**5.3. Gestational diabetes**

progesterone, and sex steroids compared with singleton pregnancies could play an important

The effect of maternal age also influences the risk of preterm birth. Some studies suggest that even after adjusting for cofounders such as hypertension, diabetes, race, and mode of conception, maternal age over 40 years is an independent risk factor for preterm delivery [47, 51].

The widespread availability of reproductive technology has increased the percentage of multiple gestations and preterm delivery as an aftermath. Therefore, it is our duty to inform women of the risk of this type of pregnancies and enforce the use of the different strategies in

As we have seen before, mean BP decreases during the first and second trimesters secondary to the reduction of peripheral resistances and starts to increase reaching values similar to

Preeclampsia (PE) is a hypertensive disorder that appears during pregnancy. PE is a major obstetric complication that causes 15–20% of maternal mortality worldwide, especially in developing countries [52]. It is characterised by the presence of high BP (> 140/90 mmHg) and proteinuria (> 300 mg/dL) beyond 20 weeks of pregnancy. The finding of higher values of BP before this stage of pregnancy is considered chronic hypertension, which can also worsen in the second half of pregnancy, with what we call superimposed preeclampsia. The physiopa-

In the last decades, several aetiologies have been described. Some authors suggest that it appears secondary to an abnormal vascular response of the uterine blood vessels to trophoblast invasion, causing platelet aggregation and endothelial dysfunction [52–54]. The increase of BP during pregnancy can also have an effect on the foetus, developing complications such as low birth weight, oligoamnios, and intrauterine growth restriction [54, 55]. In addition, preeclampsia is considered severe when it affects multiple organs, finally producing pulmonary oedema, renal failure, seizures, thrombocytopenia, elevation of liver enzymes, and dis-

The rate of preeclampsia ranges between 2 and 7% in healthy nulliparous women [54, 56, 57]. These rates increase to 14% in twin pregnancies [58]. Preeclampsia is regarded as typical of the first pregnancy. In spite of this, the risk of developing preeclampsia in subsequent pregnancies

Numerous studies proposed several risk factors to classify a specific group of women who are at a high risk of developing preeclampsia, including nulliparity, older age, chronic hypertension, and diabetes mellitus [59–61]. Other studies indicate that, after adjusting for other cofounders, women of advanced maternal age are 1.5 times more likely to have preeclampsia compared to those under 35 years of age [62]. Multiple pregnancy is a moderate risk factor for the development of pre-eclampsia during pregnancy. Women with multiple pregnancy, who have any of the other moderate risk factors for pre-eclampsia (first pregnancy, age 40 years

role in the physiopathology of the syndrome [49, 50].

order to achieve singleton pregnancy.

non-pregnant women in the third trimester.

seminated intravascular coagulation [54].

raises till 18% [58].

thology of this multisystemic disorder still remains unknown.

**5.2. Preeclampsia**

106 Multiple Pregnancy - New Challenges

Gestational diabetes mellitus (GDM) is a diabetic state diagnosed for the first time in pregnancy. It is one of the most common metabolic disorders in pregnancy. GDM complicates 3–5% of pregnancies and it is considered a risk factor for adverse perinatal outcomes, such as macrosomia, shoulder dystocia, cerebral palsy, and foetal death [64–66]. It is defined as basal glucose ≥126 mg/dl (7.0 mmol/l), HbA1c ≥ 6.5% (47.5 mmol/mol), or glucose levels ≥200 mg/dl (11.1 mmol/l) at any time of the day or screen positive for any of the GDM tests available [67].

Diabetes predisposes pregnant women to suffer urine infections, hypertensive disorders, and prematurity. It is well known that pregestational diabetes can cause foetal malformations, intrauterine growth restriction, stillbirth, and congenital heart disease probably due to vascular alterations in mothers. Both gestational and pregestational diabetes have effects on the foetus secondary to hyperinsulinemia, such as macrosomia, polyhydramnios, and foetal lung immaturity that may cause foetal neonatal distress.

Women of advanced maternal age are at a higher risk of developing GDM [68]. Twin pregnancies have also been related to GDM [69]. The development of GDM usually indicates a reduced pancreatic reserve in the pregnant mother and is a marker of pre-diabetes, putting them at a higher risk of developing diabetes mellitus type 2 in the future. It is essential to highlight the importance of adopting healthy habits during pregnancy in order to avoid consequences for the future health of both the mother and the baby.

Gestational diabetes in twins is also associated with an increased risk of hypertensive disorders, macrosomia, and preterm birth, but it reduces the risk for low birth weight [70]. Furthermore, it has been suggested that gestational diabetes could potentially benefit twin pregnancies, as low 5-min Apgar score and neonatal death are reduced in twins compared to singletons when this maternal complication is present, maybe due to the increased birth weight of the twin pairs [71, 72]. However, growth in the twin pair tends to be asymmetric when GDM or glucose intolerance is present [73].

Early diagnosis and treatment are essential in order to avoid complications during pregnancy. Nowadays, guidelines from different countries recommend the screening for gestational diabetes in women with risk factors such as previous history of gestational diabetes, obesity (body mass index over 30 kg/m2 ), and previous delivery of a macrosomic baby [74–76]. Some of them support the use of a universal screening test in the second trimester and also in the first trimester in every woman over the age of 35 [77]. However, the increase in maternal age over the last years implies offering this diagnostic test to a very high percentage of the pregnant population [70]. Given the importance of early treatment, all twin pregnancies, as well as in the case of advanced maternal age, first trimester screening should be considered, although there is no international agreement [78].

**5.6. Venous thrombosis**

**5.7. Stillbirth**

educational levels.

**maternal age**

**6.1. Delivery mode and time of delivery**

increased risk of chromosomal abnormalities [80].

The incidence of deep venous thrombosis is increased three times during pregnancy. Pulmonary embolism may occur in 1 in every 1000 pregnancies and represents the leading non-obstetrical cause of maternal death [88]. Both age older than 35 years and multiple pregnancy are listed as risk factors for venous thromboembolism. If we consider that the presence of thrombophilia is more common in women undergoing IVF and that deep venous thrombosis is also more common in these women [89, 90], we could conclude that women of advanced maternal age and carrying a multiple pregnancy definitely represent a high-risk group for venous thromboembolism. Under any other risk factor, thromboprophylaxis should be considered carefully.

Multiple Pregnancy in Women of Advanced Reproductive Age

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Advanced maternal age has been associated with an increased incidence of stillbirth [91]. A mechanism under this increase is placental dysfunction, which accounts for around 65% of stillbirths, and it has been observed more frequently in mice models and humans with age. Placentas from older mothers (35–39 and ≥ 40 years old) are less efficient in the sense that foetal/placenta weight ratio was lower than placentas from controls under 30 years old. They seem to be bigger in size and display mechanisms to ameliorate function, like increased relaxation of myometrium arteries and increased amino acid transport, but this does not correlate with a higher birth weight in the offspring. The hypothesis is that an increased size could be an adaptive mechanism trying to make up for placental dysfunction [92]. It has also been suggested that the greater contribution to stillbirth in older mothers could arise from their

Twin pregnancies are also high risk for stillbirth and neonatal death, increasing thirteenfold in monochorionic and fivefold in dichorionic pregnancies compared to singletons [93, 94].

Although this is not under the scope of this chapter, advanced paternal age has also been associated with stillbirth and death of the child before 5 years of age [95, 96]. The risk might be linked to a higher rate of sperm chromatin or chromosomal aberrations. Interestingly, this association dissolves when adjusting for paternal education level, when the association between advanced maternal age and the risk of stillbirth is independent of socioeconomic and

**6. Delivery and post-partum care in twin pregnancies in advanced** 

Advanced maternal age is associated with a high frequency of caesarean delivery. Many factors participate in this. For instances, a more frequent prolonged labour due to worse myometrial function and decreased flexibility of pelvic joints [97], increased frequency of large babies
