**3. Predisposing factors for a high-order pregnancy**

There have been described several factors related to increased incidence of multiple pregnancy, in particular twin pregnancy. Factors predisposing to a multiple pregnancy differ between monozygotic and multizygotic pregnancies in nature. The difficulty to determine any predisposing factors for quadruplet and higher order pregnancies lies in the limited series of patients and the lack of available data. Therefore, many factors associated with twin pregnancies are also considered to have a possible influence on the incidence of high-order pregnancies.

Before the introduction of modern infertility treatments, the prevalence of monozygotic twinning was relatively constant among different origins, oscillating between 3 and 5 per 1000 live births [27]. On the other hand, the prevalence of dizygotic twinning differs concerning race, maternal age, and family history of twinning. Black women have the highest rate of dizygotic twins followed by Asian women and finally white women. Moreover, women with a family history for dizygotic twinning, such as a previous dizygotic pregnancy or being part of or related to a set of dizygotic twins, have greater probability to conceive dizygotic twins compared to women with no family history [14].

significance between the cessation of oral contraceptives and the incidence of monozygotic or dizygotic twinning. In the same study, no significance was found between the time after cessation of contraceptives and the occurrence of twin pregnancy. As far as high-order preg-

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Wen et al. in a study in 2004 [44] observed that women with high-order pregnancies were tended to be white (78.8% for twins, 89.4% for triplets, and 94.8% for quadruplets and more) and older (67.6% of mothers of triplets, 64.6% of quadruplets, and 46.3% of twins were older than 30 years). Moreover, they were more likely to be married (72% for twins, 90.6% for triplets, and 97.4% for quadruplets and more) and of higher education. Mothers of triplets, quadruplets, and more were less likely to have smoked during pregnancy and more likely to have received prenatal care earlier (93.6 and 94.6% for triplets and quadruplets in first trimester compared to the 85.4% for twin pregnancies). Finally, they were more likely to be women undergoing their first pregnancy (34.1% for twins, 51.2% for triplets, and 52.7% for quadruplets and higher). In a study by Luke and Brown in 2008 [45], which included the U.S. births from 1995 to 2000, the same demographic characteristics are evident among mothers of quadruplets, white, older

Nowadays, the most important predisposing factor for multiple pregnancy is modern fertility techniques. Induction of ovulation, the transfer of more than one embryos, IVF, ICSI, assisted hatching, or even the culture media have all been associated with increased incidence of a multiple gestation [14]. Some of the above have been strongly associated with multiple pregnancy, and regulations have been established in many countries either by law or official guidelines in order to reduce the incidence and any eventual complications of a multiple pregnancy (for instance, there is a limitation of the number of embryos allowed to be transferred). Many studies exist in literature, including case reports, for quadruplet/quintuplet pregnancies after single/double blastocyst transfer. Quadruplet pregnancies have been reported after the transfer of only one [46] or two embryos [47–49], with variable chorionicity. There are also case reports of quintuplets originated from one fertilized egg (the Dionne quintuplets) and

Early diagnosis of a multiple pregnancy is crucial for achieving the best outcome and for preventing as many complications as possible, either maternal or fetal [53]. The preferred method to diagnose a multifetal gestation is by ultrasonography. This method is accurate enough to reveal a multiple pregnancy by the fourth week of gestation, although the number of yolk or

The term "vanishing fetus" or "natural fetal reduction" is used to describe the loss, through miscarriage, of one or more fetuses during a multiple gestation. This phenomenon can be observed up to the 16th week of pregnancy, and it can be either asymptomatic or it can present with bleeding, pain, or abdominal cramps. Before the introduction of ultrasound, a vanishing fetus could only be diagnosed after delivery [55]. Dickey et al. estimated that the prevalence of a vanishing

nancies are concerned, there are no available data due to the limited number of cases.

women of higher education and at lower parity, married, and non-smokers.

two [50, 51] or three blastocysts [52].

**4. Diagnosis of a multifetal pregnancy**

gestational sacs can be misleading as early in pregnancy [54].

Since the early 1970s, maternal age was considered an important factor that could influence the conception of a multiple pregnancy, with a reported fourfold increase of dizygotic twinning rate between the ages of 15 and 37 [28]. Maternal age does not seem to affect monozygotic multiple pregnancy rates, as shown in multiple studies [29]. Women between the ages of 35 and 41 are more likely to have a multiple gestation. The increment in multifetal pregnancies is probably related to higher basal FSH levels for women over the age of 35 compared to younger women. Higher levels of FSH can be associated with the maturation of multiple follicles in natural cycles and consequently the occurrence of a multiple pregnancy [30].

There is evidence that a woman's somatometric parameters are associated with a multiple pregnancy. Women with a BMI over 30 are more likely to conceive more than one babies compared to women with normal BMI [31–34]. Noteworthy, a higher BMI increases the probability of multizygotic pregnancies but not monozygotic ones. Women's height has been associated with multiple pregnancies, even though its impact is less important than weight [34]. Women who are taller than 173 cm seem to have higher probability for dizygotic twinning compared to women shorter than 165 cm [31, 33].

Some lifestyle choices have also been proposed as predisposing factors for multiple pregnancy. Multivitamins and folic acid supplementation have been associated with an increased incidence of multiple gestation, even though the results were not statistically significant [35]. In order to confirm that the use of folic acid increases the rates of multiple pregnancies (up to 40%), more trials have to be performed [36]. Coffee consumption, smoking, and alcohol have also been evaluated for their possible positive correlation with multiple pregnancy without fertility treatments [37]. This observation is surprising, since smoking and alcohol are known to have negative effects on the fetus and the pregnancy outcome. Kapidaki in 1995 [38] showed that for each cup of coffee per day there was an increase in the odds for multifetal pregnancy. Parazzini in 1996 [37], on the other hand, found no relation between multiple pregnancy and the extent of coffee drinking. In the same study, however, they found that women who were drinking ≥15 alcohol units per week and those who were smoking ≥10 cigarettes per day were more likely to conceive a multifetal pregnancy. In any case, more studies are necessary in order to have results that are more reliable.

The use of contraceptive pill and the time after its discontinuation are associated with multiple pregnancy. The theory behind this affirmation is an increase in the secretion of gonadotropins shortly after the cessation of the pill that could result in multiple pregnancies. Many studies, since the 1970s [39–42], have denoted an increase in twin pregnancies after the cessation of oral contraceptive pills. A study by Campbell in 1987 [43], however, found no statistical significance between the cessation of oral contraceptives and the incidence of monozygotic or dizygotic twinning. In the same study, no significance was found between the time after cessation of contraceptives and the occurrence of twin pregnancy. As far as high-order pregnancies are concerned, there are no available data due to the limited number of cases.

Wen et al. in a study in 2004 [44] observed that women with high-order pregnancies were tended to be white (78.8% for twins, 89.4% for triplets, and 94.8% for quadruplets and more) and older (67.6% of mothers of triplets, 64.6% of quadruplets, and 46.3% of twins were older than 30 years). Moreover, they were more likely to be married (72% for twins, 90.6% for triplets, and 97.4% for quadruplets and more) and of higher education. Mothers of triplets, quadruplets, and more were less likely to have smoked during pregnancy and more likely to have received prenatal care earlier (93.6 and 94.6% for triplets and quadruplets in first trimester compared to the 85.4% for twin pregnancies). Finally, they were more likely to be women undergoing their first pregnancy (34.1% for twins, 51.2% for triplets, and 52.7% for quadruplets and higher). In a study by Luke and Brown in 2008 [45], which included the U.S. births from 1995 to 2000, the same demographic characteristics are evident among mothers of quadruplets, white, older women of higher education and at lower parity, married, and non-smokers.

Nowadays, the most important predisposing factor for multiple pregnancy is modern fertility techniques. Induction of ovulation, the transfer of more than one embryos, IVF, ICSI, assisted hatching, or even the culture media have all been associated with increased incidence of a multiple gestation [14]. Some of the above have been strongly associated with multiple pregnancy, and regulations have been established in many countries either by law or official guidelines in order to reduce the incidence and any eventual complications of a multiple pregnancy (for instance, there is a limitation of the number of embryos allowed to be transferred). Many studies exist in literature, including case reports, for quadruplet/quintuplet pregnancies after single/double blastocyst transfer. Quadruplet pregnancies have been reported after the transfer of only one [46] or two embryos [47–49], with variable chorionicity. There are also case reports of quintuplets originated from one fertilized egg (the Dionne quintuplets) and two [50, 51] or three blastocysts [52].
