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Gestational trophoblastic disease

Gestational trophoblastic disease — usually referred to as a mole — is a very rare abnormality of pregnancy in the reproductive female that involves abnormal trophoblast proliferation. It is the result of a (purely chance) genetic error during the fertilization process that in turn causes the growth of abnormal tissue (which is not an embryo) within the uterus. The growth of this material is disproportionately rapid when compared to normal fetal growth. more...

Gardner's syndrome
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The two types of hydatidiform molar pregnancy are complete and partial.

Complete moles are the most common type of moles, and are when the mass of tissue is completely made up of abnormal cells that would have become the placenta in a normal pregnancy. There is no fetus and nothing can be found at the time of the first scan. Complete moles often have a diploid karyotype 46,XX due to fertilization of an empty ovum by a single sperm followed by replication of the haploid chromosome. On ultrasound, a complete mole has a "snow storm pattern", and the uterus is large for dates. Microscopically, there is edema of most villi, which gives the appearance of a large and random collection of grape-like cell clusters.

In a partial mole, the mass may contain both these abnormal cells and often a fetus that has severe defects. In this case, the fetus will be consumed by the growing abnormal mass very quickly. Partial moles have a triploid karyotype (69,XXX or 69,XXY) due to the fertilization of a single egg with two sperm. They also have a lower volume of tissue, and smaller hydropic villi (grape-like), as well as normal villi mixed in with the abnormal. Rarely, partial moles can progress to gestational choriocarcinoma.


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Twin Pregnancies: Eating for Three? Maternal Nutrition Update
From Nutrition Reviews, 9/1/05 by Roselló-Soberón, María E

The incidence of multifetal pregnancies has increased, mainly because of assisted reproduction treatments. This trend is reflected in increased maternal and neonatal morbidity and mortality. While the optimum maternal nutrition and weight gain patterns for singleton pregnancies is well documented, there is a paucity of information for twin pregnancies. Although it is assumed that optimum nutritional requirements and weight gains would be greater for twin than for singleton gestations, research is needed to establish the optima. This article is a collation of available recommendations for maternal nutrition and weight gain patterns in twin pregnancies.

Key words: twin pregnancy, prematurity, low birth weight, maternal weight gain, nutritional requirements

© 2005 International Life Sciences Institute

doi: 10.1301/nr.2005.sept.295-302


A twin pregnancy is defined as one in which more than one embryo is present in the uterus. There are two kinds of twin pregnancies. Monozygotic twins occur when one ovum is impregnated by one spermatozoid and the egg divides thereafter, forming two embryos. The embryos have identical chromosomes and the same sex. There are three uterine environments in which identical twins may develop: one placenta and two amniotic sacs (monochorial-biamniotic), one placenta and one amniotic sac (monochorial-monoamniotic), or two placentas and two amniotic sacs (bichorial-biamniotic).1 Dizygotic twins, which are not identical, occur when two ova are impregnated by two spermatozoids. They have different chromosomes, do not look alike, and are not necessarily of the same sex. Each embryo has its own amniotic sac and placenta.1

Multifetal pregnancies in the United States increased by 77% from 1980 to 2001,2,3 largely because of assisted reproduction treatments. The number of women with multiple pregnancies admitted to the Instituto Nacional de Perinatologia in Mexico increased from 140 in 1999 to 217 in 2003.4 Unfortunately, the increased rate of multiple pregnancies has resulted in a higher prevalence of low-birth weight (

Given this situation, it is clear that efforts need to be directed toward decreasing perinatal and maternal risk factors. This article summarizes available information on the risks associated with twin pregnancies and the effect of nutritional status on the outcome of pregnancy in women carrying twins.


Fertility-Enhancing Therapies

Fertility drugs, artificial insemination, and assisted reproductive technology are the most common factors responsible for the rising rate of multiple births. Recent reports by the Centers for Disease Control and Prevention (CDC) indicate that assisted reproductive technology was responsible for approximately 40% of the increase in triplet and higher-order multiple births that has occurred in the United States since 1996.3,5,6


Twin pregnancies are more frequent among non-Hispanic women. In the United States, two-thirds of all twin births from 1996 to 2000 were to non-Hispanic white women. The ratio of single to twin births over this period was 3009:1 for non-Hispanic white women, 3123:8 for non-Hispanic black women, and 1868:4 for Mexicans. The frequency of twin births for all Asian ethnic groups was also lower than that for non-Hispanic white women and non-Hispanic black women.2,3


Multiple births occur more frequently among older mothers, even in the absence of fertility therapy. Age alone is believed to account for 25% to 30% of the observed increase in multiple pregnancies.2,3 Women are now postponing pregnancies because of educational and employment opportunities. In the United States, one-fourth to one-third of the increase in multiple gestations is due to the postponement of childbearing.2,3


The probability of a twin pregnancy is higher if one of the parents, particularly the mother, is a twin.7

Body Mass Index

A body mass index (BMI) lower than 20 is associated with a lower risk of twin pregnancy (odds ratio = 0.71; 95% confidence interval = 0.54-0.92), while a BMI of 30 or more is associated with a higher risk (odds ratio = 1.39; 95% confidence interval = 1.05-1.84). This may partly explain the increase in the number of twin pregnancies in the United States.6-8


The maternal adaptation to a multiple pregnancy is an exaggeration of the response to a singleton pregnancy, with increased production of steroid and protein hormones due to an increase in placental mass.9,10 Progesterone and human placental lactogen secretion are higher in twin than in singleton pregnancies. These hormones affect glucose metabolism and, theoretically, there is an increased risk of insulin resistance and gestational diabetes mellitus.11,12 Impaired glucose tolerance in women with twin pregnancies is a positive predictor for an increased risk of pregnancy-induced hypertension.12

As with singleton pregnancies, many physical and biochemical changes occur in twin pregnancies. There is a reduction in peripheral resistance and blood volume increases. By week 20 of gestation, the number of erythrocytes in the blood of women with twins is 25% greater than that of women with singletons. The blood volume of women with twins increases by 50% to 60% by the end of pregnancy, but only by 40% to 50% in women with singletons. This results in a decrease of blood concentrations of hemoglobin, glucose, albumin, protein, and water-soluble vitamins. The decline in serum albumin levels contributes to the accumulation of extracellular water that occurs during pregnancy. In contrast, the serum concentrations of fat-soluble vitamins, triglycerides, cholesterol, and free fatty acids increase.11,13

The uterine volume is similar in singleton and twin pregnancies at the beginning of the second trimester, but in twin pregnancies it doubles relative to that of singletons by week 18 of gestation; by week 25 of gestation it is equivalent to that of a singleton uterus at full term.9

The placenta is the principal site of production for several hormones that regulate fetal growth and the development of maternal support tissues, and is the medium through which nutrients, oxygen, and waste products are exchanged. Any damage to or inadequacy of the placenta compromises its ability to nourish the fetus. Placental size and the number of placental cells are 15% to 20% below normal in infants experiencing intrauterine growth failure. A small placenta has a relatively smaller surface area of placental peripheral villi, which are responsible for the transfer of nutrients to the fetus. The placentas in twin pregnancies are much heavier (69%) and age within a shorter time than those of singleton pregnancies. Placental complications such as premature rupture of membranes and placental abruptio are also more frequent in multiple pregnancies.1


It is clear that certain diseases and disorders occur more frequently with multiple pregnancies than with singleton pregnancies. Multiple pregnancies are high risk, and may be complicated by prematurity, low birth weight, preeclampsia, anemia, postpartum hemorrhage, intrauterine growth restriction, neonatal morbidity, and high perinatal, neonatal, and infant mortality.9,14

Maternal Morbidity


Hypertension is the main maternal complication associated with multiple pregnancies. One theory suggests that maternal recognition of fetal and trophoblastic tissues as a foreign antigen is related to a higher risk for preeclampsia. This hypothesis is concordant with the contention that the incidence of preeclampsia differs between dichorionic and monochorionic twin pregnancies. This implies that women carrying monozygotic twins should have a lower risk of preeclampsia than those with dizygotic twins, but the results of some studies do not support this concept.15,16 The ratio of risk of gestational hypertension, preeclampsia, and eclampsia for twin compared with singleton gestations is 1.2:2.7, 2.8:4.4, and 3.4:5.1, respectively.9,15-18 One recent study suggested that an association may exist between oxidative stress and preeclampsia in cases in which the consumption of antioxidants is low.19


Women carrying twins have a greater risk of developing anemia because 1.8 times more iron is needed for multiple pregnancies.20 One study reported a 4-fold increase in the frequency of maternal anemia during twin pregnancies.21 It has been reported that there is a negative association between maternal hemoglobin levels during the first and second trimesters and parity.21 Despite this, a recent study concluded that the level at which anemia in multiple pregnancies is considered aberrant should differ from that in singleton pregnancies.22

Preterm Labor

Some studies have hypothesized that fetal hormones play a role in the induction of preterm birth; however, the effect of fetal hormones can be compensated for or masked by other factors in the complex chain of events leading to labor and preterm birth.23,24 Tan et al.23,24 found that the presence of twin male fetuses during gestation was associated with a higher risk of preterm birth, but concluded that a larger sample of experimental subjects is needed to verify these results. Preterm labor is the most serious complication of multiple pregnancies. Recent studies have shown that premature labor is seven times more frequent in multiple than in singleton pregnancies.25

It has been proposed that availability of vitamin C is a risk factor for premature rupture of chorioamniotic membranes and therefore prematurity in singleton pregnancies. As ascorbic acid is involved in the synthesis and degradation of collagen, of which chorioamniotic membranes are composed, it has been hypothesized that the recommended vitamin C intake should be increased for multiple pregnancies to sustain the integrity of the larger quantities of chorioamniotic tissue.26

Maternal Mortality

The incidence of maternal mortality associated with twin gestations is unknown. The combination of physiologic changes and perinatal pathologies, which are more common in twin gestations, certainly increases the risk of maternal death. This is a sound reason for including twin pregnancies as a separate category when compiling statistics of pregnancy-related maternal deaths.

Perinatal and Neonatal Morbidity

Because of the higher incidence of growth retardation and premature births, infants of multiple births have a higher risk of neonatal morbidity and subsequent mental and physical disability.9,14 One study reported that admittance to the neonatal intensive care unit was necessary for 19% to 26% of twins, and that they spent 12 to 17.8 days in the unit.9


Twin pregnancies are associated with a higher risk of preterm delivery than singleton pregnancies (48% compared with 11% before week 37 of gestation and 11% compared with 2% before week 32 of gestation).14 In the United States, multiple pregnancies account for 13% of all preterm births (

Low Birth Weight

Low and very low birth weight is much more common in twins than in singletons (50% compared with 6% under 2500 g; 10% compared with 1% under 1500 g).14 In the United States, twins account for 21% of all low-birth-weight babies and 25% of all very-low-birth-weight babies. The average birth weight and corresponding gestational age is 3350 g and 38.9 weeks, respectively, for singletons and 2361 g and 35.4 weeks, respectively, for twins.2

Efforts have been made to reduce the incidence of premature birth and low birth weight in twin pregnancies. A recent study has shown a significant correlation between leptin levels in amniotic fluid, gestational age at delivery (r = 0.71; P

In a study performed at the Instituto Nacional de Perinatología in México City, it was observed that primiparous adolescents pregnant with twins, who themselves had a low weight-for-height and gestational age at birth, were at higher risk of giving birth to low-birth-weight infants.14 The height, weight, and gestational age at birth decreases as the number of fetuses increases.28

Mental and Physical Disabilities

Children from multiple births usually have more developmental problems and learning deficits than those from singleton births.2,9,29 In the United States, women with twin pregnancies have a 12-fold greater risk of giving birth to a child with cerebral palsy than those with singleton pregnancies.2 Among multiple pregnancies, preeclampsia, premature rupture of membranes, and preterm delivery are associated with an increased risk of delivering children with mental and physical disabilities.2


Several studies have confirmed that maternal nutrition may play an important role in the outcome of twin gestations. Maternal weight prior to conception, weight and weight gain during pregnancy, length of gestation, and smoking are important factors influencing the outcome of twin gestations.14,20,29,30

Twins with high birth weights exhibit lower morbidity and mortality than those with low birth weights. Some studies have suggested that the optimum outcome for a twin pregnancy is a birth weight of 2500 to 2800 g at 35 to 38 weeks of gestation.30

Maternal Weight Prior to Gestation

Reliable information is available on the relationship between pre-pregnancy weight and the outcome of twin gestations. Some studies have reported that the ratio between weight and height before pregnancy does not affect the outcome of twin gestations when weight gain is 18.16 to 20.43 kg.28,31

Brown and Schloesser29 studied the birth records of approximately 2000 twins and found that very obese women were more than twice as likely to deliver twins at term than underweight women. They also found that the incidence of low birth weights declined from 32% in underweight women to 20% among obese women (P > 0.005).10,29 These findings are similar to the results of a study of 132 twin pregnancies conducted by Houlton et al.,10 in which obese women had a reduced risk of growth-retarded children.

Recent studies concluded that optimal rates of fetal growth and birth weights in twins (2850 to 2950 g at 36 weeks of gestation) depend on the rate of maternal weight gain relative to the stage of gestation in which it takes place and maternal pregravid BMI status32,33 (Table 1).

Maternal Weight Gain

The total amount and pattern of weight gain in multiple pregnancies differs from that in singleton pregnancies. It has been reported that weight gain begins earlier (as early as 8 weeks of gestation) and proceeds at a faster rate in twin than in singleton pregnancies.9 The National Academy of Sciences suggests that women carrying twins should aim for a weekly weight gain of 0.75 kg during the second and third trimesters of gestation; this is equivalent to a total weight gain of 16 to 20.5 kg.10,31

Campbell et al.34 reported that the mean weight gain at 36 weeks of gestation was 14.6 kg for twin pregnancies and 11.1 kg for singleton pregnancies. Recent studies have shown that total weight gain during pregnancy is strongly associated with infant outcome. A total weight gain of 20 kg is usually considered optimum for a favorable fetal outcome in twin gestations.9,31 This supports the idea that women carrying twins who gain adequate weight have a decreased risk of delivering low-birth-weight infants. Pederson et al.31 reported that women who gained 20 kg by 37 weeks of gestation had infants with adequate birth weight and better Apgar grades than women who gained 18.6 kg.

The study at the Instituto Nacional de Perinatología14 showed that women who had a weight-to-height ratio higher than 115% at any gestational stage had a 2.5-fold less risk of delivering infants with a low birth weight. Other studies have suggested a total weight gain of 18.2 to 20.5 kg by 37 weeks of gestation or a weight gain of 10.9 kg by 24 weeks as appropriate norms.9,10,35,36

Maternal Weight Gain Pattern

The pattern of maternal weight gain is associated with birth weight and length of gestation. In general, women carrying twins gain more weight at the beginning of pregnancy than do women with singleton pregnancies.9 A low early gain (under 385 g/week before 24 weeks of pregnancy) is associated with poor intrauterine growth and higher morbidity among twins, even when a higher gain is achieved after this stage. This is because maternal nutrient reserves deposited in early pregnancy are utilized in late pregnancy for placental growth.9,32,35,37,38

Luke et al.38 have shown that low weight gain is consistently associated with reduced twin birth weights. Early- and mid-gestation weight gains seem to exert a greater effect on twin birth weights and the development of preeclampsia in twin gestations.

Deposition of body fat during pregnancy may influence the complex hormonal mechanisms that mediate intrauterine growth. The relationship between poor weight gain, inadequate intrauterine growth, and weight gain in early pregnancy or between 28 and 32 weeks of gestation may reflect the hormonal role of the body fat on birth weight. Some studies of singleton pregnancies have reported that body fat changes correlate best with birth weights and duration of pregnancy.35,37

The maturation process of the placenta is accelerated in twin gestations. Consequently, the period defined as "term" for singleton infants may well equate to "post term" for twins. For this reason, the ideal length of pregnancy should be defined as that which is associated with the lowest morbidity and the maximum intrauterine growth relative to gestational age.35 Luke et al.35 reported that approximately 70% of ideal twin pregnancies occurred between 35 and 38 weeks of gestation. Intrauterine growth of singletons and twins diverged at 30 weeks and was significantly different by 35 weeks. From 39 weeks on, the weight of the larger of a twin pair deviated significantly from the mean for singletons, and there was an increased risk of growth retardation for both the smaller and larger of the twin pair. These findings suggest that intrauterine growth of twins stops after 39 weeks.35


The health benefits of physical activity during pregnancy are well documented. The Centers for Disease Control and Prevention and the American College of Sports Medicine have recommended 30 minutes or more of moderately intensive physical activity on most, and preferably all, days of the week. The recommendation also promotes exercise for sedentary women and advises a medical evaluation before exercising for those with medical or obstetric complications. The latter could be interpreted to include women with multiple pregnancies. The 2002 Guidelines of the American College of Obstetricians and Gynecologists for exercise during pregnancy and the postpartum period contraindicate aerobic exercise during multiple pregnancies and for those at risk of premature labor.39-41

As mentioned previously, hypertension is the main maternal complication associated with multiple pregnancies. However, some studies suggest that regular prenatal exercise may prevent or delay the evolution of the disease. This is possibly because of the stimulation of placental growth and vascularity, reduction of oxidative stress, and reversal of maternal endothelial dysfunction that is induced by exercise.41,42 A number of studies have established that regular leisurely physical activity has no harmful effect on birth outcome and that it may even reduce the risk of low birth weight. In contrast, sedentary activities such as long periods of television viewing are related to an increased risk of preterm delivery.43-45


Nutrition during pregnancy plays an important role in the growth and development of the fetus and in the maintenance of maternal health. A twin pregnancy represents a state of increased nutritional requirement, resulting in a greater depletion of maternal nutritional reserves.


To our knowledge, no studies have been conducted on the energy requirements of women carrying twins. However, evidence of greater weight gain, larger tissue mass (blood, placenta, uterus, fetal weight), and elevated maternal energy expenditure during multiple pregnancies suggests that energy requirements are elevated.7,20 While it is not possible to make specific recommendations on energy requirements, women with twin pregnancies theoretically need double the 300 kcal needed for a singleton pregnancy.20 It is estimated that women with twin pregnancies need to consume 35,000 kcal more than women with singleton pregnancies to attain a weight gain of 20 kg. This represents 150 kcal per day more than that recommended for singleton pregnancies. The adequacy of energy intake for a twin pregnancy could be assessed by monitoring weight gain.7


Serum glucose concentration is lower during a twin pregnancy than during a singleton pregnancy because the change in carbohydrate metabolism that occurs during normal pregnancy is magnified in twin gestations. This indicates that there is a more rapid depletion of glycogen and fat deposits. Ketonuria is related to an increased risk of preterm delivery. This is possibly partially responsible for the greater incidence of preterm births during multiple gestations. Luke et al.1,38 found that dietary therapy in which 20% of energy intake is derived from protein, 40% from low-glycemic-index carbohydrates, and 40% from fat prevents fluctuations in blood glucose concentrations and provides additional calories.


The availability of amino acids is important for fetal growth. As the mass of proteinaceous tissues is increased in twin pregnancies, the need for protein is also increased. There is sufficient evidence to indicate that reduced maternal substrate availability has an adverse effect on placental size and potentiates growth retardation.46 Hytten and Leicht47 demonstrated that women store 925 g of protein during singleton pregnancies (400 g is deposited in the fetus, 100 g in the placenta, and 425 g in the mother).47 Theoretically, requirements would be satisfied by an increase of 10 g of protein per day of gestation for singleton pregnancies and 20 g per day for twin pregnancies, which is equivalent to an increase in food intake of 70 to 80 g per day of gestation.20


To our knowledge, there are no studies to giving recommended levels of total fat intake for twin pregnancies. It could be reasonable to recommend that no more than 30% of total energy intake should be derived from fat, considering that the intake of saturated fat should not exceed one-third of total fat intake and that monounsaturated fat intake should be greater than that of polyunsaturated fat.20

Brown et al.7 reported that the essential fatty acid requirements are increased in multifetal gestation. They also reported that several studies have found lower concentrations of essential fatty acids in women with multifetal pregnancy, and that this is associated with impaired vision and neural development in their progeny.7

Vitamins and Minerals

The precise requirement for vitamins and minerals in twin pregnancies is unknown. Iron requirements certainly increase in twin pregnancies because of an increase in red blood cell mass. The few studies that have evaluated iron status in women carrying twins have reported that hemoglobin concentrations during the first and second trimesters of gestation are lower, the rate of anemia is higher, and residual iron deficiency anemia is present in babies up to 6 months of age. Iron deficiency anemia during the second and third trimesters is associated with preterm delivery.1,22,38 Iron requirements have been estimated for multiple pregnancies based on fetal and placental needs and the maternal plasma volume expansion.20 This estimate indicates that women with twin pregnancies need 1.8-fold more iron than women with singleton pregnancies (Table 2).20 The US Institute of Medicine (IOM) recommends 30 mg of iron after the 12th week of gestation.10

Some studies have shown that calcium supplementation during pregnancy reduces the risk of preterm deliveries among high-risk women such as teenagers and women consuming low-calcium diets.48,49 Women have several mechanisms that compensate for the increase in calcium requirements during pregnancy. Okah et al.50 reported a greater bone resorption index during multiple gestations, a greater serum 25(OH) vitamin D concentration, and a lower 1,25(OH)2 vitamin D concentration in multiple pregnancies. This may be due to a greater consumption of vitamin D and minerals by women carrying more than one fetus.

The IOM recommends the same supplementation scheme of folic acid for women with twin pregnancies as for women with singleton pregnancies.51 Some studies suggest that periconceptional and postconceptional supplementation with high doses of folic acid and multivitamins are associated with a small increase in the incidence of twin pregnancies, but this hypothesis remains controversial.52-54

Newman et al.55 estimated vitamin C needs for twin pregnancies (150 mg/d) from dietetic recommendations for singleton pregnancies (70 mg/d).

The IOM recommends that women bearing more than one fetus be given a daily supplement that contains 15 mg zinc, 2 mg copper, 250 mg calcium, 2 mg vitamin B6, 300 µg folic acid, 50 mg vitamin C, 5 µg vitamin D, and 30 mg iron after the 12th week of gestation.7,10


Maternal nutrition is important for optimal fetal growth and development and for the maintenance of good maternal health. Dietary recommendations for women with singleton pregnancies are well established, but further research is needed to establish valid recommendations for women carrying more than one fetus. Several studies have linked good maternal nutrition and weight gain in twin pregnancies to positive outcomes such as a reduced incidence of low birth weights, morbidity, and mortality.


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3. Smulian JC, Ananth CV, Kinzler WL, Kontopoulos E, Vintzileos AM. Twin deliveries in the USA over three decades: an age-period-cohort analysis. Obstet Gynecol. 2004;104:278-285.

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María E. Roselló-Soberón, Laiza Fuentes-Chaparro, and Esther Casanueva, PhD

Ms. Roselló-Soberón and Fuentes-Chaparro are with the Departamento de Investigación en Nutrición, Instituto Nacional de Perinatología, Montes Urales, Mexico; Dr. Casanueva is with the Subdirección de Investigación en Salud Pública, Institute Nacional de Perinatología, México City, México.

Address for correspondence: María E. Roselló-Soberón, Institute Nacional de Perinatología, Montes Urales 800 México DF CP 11000; Phone: 55-20-99-00, ext. 120; Fax: 55-40-29-47; E-mail:

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