**6. Multifetal pregnancy reduction**

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.

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

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

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

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,

but there no studies estimating the exact daily requirements [91].

was administered more than 14 days before [98].

circulation.

168 Multiple Pregnancy - New Challenges

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 with more than four fetuses to twins holds the best outcome. When the median gestational age at delivery was compared, this was higher for >4 fetuses reduced to twins rather than triplets (36 vs. 31 weeks respectively) and for quadruplets reduced to singletons rather than twins (38 vs. 36 weeks respectively). Evans in 2014 [66] showed a 25% decrement of fetal loss when quadruplet pregnancies were reduced to either twins or singletons. In the same line, when quintuplets were reduced to twins, the risk of fetal loss was decreased by 50%.

obstetric complications. When he compared the outcomes of reduced twins between the 10th and 11th week of gestation from triplet or quadruplet pregnancies, there were still no significant differences between the two groups. Wang in 2007 [126] studied 37 multifetal pregnancies reduced between the 12th + 1 and 25th week of gestation. He concluded that the incidence of preeclampsia is decreased after reduction. Boulot in 1993 [124], from a series of 61 multifetal pregnancies, concluded that the rate of miscarriage is lower when the aim of the reduction is twins rather than singletons. However, he found that the miscarriage rate was significantly lower when one fetus was reduced compared to 2 fetuses (6 vs. 24% respectively, p < 0.05). In another study by Timor-Tritsch in 2004 [127], the total pregnancy loss (at less than 24 weeks) for reduced quadruplets was at 1.8% (2.4% for the transabdominal route and 0% for the transvaginal route, p = 0.56). In the same study, the total pregnancy loss (at less than 24 weeks) for reduced quintuplets was at 14.3% (15.4% for the transabdominal route and 12.5% for the transvaginal route, p = 0.65). Multiple studies have concluded that the birth weight, gestational age at delivery, and perinatal mortality rate were directly correlated with the final number of fetuses [112, 128, 129]. Reductions of more than one fetus can be done in one session; however, when 5 or more fetuses need to be reduced to a singleton, two sessions seem to have better results than one, with 1 week

Quadruplets and Quintuplets

171

http://dx.doi.org/10.5772/intechopen.80338

Another point to consider when counseling a couple about fetal reduction is the possibility of one of the remaining fetuses to develop intrauterine growth restriction. There is evidence that fetal reduction is not associated with an increased risk of intrauterine growth restriction, unless it is performed on a high-order pregnancy [130]. Depp et al. in 1996 [131] have shown that when quadruplet and higher order pregnancies were reduced to twins the incidence of one or more IUGR among fetuses was greater compared to non-reduced twins. The frequency of discordance was directly linked to the pre-reduction fetal number. The frequency in the non-reduced twin cohort was at 16.3%, and the rate of discordance for quadruplets reduced to twins was at 26.1%,while for higher order reductions reduced to

When discussing with a couple about the risks of multifetal pregnancy and the option for fetal reduction, the psychological strain needs to be addressed and properly managed. The first reaction of a couple when a multiple pregnancy is diagnosed is generally favorable, although parents need to be counseled about the risks of a multifetal pregnancy. A proposed fetal reduction can cause anxiety to the couple, but eventually the majority of patients accept to abort some fetuses in order to preserve the lives of the others [132]. Specifically, when quadruplets or more fetuses are involved, couples are more inclined to go through a reduction procedure [133], and in some cases, they consider reduction as mandatory [121], although

The delivery of high-order pregnancies is challenging for the mother, the obstetricians, and pediatricians. Malpresentations are common, while the babies often require intensive care and special treatment, considering that more than 90% of high-order pregnancies are born

interval between the sessions [66].

ethical issues may always be a concern.

**7. Delivery of a quadruplet or quintuplet pregnancy**

twins was at 34.2%.

Fetal reduction can be done either transabdominally or transvaginally. When the transabdominal approach is used, the proposed time frame is between the 10th and 16th week of gestation, although the optimal timing is often arbitrary (Davis in 2014 [113] cited four different time frames suggested by four different researchers). Fetal reduction using the transvaginal approach can be performed earlier in the pregnancy when the placenta and the embryo are smaller. There is some skepticism concerning the transvaginal approach and the possibility of introducing vaginal bacteria [114]. Therefore, each center follows the practice they are more experienced in, since it has been shown to affect significantly pregnancy outcomes in terms of fetal loss and prematurity. Evans et al. in 2001 [115] studied the evolution of pregnancy outcomes across time: before 1991, from 1991 to 1994, and after 1994. Loss rates decreased from 13.2 to 9.7 to 6.4%, respectively. More specifically, loss rates for quadruplets reduced to twins were 13% before 1994 and only 6.6% thereafter, although it is difficult to identify whether experience, better ultrasonography techniques, or both played the most important role.

Fetal reduction is usually done by directly injecting KCL as a cardiotoxic agent, although aspiration of the embryonic parts has also been used [116]. Another reduction method used is thermocoagulation [117], either bipolar cord coagulation or radiofrequency ablation with similar results [118, 119]. Ligation of the cord as well as suture and compression of the cord on the uterine wall have also been used for fetal reduction [120].

First trimester reduction is a relatively simple and safe procedure with good results [121]. Nevertheless, many authors propose to perform fetal reduction in the second trimester after prenatal screening and possible detection of fetal abnormalities. Geva et al. in 2000 [122] published a series of 38 multifetal reduction procedures in the second trimester compared to 70 fetal reduction procedures in the first trimester. He included four quadruplet gestations in the first group and 18 in the second. The mean gestational age for quadruplets reduced to twins in the second trimester was higher compared to quadruplets reduced to twins in the first trimester (36.7 ± 1.2 vs. 33.6 ± 3.9 weeks respectively, p = 0.01). Accordingly, the mean birth weight of quadruplets reduced to twins in the second trimester was higher compared to the mean birth weight of quadruplets reduced to twins in the first trimester (2111 ± 3089 g vs. 1762 ± 503 g respectively) (statistically significant). When all pregnancy complications were compared, no statistically significant difference was found between the two groups, except for premature labor (p = 0.046). The authors concluded that when the second trimester is chosen for reduction, detection of fetal abnormalities and selection of an affected fetus can improve the outcome to similar results as for a first trimester reduction. This observation motivated several authors to propose the 15th–16th week of pregnancy as the optimal moment for fetal reduction [113].

Fetal reduction has shown to be a valuable option for high-order pregnancies (≥4) [123, 124]. Antsaklis et al. in 1999 [125] compared the outcomes of reduced twins (from quadruplets and triplets) to unreduced twins. There was no difference in regard to perinatal or obstetric complications. When he compared the outcomes of reduced twins between the 10th and 11th week of gestation from triplet or quadruplet pregnancies, there were still no significant differences between the two groups. Wang in 2007 [126] studied 37 multifetal pregnancies reduced between the 12th + 1 and 25th week of gestation. He concluded that the incidence of preeclampsia is decreased after reduction. Boulot in 1993 [124], from a series of 61 multifetal pregnancies, concluded that the rate of miscarriage is lower when the aim of the reduction is twins rather than singletons. However, he found that the miscarriage rate was significantly lower when one fetus was reduced compared to 2 fetuses (6 vs. 24% respectively, p < 0.05). In another study by Timor-Tritsch in 2004 [127], the total pregnancy loss (at less than 24 weeks) for reduced quadruplets was at 1.8% (2.4% for the transabdominal route and 0% for the transvaginal route, p = 0.56). In the same study, the total pregnancy loss (at less than 24 weeks) for reduced quintuplets was at 14.3% (15.4% for the transabdominal route and 12.5% for the transvaginal route, p = 0.65). Multiple studies have concluded that the birth weight, gestational age at delivery, and perinatal mortality rate were directly correlated with the final number of fetuses [112, 128, 129]. Reductions of more than one fetus can be done in one session; however, when 5 or more fetuses need to be reduced to a singleton, two sessions seem to have better results than one, with 1 week interval between the sessions [66].

with more than four fetuses to twins holds the best outcome. When the median gestational age at delivery was compared, this was higher for >4 fetuses reduced to twins rather than triplets (36 vs. 31 weeks respectively) and for quadruplets reduced to singletons rather than twins (38 vs. 36 weeks respectively). Evans in 2014 [66] showed a 25% decrement of fetal loss when quadruplet pregnancies were reduced to either twins or singletons. In the same line,

Fetal reduction can be done either transabdominally or transvaginally. When the transabdominal approach is used, the proposed time frame is between the 10th and 16th week of gestation, although the optimal timing is often arbitrary (Davis in 2014 [113] cited four different time frames suggested by four different researchers). Fetal reduction using the transvaginal approach can be performed earlier in the pregnancy when the placenta and the embryo are smaller. There is some skepticism concerning the transvaginal approach and the possibility of introducing vaginal bacteria [114]. Therefore, each center follows the practice they are more experienced in, since it has been shown to affect significantly pregnancy outcomes in terms of fetal loss and prematurity. Evans et al. in 2001 [115] studied the evolution of pregnancy outcomes across time: before 1991, from 1991 to 1994, and after 1994. Loss rates decreased from 13.2 to 9.7 to 6.4%, respectively. More specifically, loss rates for quadruplets reduced to twins were 13% before 1994 and only 6.6% thereafter, although it is difficult to identify whether experience, better ultrasonography techniques, or both played the most important role.

Fetal reduction is usually done by directly injecting KCL as a cardiotoxic agent, although aspiration of the embryonic parts has also been used [116]. Another reduction method used is thermocoagulation [117], either bipolar cord coagulation or radiofrequency ablation with similar results [118, 119]. Ligation of the cord as well as suture and compression of the cord

First trimester reduction is a relatively simple and safe procedure with good results [121]. Nevertheless, many authors propose to perform fetal reduction in the second trimester after prenatal screening and possible detection of fetal abnormalities. Geva et al. in 2000 [122] published a series of 38 multifetal reduction procedures in the second trimester compared to 70 fetal reduction procedures in the first trimester. He included four quadruplet gestations in the first group and 18 in the second. The mean gestational age for quadruplets reduced to twins in the second trimester was higher compared to quadruplets reduced to twins in the first trimester (36.7 ± 1.2 vs. 33.6 ± 3.9 weeks respectively, p = 0.01). Accordingly, the mean birth weight of quadruplets reduced to twins in the second trimester was higher compared to the mean birth weight of quadruplets reduced to twins in the first trimester (2111 ± 3089 g vs. 1762 ± 503 g respectively) (statistically significant). When all pregnancy complications were compared, no statistically significant difference was found between the two groups, except for premature labor (p = 0.046). The authors concluded that when the second trimester is chosen for reduction, detection of fetal abnormalities and selection of an affected fetus can improve the outcome to similar results as for a first trimester reduction. This observation motivated several authors to propose the 15th–16th week of pregnancy as the optimal moment for fetal reduction [113].

Fetal reduction has shown to be a valuable option for high-order pregnancies (≥4) [123, 124]. Antsaklis et al. in 1999 [125] compared the outcomes of reduced twins (from quadruplets and triplets) to unreduced twins. There was no difference in regard to perinatal or

on the uterine wall have also been used for fetal reduction [120].

when quintuplets were reduced to twins, the risk of fetal loss was decreased by 50%.

170 Multiple Pregnancy - New Challenges

Another point to consider when counseling a couple about fetal reduction is the possibility of one of the remaining fetuses to develop intrauterine growth restriction. There is evidence that fetal reduction is not associated with an increased risk of intrauterine growth restriction, unless it is performed on a high-order pregnancy [130]. Depp et al. in 1996 [131] have shown that when quadruplet and higher order pregnancies were reduced to twins the incidence of one or more IUGR among fetuses was greater compared to non-reduced twins. The frequency of discordance was directly linked to the pre-reduction fetal number. The frequency in the non-reduced twin cohort was at 16.3%, and the rate of discordance for quadruplets reduced to twins was at 26.1%,while for higher order reductions reduced to twins was at 34.2%.

When discussing with a couple about the risks of multifetal pregnancy and the option for fetal reduction, the psychological strain needs to be addressed and properly managed. The first reaction of a couple when a multiple pregnancy is diagnosed is generally favorable, although parents need to be counseled about the risks of a multifetal pregnancy. A proposed fetal reduction can cause anxiety to the couple, but eventually the majority of patients accept to abort some fetuses in order to preserve the lives of the others [132]. Specifically, when quadruplets or more fetuses are involved, couples are more inclined to go through a reduction procedure [133], and in some cases, they consider reduction as mandatory [121], although ethical issues may always be a concern.
