only 0.8%. In developed countries, most multifetal pregnancies result from infertility treatments. Ovulation induction, in vitro fertilization (IVF) and other assisted reproductive techniques dramatically increase the frequency not only of twinning, but also of conceiving higher order multiple gestations (triplets, quadruplets and more); (Fig. 35.2). Table 35.1 lists recent outcome data approximating the frequency of multi-fetal pregnancies in the USA, dependent on the means of conception. If one uses Hellin’s theorem to calculate the expected frequency of twins in Nigeria, which has the highest spontaneous twinning rate in the world, one can see the impact of infertility treatment on the higher-order multiple gestations. Hellin’s theorem states that if the frequency of twinning is n in a population, then the frequency of triplets is n2, quadruplets n3, and so on. Using n = 0.05 for the Nigerian tribes, one would only expect 0.25% triplet and 0.012% quadruplet gestations. Thus, infertility treatment can increase the risk of triplets 20-fold and quadruplets 80-fold over the world’s most “twinningest” people.
Although infertility treatment dramatically increases the frequency of nonidentical multiples, the rate of monozygous twinning is also double that expected in these women. A disproportionate number of these monozygotic twins are also monochorionic. Transfer of day 5 blastocysts into the uterus during IVF is associated with a higher rate of monozygotic twins than transfer of day 3 zygotes. The stimuli for monozygotic twinning following ovulation induction alone have not been identified. Elevated gonadotropins promote recruitment of more than one ovarian follicle in a given cycle and represent the single most important risk factor for dizygotic conceptions. This is most evident during infertility treatments where the use of injected gonadotropins is associated with the development of multiple ovulatory follicles. The increased rates of spontaneous twinning seen with black race, advancing maternal age, parity and heredity are also related to elevations in endogenous gonadotropins, most notably in FSH.
Pregnancy risks with multiple gestations The inherent risk in multiple gestations depends largely on whether single or multiple placentas are present and on whether there is a shared amniotic sac. All monochorionic twins have some degree of vascular connection within the placental bed. In about 15% of monochorionic twin pregnancies, these vascular connections permit the exchange of blood between the two fetuses. When this occurs, the hemodynamics of the two twins can become so deranged that one fetus will preferentially pump extra blood into the other (“twin–twin transfusion syndrome”). The “donor” twin becomes anemic and produces an abnormally low amount of amniotic fluid, whereas the “recipient” twin is volume overloaded and produces excessive amounts of amniotic fluid. Fetuses in multiple gestations also have an increased risk for abnormal insertion of the umbilical cord onto the placenta. The umbilical cord typically inserts into the middle of the placental disc and is completely surrounded by a protective layer of Warton’s jelly. With multiple gestations, each fetus has an increased incidence of having its cord insert along the edge of the placenta (velamentous insertion). Cords with velamentous insertions are not completely surrounded by Warton’s jelly and can be kinked or compressed more readily than more protected cords. Such compression can result in suboptimal fetal blood flow. The umbilical cords of monoamniotic twins invariably become entangled. This leads to fetal deaths in over half of the cases.
In addition to the problems that can arise from their placentas and membranes, monozygotic twins are also at increased risk of chromosomal abnormalities and congenital malformations. Because affected twin pairs are often discordant for the abnormality, it is presumed that whatever intrauterine events caused these embryos to divide can also randomly increase the risk for disordered embryonic development.
All multiple gestations are at risk for growth restriction of one or more of the fetuses. The risk increases as the number of fetuses increases. There are many possible causes for fetal growth restriction in multiple gestations. Suboptimal perfusion of the area of placental implantation of one or more fetus can cause fetal growth restriction. Velamentous umbilical cord insertions may also cause decreased fetal perfusion and growth restriction, as can donation of blood to a co-twin in the twin–twin transfusion syndrome.
All multiple gestations are at risk for preterm labor (Chapter 37). The risk increases in parallel with increasing numbers of fetuses. Uterine distension may explain the early onset of labor in pregnancies complicated by multiple gestations; however, other nonmechanical factors may also be involved.