**5. Complications and management of quadruplet/quintuplet pregnancies**

Women with quadruplets and higher-order pregnancies are at increased risk for obstetric complications compared to women with twin pregnancies. Moreover, a dose-response relationship can be found for certain complications of the pregnancy. Wen et al. [44] in 2004 compared the outcomes in women with twins, triplets, quadruplets, and high-order pregnancies from 1995 to 1997. They concluded that women with triplets and more were in greater risk for pregnancy associated hypertension, eclampsia, anemia, diabetes mellitus, placental abruption, premature rupture of the membranes, and cesarean delivery, even after the adjustment for important confounding factors. Wen also compared the maternal health outcomes. Women with triplets, quadruplets, and higher order are predisposed to develop pregnancyassociated hypertension and diabetes mellitus (7.68% for twins, 10.32% for triplets, and 11.57% for quadruplets and higher order for hypertension, while for diabetes mellitus the rates were 3.34% for twins, 5.97% for triplets, and 6.75% for quadruplets and higher order). Twins were less frequently delivered by cesarean section (51.21% compared to 86.78 and 84.87% for triplets and quadruplets or higher, respectively) and had less chances for a premature rupture of the membranes (6.66% for twins, 11.17% for triplets, and 10.65 for quadruplets and more). The rise in rates for cesarean delivery as the number of fetuses increases could also explain the low rates of induction of labor and use of forceps and vacuum among triplets and quadruplets compared to twin pregnancies. The study by Luke and Brown in 2008 [45] also came to the same results that quadruplet pregnancies have greater chances for pregnancy-associated complications when compared to twin pregnancies. In the study by Luke and Brown, the p-value was <0.0001 for diabetes mellitus, incompetent cervix, induction of labor, stimulation of labor, tocolysis, cesarean delivery, premature rupture of the membranes, infant death of ≥1 baby, birth at ≤29 weeks of pregnancy, and <0.05 for pregnancy-associated hypertension and eclampsia.

fetus before the 12th week of a quadruplet pregnancy could be as high as 65% with great variability among different researchers [56]. They also showed that the probability of a spontaneous absorption in a multiple pregnancy was directly related to the initial number of gestational sacs and to maternal age (p < 0.001 and p < 0.01, respectively). In the same study, they concluded that the average duration of reduced twin pregnancies with initially four sacs was 11 days shorter when compared to the duration of unreduced twin pregnancies (254 days–243 days, p < 0.001). In addition, the birth weight of naturally reduced twins was lower compared to the weight of

Ultrasonography plays an important role in the diagnosis of chorionicity and placentation of a pregnancy. Determining chorionicity is crucial, since twin and triplet pregnancies with at least one monochorionic pair have greater perinatal morbidity and mortality [57, 58]. Perinatal mortality in quadruplets tends to be five times higher when a monochorionic set is present compared to quadra-chorionic [57]. Adeghite et al. in 2007 [59] compared the differences in neonatal complications between quadra-chorionic quadramniotic and trichorionic newborns. There was statistically significant higher incidence for almost all complications considered within the trichorionic group. This group also had statistically significant higher rates in neonatal death when compared to the quadra-chorionic group. Furthermore, trichorionic infants were born much earlier and weighed less compared to the quadra-chorionic ones: 28 vs. 32 weeks and 69% <1000 g vs. 13% <1000 g (p < 0.001), respectively. There was no difference between the groups in regard to the mode of delivery. Some data suggest that the use of modern infertility treatment methods is associated with monozygotic twinning, although the data for some of these methods are conflicting [60]. Since 75% of monozygotic twins are also monochorionic [61], women who have undergone such treatments and have a multifetal gestation must be suspected for monochorionicity. Chow et al. in 2001 in a study of 464 multiple gestations showed that in multiple gestations arising from artificial reproduction treatments, there is a correlation between the number of fetuses and the rates of monochorionic pairs [62]. Monochorionic pairs were present in only 2.1% of twin pregnancies, while in quadruplet and quintuplet pregnancies the rates were as high as 25% (p < 0.05). Chow et al. finally confirmed the observation made in earlier studies that a monochorionic pair is more likely to be found in a naturally conceived gestation. Early ultrasound evaluation can identify placentation correctly in over 90% of multiple gestations, and in case this is not possible, the gestation should be treated as monochorionic [17]. The data regarding the incidence of placenta previa in a multiple gestation are conflicting. Some of them suggest that placenta previa is up to 40% more common in twin pregnancies [63], probably due to limited space in the endometrial cavity [64], whereas others argue that

the incidence of placenta previa is not correlated with the number of embryos [65].

Women with quadruplets and higher-order pregnancies are at increased risk for obstetric complications compared to women with twin pregnancies. Moreover, a dose-response

**5. Complications and management of quadruplet/quintuplet** 

**pregnancies**

unreduced twins (2024 ± 668 g compared to 2453 ± 575 gr, p < 0.003).

164 Multiple Pregnancy - New Challenges

Multiple pregnancies present increased spontaneous loss rates, and these rates increase in parallel with the increase of the number of the fetuses. The authors estimate that a quadruplet pregnancy has a 25% chance for a spontaneous loss, while a quintuplet has three times more, up to 75%. This rise is more obvious when these rates are compared with the ones for a twin and a triplet pregnancy (8 and 15 respectively) [66].

Preterm labor has been proven the most common maternal complication in high-order pregnancies [67], and it is directly associated with the increased perinatal morbidity and mortality observed in these pregnancies, while the rates of pregnancy complications seem to be raised alongside the increase of the number of fetuses [14]. More than 90% of highorder pregnancies are born prematurely, with the approximate gestational age at delivery for quadruplets to be estimated around 29.5 weeks, while for quintuplets this point is up to 29 weeks of gestation [17]. In USA, in 2016, the 93% of quadruplets (217 cases) and the 100% of quintuplets and higher order pregnancies (31 cases) have been born before the 34th week of gestation [12].

In order to prolong the pregnancy, several methods have been used. Bed rest, either hospitalization or home rest, is a method still widely used. Although some researchers considered bed rest the most important mode of treatment and it was used to be advised to all patients [53], Crowther in 2001 [68] for a Cochrane review synthesized seven controlled trials including twin and triplet gestations. Bed rest has been proven ineffective to reduce preterm labor, while on the same time it was psychologically distressing.

Another method widely used for reduction of preterm labor in high-order pregnancies was prophylactic cervical cerclage. In the 1970s, it was suggested that prophylactic cervical cerclage could be beneficial in the prevention of preterm labor for multiple pregnancies [69]. More than 40 years after that, prophylactic placement of cervical cerclage—transabdominal or transvaginal—is considered of undetermined value [70] or of no significance regardless of the indication [71]. Straus in 2002 compared a group of quadruplet and quintuplet pregnancies with cerclage and one without and found that the birth weight was higher in the cerclage group (p < 0.001). Despite the higher birth weight in the cerclage group, it was also evident that the perinatal morbidity and mortality were higher (69 vs. 32% for the non-cerclage group for morbidity and 10.26 vs. 5.55% for mortality), although the results due to the small number of cases were of no statistical significance. Strauss concluded that in order to see if prophylactic placement of cervical cerclage has anything to offer to multiple pregnancies, randomized controlled studies have to be made, something difficult due to the limited number of multiple pregnancies.

and 3.1% for singletons [79]. In the same study, the proportion of preterm birth attributable to premature rupture of the membranes for extremely preterm gestational ages (before 28 weeks of pregnancy) was 50% for quadruplets and 100% for higher order pregnancies compared to 26.9, 34.6, and 26.5% for triplets, twins, and singletons, respectively (p < 0.001). On the other hand, premature rupture of the membranes for late preterm gestational ages (34–37 weeks of gestation) contributed to 10% of quadruplets, 12.2% of triplets, 11% of twins, 10.2% of singletons, while no high-order pregnancies could reach that gestational age (p < 0.001). Finally, for quadruplets and high-order pregnancies, Caucasian race was a common aggravating factor, and premature rupture of the membranes in multifetal gestations increased with gestational

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Hypertensive disorders of pregnancy are more common among multiple pregnancies, in particular quadruplet pregnancies have a reported incidence of pregnancy-associated hypertension up to 40% with earlier and more severe onset [80]. Day in 2005 [81] showed that the rate of mild and severe preeclampsia is similar for triplets and quadruplets, with the exclusion of women who delivered before 28 weeks. The rates for development of any pregnancyassociated hypertensive disorder were 19.6% for quadruplets, 20% for triplet pregnancies, 12.7% for twins, and 6.5% for singleton pregnancies. The same study showed that the rates for severe pregnancy-associated hypertensive disorders were 1.1, 3.1, 1.6, and 0.5% for quadruplet, triplet, twin, and singleton pregnancies, respectively. When comparing quadruplet with singleton pregnancies, quadruplets were strongly associated with severe pregnancy hypertension disorders (p < 0.01). The studies by Wen in 2004 [64] and Luke and Brown in 2008 [65] also showed that women with quadruplets are more likely to develop pregnancy-associated hypertension compared to twins. Since placenta plays an important role in preeclampsia [82], the increased mass of the placenta in multifetal pregnancies is probably associated with the occurrence of preeclampsia. Preeclampsia is often atypical, with hypertension not always present, but with abnormal laboratory values. Hardardottir in 1996 [83] reported that in a series of three cases delivered for preeclampsia among eight quadruplet pregnancies, only one developed hypertension, none proteinuria, one had edema, and two had elevated uric acid >5 mg/dl. In the same study, the mean age for women with quadruplets and preeclampsia was 34 years and without preeclampsia was 28.6 years, with no statistical significance. Despite the progress in understanding the pathogenesis of preeclampsia, little progress has

Molar pregnancy coexisting with live fetuses is a rare condition, with cases resulting to the delivery of a live fetus to be even scarcer. There are reports of quadruplet pregnancies with coexisting mole with different management and outcomes. The outcome does not usually include viable fetuses [85]. No guidelines for the management of a multiple pregnancy coexisting with a complete hydatidiform mole and live fetuses occur. Therapeutic abortion is always an option to consider, since the chances for delivering a live fetus are very low and the maternal risks are very high [86]. Tariq in 2014 [87] published a case report of a molar pregnancy diagnosed at 22 weeks where continuation of the pregnancy with close surveillance was decided. The mother was under close monitoring and went into preterm labor at

plurality and occurred at earlier gestational age.

been made in terms of treatment [84].

33 weeks. Three viable fetuses were delivered.

Tocolysis is also another method for the prevention or delay of preterm labor. Several researchers and clinicians used several different medicines, as prophylactic treatment. Prophylactic tocolysis is not recommended since the data show no effect on risk reduction for preterm birth and further studies are needed [72]. Prolonged use of these medicines is also not recommended since tocolysis does not seem to have a significant result to extend the pregnancy for more than 7 days [73].

Cervical pessary is another widely used strategy to prevent preterm labor. Research has been made for singleton and twin pregnancies, with conflicting results [74]. For multiple pregnancies, Liem et al. [75] in a randomized controlled trial, cervical pessaries were not effective in preventing preterm birth, but showed some success for cases with a cervical length of less than the 25th percentile, but further research is needed with more patients. The researchers also noted the low cost of a pessary and the fact that it was well tolerated by the women in the trial, making it a choice to consider in developing countries.

Another strategy used to prolong a multiple pregnancy is the use of progesterone, with vaginal distribution to be preferred than the intramuscular one in terms of fewer maternal side effects [76]. Although for singleton pregnancies, progesterone is considered an effective choice, for multiple pregnancies there is insufficient evidence for the recommendation of its use, with or without a short cervical length, despite the use of 17-alpha-hydroxy-progesteronecaproate by some experts in women with multiple pregnancy and prior spontaneous preterm birth [77].

It is estimated that about 25–30% of preterm labor is the result of preterm premature rupture of the membranes [78]. Luke and Brown in 2008 [65] published a study in which they compared risk rates for maternal and neonatal complications among high-order pregnancies. According to their results, quadruplet pregnancies are more likely to be diagnosed with preterm premature rupture of the membranes (10.64% compared to 9.61% for triplets and 6.17% for twin pregnancies, p < 0.001). In another retrospective cohort study of more than 290,000 live births, premature rupture of the membranes complicated 19.6% for quadruplet and 100% for higher order (>4) pregnancies compared to 19.3% for triplets, 11.2% for twins, and 3.1% for singletons [79]. In the same study, the proportion of preterm birth attributable to premature rupture of the membranes for extremely preterm gestational ages (before 28 weeks of pregnancy) was 50% for quadruplets and 100% for higher order pregnancies compared to 26.9, 34.6, and 26.5% for triplets, twins, and singletons, respectively (p < 0.001). On the other hand, premature rupture of the membranes for late preterm gestational ages (34–37 weeks of gestation) contributed to 10% of quadruplets, 12.2% of triplets, 11% of twins, 10.2% of singletons, while no high-order pregnancies could reach that gestational age (p < 0.001). Finally, for quadruplets and high-order pregnancies, Caucasian race was a common aggravating factor, and premature rupture of the membranes in multifetal gestations increased with gestational plurality and occurred at earlier gestational age.

Another method widely used for reduction of preterm labor in high-order pregnancies was prophylactic cervical cerclage. In the 1970s, it was suggested that prophylactic cervical cerclage could be beneficial in the prevention of preterm labor for multiple pregnancies [69]. More than 40 years after that, prophylactic placement of cervical cerclage—transabdominal or transvaginal—is considered of undetermined value [70] or of no significance regardless of the indication [71]. Straus in 2002 compared a group of quadruplet and quintuplet pregnancies with cerclage and one without and found that the birth weight was higher in the cerclage group (p < 0.001). Despite the higher birth weight in the cerclage group, it was also evident that the perinatal morbidity and mortality were higher (69 vs. 32% for the non-cerclage group for morbidity and 10.26 vs. 5.55% for mortality), although the results due to the small number of cases were of no statistical significance. Strauss concluded that in order to see if prophylactic placement of cervical cerclage has anything to offer to multiple pregnancies, randomized controlled studies have to be made, something difficult due to the limited number of multiple

Tocolysis is also another method for the prevention or delay of preterm labor. Several researchers and clinicians used several different medicines, as prophylactic treatment. Prophylactic tocolysis is not recommended since the data show no effect on risk reduction for preterm birth and further studies are needed [72]. Prolonged use of these medicines is also not recommended since tocolysis does not seem to have a significant result to extend the pregnancy for

Cervical pessary is another widely used strategy to prevent preterm labor. Research has been made for singleton and twin pregnancies, with conflicting results [74]. For multiple pregnancies, Liem et al. [75] in a randomized controlled trial, cervical pessaries were not effective in preventing preterm birth, but showed some success for cases with a cervical length of less than the 25th percentile, but further research is needed with more patients. The researchers also noted the low cost of a pessary and the fact that it was well tolerated by the women in the

Another strategy used to prolong a multiple pregnancy is the use of progesterone, with vaginal distribution to be preferred than the intramuscular one in terms of fewer maternal side effects [76]. Although for singleton pregnancies, progesterone is considered an effective choice, for multiple pregnancies there is insufficient evidence for the recommendation of its use, with or without a short cervical length, despite the use of 17-alpha-hydroxy-progesteronecaproate by some experts in women with multiple pregnancy and prior spontaneous preterm birth [77]. It is estimated that about 25–30% of preterm labor is the result of preterm premature rupture of the membranes [78]. Luke and Brown in 2008 [65] published a study in which they compared risk rates for maternal and neonatal complications among high-order pregnancies. According to their results, quadruplet pregnancies are more likely to be diagnosed with preterm premature rupture of the membranes (10.64% compared to 9.61% for triplets and 6.17% for twin pregnancies, p < 0.001). In another retrospective cohort study of more than 290,000 live births, premature rupture of the membranes complicated 19.6% for quadruplet and 100% for higher order (>4) pregnancies compared to 19.3% for triplets, 11.2% for twins,

trial, making it a choice to consider in developing countries.

pregnancies.

more than 7 days [73].

166 Multiple Pregnancy - New Challenges

Hypertensive disorders of pregnancy are more common among multiple pregnancies, in particular quadruplet pregnancies have a reported incidence of pregnancy-associated hypertension up to 40% with earlier and more severe onset [80]. Day in 2005 [81] showed that the rate of mild and severe preeclampsia is similar for triplets and quadruplets, with the exclusion of women who delivered before 28 weeks. The rates for development of any pregnancyassociated hypertensive disorder were 19.6% for quadruplets, 20% for triplet pregnancies, 12.7% for twins, and 6.5% for singleton pregnancies. The same study showed that the rates for severe pregnancy-associated hypertensive disorders were 1.1, 3.1, 1.6, and 0.5% for quadruplet, triplet, twin, and singleton pregnancies, respectively. When comparing quadruplet with singleton pregnancies, quadruplets were strongly associated with severe pregnancy hypertension disorders (p < 0.01). The studies by Wen in 2004 [64] and Luke and Brown in 2008 [65] also showed that women with quadruplets are more likely to develop pregnancy-associated hypertension compared to twins. Since placenta plays an important role in preeclampsia [82], the increased mass of the placenta in multifetal pregnancies is probably associated with the occurrence of preeclampsia. Preeclampsia is often atypical, with hypertension not always present, but with abnormal laboratory values. Hardardottir in 1996 [83] reported that in a series of three cases delivered for preeclampsia among eight quadruplet pregnancies, only one developed hypertension, none proteinuria, one had edema, and two had elevated uric acid >5 mg/dl. In the same study, the mean age for women with quadruplets and preeclampsia was 34 years and without preeclampsia was 28.6 years, with no statistical significance. Despite the progress in understanding the pathogenesis of preeclampsia, little progress has been made in terms of treatment [84].

Molar pregnancy coexisting with live fetuses is a rare condition, with cases resulting to the delivery of a live fetus to be even scarcer. There are reports of quadruplet pregnancies with coexisting mole with different management and outcomes. The outcome does not usually include viable fetuses [85]. No guidelines for the management of a multiple pregnancy coexisting with a complete hydatidiform mole and live fetuses occur. Therapeutic abortion is always an option to consider, since the chances for delivering a live fetus are very low and the maternal risks are very high [86]. Tariq in 2014 [87] published a case report of a molar pregnancy diagnosed at 22 weeks where continuation of the pregnancy with close surveillance was decided. The mother was under close monitoring and went into preterm labor at 33 weeks. Three viable fetuses were delivered.

Gestational diabetes can be expected to be more common among women with multifetal pregnancy. It has been shown that women with twins have higher rate of gestational diabetes than women with singleton pregnancies [88] and women with triplets tend to have higher rates than twins [89]. Wen in 2004 [64] showed a direct relationship between the number of fetuses and the rates of gestational diabetes. Luke and Brown [65] in 2008 confirmed these results by comparing twin and quadruplet pregnancies (p-value < 0.0001). The rarity of quadruplet and quintuplet pregnancies makes further research necessary in order to confirm that the rise in gestational diabetes rates continues among quadruplet and quintuplet pregnancies.

and high-order infants have comparable rates compared to singletons and twins of the same gestational age [70, 100]. In a retrospective study by Hernandez in 2009 [101], 26% of multiple pregnancies had at least one death (including triplets). In particular, 54% of quadruplet and 100% of quintuplet pregnancies had at least one death, while the average weight at birth was 750 g for dead quadruplets and 1341 g for surviving quadruplets (p < 0.0007). Chibber in 2003 [102] in a study including 100 triplet, 27 quadruplets, and 10 quintuplet pregnancies showed that low birth weight is crucial for perinatal mortality and morbidity, with low birth weight complicating most of the 34 neonatal deaths in the quadruplet and quintuplet groups. Multiples are at increased risk of growth problems compared to singletons, with the degree of intrauterine growth restriction to increase as the number of fetuses increase. In the USA, in 2016, 77.1% of quadruplets were below 1500 g and 96.2% below 2500 g. When considering quintuplets and more, these rates rise up to 80.7 and 100%, respectively. The limited space in uterus and the limited nutrient supply might be responsible for low birth weight [103].

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A low Apgar score at birth is a common concern for neonatologists when a high-order pregnancy ends. Chibber in 2003 [102] highlighted the differences between triplet and higher pregnancies when the Apgar scores of the first and fifth minute were compared. The mean first-minute Apgar score for triplets was 7.8, while for quadruplets and quintuplets was only 6.2 (p < 0.01). When compared the five-minute Apgar score, this was 8.8 for triplets and 7.2 for quadruplets and quintuplets (p < 0.05). Skrablin et al. in 2000 [99] also observed statistical significances in their study, with the mean first-minute Apgar score for triplets to be 6.4 and for quadruplets-quintuplets 4.9 (p = 0.003) and the five-minute Apgar score to be 7.6 for

There are also some rare complications which have been reported in high-order pregnancies, but due to the limited number of cases, no guidelines are available. Fetofetal transfusion has been reported in quadruplet pregnancies [104–106] as well as quadruplet pregnancies with conjoined twins [107, 108]. Another complication that has been described in a quadruplet pregnancy was the rupture of an unscarred uterus, raising the debate of the ideal delivery time for a high-order pregnancy [109]. High-order pregnancies have significant higher rates of peripartum hysterectomy compared to singleton pregnancies [110], although the data from

High-order pregnancies hold a significant risk of miscarriage as well as neonatal and maternal morbidity and mortality. Fetal reduction, since its introduction in 1988 by Evans and his associates [111], has shown encouraging results in regard to the outcome of a multiple pregnancy [66]. Antsaklis et al. in 2004 [112] in a series of 313 multiple pregnancies showed that fetal reduction can reduce the risk of pregnancy loss and severe prematurity in quadruplets and higher order pregnancies and result, in most cases, in at least one live neonate. In particular, he compared the two largest groups, that is triplets and quadruplets reduced to twins, as for miscarriage (8.25 vs. 8.96%), preterm delivery defined as <33 weeks (11.18 vs. 19.67%), and total fetal loss rate (15.41 vs. 14.93%). Altogether, the reduction of a high-order pregnancy

Unfortunately, there are no specific data for quadruplets and quintuplets.

triplets and 6 for quadruplets and quintuplets (p = 0.01).

quadruplet and quintuplet pregnancies are limited.

**6. Multifetal pregnancy reduction**

Women carrying multiples are at increased risk for urinary tract infection, with the rates for multiple pregnancies to be up to 4.6% compared to 3.7% for singleton pregnancies [90], possibly because of the larger size of the uterus or the levels of progesterone in the maternal circulation.

Nutrition and weight gain are of great importance in a multifetal pregnancy. Unfortunately, there are no recommendations available for quadruplet and quintuplet pregnancies. What is expected, is that weight gain might be faster than with triplets and twins, and although there are recommendations for singletons, twins and triplets, that has not yet been possible for higher-order pregnancies [91]. Multivitamin supplements such as folic acid, calcium, and vitamins are recommended, due to the high nutrient needs of the mother and the fetuses. Anemia and iron deficiency are the most common pregnancy-related complications [92, 93] and are associated with a series of maternal and neonatal complications, such as preterm delivery [94], low birth weight [95], birth asphyxia [92], and iron deficiency in high-risk infants [96]. Anemia and iron deficiency are more prevalent among women with a multifetal pregnancy compared to women carrying singletons, so nutriments and supplements containing iron are highly recommended [93]. Vitamin D and calcium through supplements, essential fatty acids through fresh or canned oil-rich fish, and additional energy and macronutrients are advised but there no studies estimating the exact daily requirements [91].

The positive effect of corticosteroid administration in singleton pregnancies is well established. In multifetal gestations however, the datas are still limited. There have been reports suggesting that betamethasone administration in quadruplet births is associated with increased uterine contractions, preterm labor with cervical change, and preterm labor requiring tocolysis [97]. Despite that, a single course of corticosteroids is recommended for all multifetal pregnant women at risk of preterm delivery between 24 and 0/7 weeks and 33 and 6/7 weeks of gestation. In addition, a single repeat dose should be administered to women less than 34 weeks of gestation, at risk of preterm delivery within 7 days, and whose prior dose of corticosteroids was administered more than 14 days before [98].

Quadruplets and quintuplets have higher neonatal and perinatal mortality compared to triplets. Skrablin et al. in 2000 [99] published a study of 51 quadruplet and quintuplet pregnancies compared to 156 triplet pregnancies. They found no significant difference when compared the two groups for stillborns and neonatal mortality ≥28 weeks. On the other hand, they observed a statistically significant difference when they compared neonatal deaths (p = 0.02), the "Discharged Alive" (76.3% for triplets, 54.9% for quadruplets and quintuplets, p = 0.003), early neonatal mortality for ≥1000 g (p = 0.04), and perinatal mortality for >24 and ≥28 weeks of pregnancy (both p = 0.005). Mortality and morbidity seem to be related with preterm delivery, and high-order infants have comparable rates compared to singletons and twins of the same gestational age [70, 100]. In a retrospective study by Hernandez in 2009 [101], 26% of multiple pregnancies had at least one death (including triplets). In particular, 54% of quadruplet and 100% of quintuplet pregnancies had at least one death, while the average weight at birth was 750 g for dead quadruplets and 1341 g for surviving quadruplets (p < 0.0007). Chibber in 2003 [102] in a study including 100 triplet, 27 quadruplets, and 10 quintuplet pregnancies showed that low birth weight is crucial for perinatal mortality and morbidity, with low birth weight complicating most of the 34 neonatal deaths in the quadruplet and quintuplet groups. Multiples are at increased risk of growth problems compared to singletons, with the degree of intrauterine growth restriction to increase as the number of fetuses increase. In the USA, in 2016, 77.1% of quadruplets were below 1500 g and 96.2% below 2500 g. When considering quintuplets and more, these rates rise up to 80.7 and 100%, respectively. The limited space in uterus and the limited nutrient supply might be responsible for low birth weight [103]. Unfortunately, there are no specific data for quadruplets and quintuplets.

A low Apgar score at birth is a common concern for neonatologists when a high-order pregnancy ends. Chibber in 2003 [102] highlighted the differences between triplet and higher pregnancies when the Apgar scores of the first and fifth minute were compared. The mean first-minute Apgar score for triplets was 7.8, while for quadruplets and quintuplets was only 6.2 (p < 0.01). When compared the five-minute Apgar score, this was 8.8 for triplets and 7.2 for quadruplets and quintuplets (p < 0.05). Skrablin et al. in 2000 [99] also observed statistical significances in their study, with the mean first-minute Apgar score for triplets to be 6.4 and for quadruplets-quintuplets 4.9 (p = 0.003) and the five-minute Apgar score to be 7.6 for triplets and 6 for quadruplets and quintuplets (p = 0.01).

There are also some rare complications which have been reported in high-order pregnancies, but due to the limited number of cases, no guidelines are available. Fetofetal transfusion has been reported in quadruplet pregnancies [104–106] as well as quadruplet pregnancies with conjoined twins [107, 108]. Another complication that has been described in a quadruplet pregnancy was the rupture of an unscarred uterus, raising the debate of the ideal delivery time for a high-order pregnancy [109]. High-order pregnancies have significant higher rates of peripartum hysterectomy compared to singleton pregnancies [110], although the data from quadruplet and quintuplet pregnancies are limited.
