**4. Pathogenesis of twinning**

#### **4.1. Monozygotic gestation**

One-egg twins result from a single fertilized oocyte. Depending on the spontaneous embryo preimplantation division at various stages of development into two genetically identical structures, three types of monozygotic pregnancies are distinguished according to Corner's embryologic theory as shown in Figure 2 [22]:

**Figure 2.** Three types of monozygotic placenta and membrane. A: dichorionic diamniotic. B: monochorionic diamniot‐ ic. C: monochorionic monoamniotic. From The Lancet, *JudithGHall* [23], with permission from the publisher.


The monozygotic twinning phenomenon happens in a proportion of 1:250 multiple pregnan‐ cies [5]. Usually, they share the same genetic and physical features; however, a simultaneous chromosomal error may result in heterokaryotypic monozygotes, especially in very early splits [24]. Mothers originated from a monozygotic pregnancy have exceeding rates of monozygotic twins. Despite being relatively constant and independent of factors such as ethnicity, maternal age and parity, the occurrence of monozygotic twinning is increased with in vitro fertilization and ovarian stimulation [5].

## **4.2. Dizygotic gestation**

**4. Pathogenesis of twinning**

embryologic theory as shown in Figure 2 [22]:

One-egg twins result from a single fertilized oocyte. Depending on the spontaneous embryo preimplantation division at various stages of development into two genetically identical structures, three types of monozygotic pregnancies are distinguished according to Corner's

**Figure 2.** Three types of monozygotic placenta and membrane. A: dichorionic diamniotic. B: monochorionic diamniot‐

**•** Dichorionic diamniotic if the division of the blastomerers occurs within 72 hours postfertilization. The amnion and the chorion have not yet developed, resulting in two inde‐

**•** Monochorionic diamniotic when the division of the blastocyst occurs between day 4 and day 7 post-fertilization. The chorion is already formed but not the amnion, culminating in

**•** Monochorionic monoamniotic if the division of the embryoblast occurs after day 8 postfertilization. The chorion and the amnion are fully grown, configuring monoplacental monozygotic twins as well. Even later division, usually after the 13th day, gives rise to

The monozygotic twinning phenomenon happens in a proportion of 1:250 multiple pregnan‐ cies [5]. Usually, they share the same genetic and physical features; however, a simultaneous

ic. C: monochorionic monoamniotic. From The Lancet, *JudithGHall* [23], with permission from the publisher.

pendent embryonic discs and diplacental monozygotic twins.

monoplacental monozygotic twins.

conjoined twins, since the germ disc is completed.

**4.1. Monozygotic gestation**

206 Contemporary Gynecologic Practice

Two-egg twins result from simultaneous ovulation of two ova fertilized by two different spermatozoa. Thus, necessarily, two chorionic sacs are developed even in cases of fused placenta [25]. Both zygotes have different genetic constitutions, on average sharing 50% of their genes, and they can be of the same or opposite sexes [13]. Almost 75% are of the same sex, with both male twins in 45% of cases [24]. An excessive follicular recruitment occurs in 31% of mothers of dizygotic twins, who have greater basal follicle-stimulating hormone (FSH) concentration and pulse frequency, associated with elevated secretion of gonadotropinreleasing hormone (GnRH). These findings suggest that multiple ovulations are extragona‐ dally determined [5].

Season is known to influence the dizygotic twinning process as well as the use of folic acid and oral contraceptives. Evidences suggest a slight tendency for dizygotic twins to be conceived at summer and autumn, which probably reflects the light's effect on pineal gland and the release of higher titles of FSH [5, 13]. A recent systematic review indicates a possible positive association between the use of periconceptional folic acid and increased twinning, but additional well-designed studies are needed [26]. Several researches showed raised risk for multiple pregnancies after discontinuation of oral contraceptives due to a temporary increase of FSH levels [27, 28].

Whether there is a recessive or dominant inheritance pattern for dizygotic twinning is still controversial. The fact is that a substantially greater female genetic contribution was observed, in contrast with limited evidence for a paternal effect [29, 30]. Genetic mutations could not yet be definitively associated as a cause of hereditary dizygotic twinning, but genetic mapping studies support a mechanism of inheritance connected to chromosomes 2, 7 and 18. Further investigations are needed [13].

#### **4.3. Other forms of multiple gestation**

Superfecundation is the fertilization of two or more ova from the same ovulation cycle by sperm released at intercourse on different occasions, not necessarily from the same partner (heteropaternal superfecundation). Cases of twins with different fathers have been reported since 1940 by red cell antigen typing, and these findings were later endorsed by human leukocyte antigen (HLA) typing [31, 32]. Genetic disease studies and circumstances of disputed paternities allowed more accurate diagnosis [33]. Recently, a case of heteropaternal superfe‐ cundation was reported in a pair of Danish twins [34].

Superfetation is the fertilization of 2 ova released in different menstrual cycles, resulting in the onset of a subsequent pregnancy during an ongoing pregnancy. The occurrence is more rare than superfecundation and only few human cases have been described [35]. Confirmation requires ultrasound scanning during the first trimester, but neurosonography with detailed ophthalmic examination may support the diagnosis. Superfetation has innumerous antenatal implications although it is very difficult to retrospectively confirm the diagnosis postnatally [36]. Considering the absence of substantial evidence, we believe the superfetation mechanism could only be possible in theory.
