Obstetric Management of Multiple Gestation and Birth

Isaac Blickstein and Eric S. Shinwell

The human female is programmed by nature to mono-ovulate, to nurture one fetus, and to take care of one neonate at a time. This natural pattern results in the relatively rare birth of twins (about 1 per 80 to 100 births) and in the extremely rare occurrence of high-order multiple gestations. The rarity of high-order multiple gestations can be appreciated by the quasi-mathematical Hellin-Zellany rule for twins, triplets, and quadruplets.¹⁵ According to this rule, if the frequency of twins in a population is 1/N, the frequency of triplets would be 1/N², and that of quadruplets would be 1/N³.

The Hellin-Zellany relationship was found to be accurate as long as the population remained homogeneous, and natural procreation occurred. In the middle of the twentieth century, however, it became apparent that deviations from the rule occur mainly because of racial differences in the frequency of dizygotic twinning.

This ordinary circumstance did not change until the emergence of effective treatment of infertility. Thereafter it became clear that within an infinitely small fraction in human history, all we knew about natural multiples has been profoundly changed. Physician-made (iatrogenic) multiple gestations are now seen in most developed countries, with frequencies approaching 50% of twins and more than 75% of high-order multiple gestations. The contribution of infertility treatment can be appreciated from data of the Israel Neonatal Network. The data indicate that among infants weighing less than 1500 g, 10% of singletons were conceived by assisted reproduction compared with 60% of twins and 90% of triplets.⁴⁷

Biology

Most human conceptions (>99.2%) emerge from a single zygote (i.e., monozygotic [MZ]), resulting from the fertilization of a single egg by a single spermatozoon. In the remaining cases, more than one egg is ovulated and fertilized, resulting in polyzygotic conceptions (i.e., dizygotic [DZ], trizygotic). This phenomenon occurs more often in taller, older, parous, heavier, and black women. Although direct and indirect evidence points to a genetic predisposition, the exact mechanism whereby the ovary is naturally stimulated to release more than one egg per cycle is unknown. All infertility treatments are associated, however, with ovarian stimulation and polyovulation. The contribution of infertility treatments to polyzygotic gestations has become extremely significant since the 1970s.

Most MZ conceptions result in singleton births. In a small fraction of cases (0.4% of all natural conceptions), the zygote splits to form an MZ twin gestation. The mechanism of zygotic splitting is unclear. It has been postulated (but never completely established) that all forms of assisted reproduction produce a breach in the integrity of the zona pellucida—the acellular layer of the egg—resulting in herniation of the part of the early embryo through that gap and splitting of the embryo.

The frequency of MZ splitting is also increased with all methods of assisted reproduction.¹⁶ The true incidence of zygotic splitting after assisted reproduction is unknown. In a large study of single-embryo transfers, a sixfold increase in zygotic splitting was found. The frequency was not influenced by using fresh versus frozen-thawed embryos or by performing embryo transfers during a spontaneous versus an induced cycle.¹⁶ A more recent hypothesis suggests that the potential to undergo splitting might be an inherent characteristic of the oocyte.²⁴

The second point to consider is the placental arrangement (see Chapter 27). Dizygotic twins have two placentas (separate or fused), each with chorion and amnion, forming the so-called dichorionic (DC) placenta. Placentation of the MZ twins is postulated to depend, however, on the stage of embryonic development at which the split occurs. It is believed that early splits (about one third) result in DC placentas, whereas later splits result in monochorionic (MC) placentas. If the amnion has not yet differentiated, the MC placenta includes two amniotic sacs: the MC-diamniotic placenta (about two thirds of the cases). If the split occurs later than 8 days after fertilization, an MC-monoamniotic placenta develops. Finally even later splits result in all varieties of conjoined twins. However, one should remember that this well-known theory has never been proved.

When describing a multiple gestation, one must differentiate between zygosity and chorionicity. Because MZ conceptions with a DC placenta cannot be differentiated clinically from same-sex DZ twins (half of DZ conceptions) who also have a DC placenta, zygosity can be determined with certainty only in the DC—unlike sex twins (all must be DZ conceptions) and in twins with an MC placenta (all must be MZ conceptions). Simple calculation reveals that we are blind to zygosity in about 45% of the cases, and zygosity determination must be performed by DNA testing. Thus nothing should be said about zygosity to parents of same-sex twins with a DC placenta.

Maternal Consequences

When discussing maternal complications during multiple gestation, two important issues should be considered. The first issue involves the significant changes in the roles of women in Western societies witnessed after World War II. The new roles in society were facilitated by effective contraception, allowing ample time to achieve education and a career. This change resulted in increased maternal age at first delivery. Because age and fecundity are inversely related, however, infertility treatment to achieve a pregnancy often becomes inevitable. Because all infertility treatments carry an increased risk of multiple gestations, the end result of these sociomedical trends is an increased age of the cohort of mothers of multiples. US data clearly show that the increase in maternal age is more striking in high-order multiple gestations than in twins and in twins than in singletons, with a net result of multiples being more often delivered to older mothers in whom chronic disease conditions have already accumulated.¹⁷

The second issue involves the overwhelmed maternal homeostasis. Consider the fact that the average singleton, twin, and triplet have a similar birth weight until 28 weeks (≈1000 g). By 28 weeks, the mother of twins and the mother of triplets have accumulated twice and three times the fetal mass of singletons. This excess of fetal mass must come from either existing maternal resources or from supplemental energy. During the third trimester, all maternal systems are overwhelmed, and some may be only a step away from clinical insufficiency.

Two examples vividly demonstrate the situation. The first is the increased frequency of clinically significant anemia as a result of depleted maternal iron stores or inadequate iron supplementation.⁴ The incidence of anemia is significantly increased among mothers of multiples. A second example relates to the increased cardiac output. It has been estimated that in the worst-case scenario (i.e., preterm labor because of infection in a multiple gestation), the cardiac output may exceed 10 L/min (two to three times the normal value). It is understandable why cardiac function so easily turns into dysfunction when additional load—in the form of β-sympathomimetic tocolysis—is administered to a patient with multiples who experiences premature contractions.⁵³

Regardless of the inherent changes in maternal physiology resulting from the multiple gestation, there are some maternal disease conditions that are more frequent in these gestations. Hypertensive disorders are two to three times more frequent,⁴⁹ and their most dangerous complication—eclampsia—is six times more frequent among mothers of multiple gestations.³⁰ Preeclamptic toxemia occurs earlier in multiples than in singletons, and often occurs in a more severe form.³ Because triplets and other high-order multiples were rare in the past, there were scant data related to hypertensive disorders in high-order multiple gestations. With the current epidemic dimensions of multiple gestations, it has been shown that the risk of hypertensive disorders depends on plurality: The risk in triplets is higher than that in twins, and the risk in twins is higher than that in singletons.⁵⁴

Although the data are still conflicting, the frequency of gestational diabetes also seems to be increased among mothers of multiples. Critical reading of the literature suggests that most stimulation tests to detect glucose intolerance of various degrees showed a diabetogenic effect of multiple gestations, whereas demographic analyses failed to show increased rates of gestational diabetes.³² The latter analyses were conducted in the era before the epidemic of iatrogenic multiples, however, and before the effect of older maternal age could be documented.³² Sivan and colleagues⁵² showed that the risk of gestational diabetes depends on plurality, as is the case for hypertensive disorders. The correlation of multiple gestation with hypertensive disorders and gestational diabetes seems to point, at least in a teleological way, to the increased placental size—hyperplacentosis—as a potential common denominator. Simoes and co-workers showed that pre-gravid obesity appears to predispose women to gestational diabetes during twin pregnancy and that there is no advantage in terms of birth weight in twins born to diabetic mothers.⁵¹

All mothers of multiples are at considerably greater risk of preterm labor and delivery. Preterm contractions with or without cervical changes quite often necessitate tocolytic treatment. Many prophylactic measures, including progestogens, cervical suture (cerclage), β-sympathomimetics, bed rest, and hospitalization, were proposed to reduce preterm birth rates (see Chapter 20). All prophylactic measures failed to reduce significantly this common complication of multiple gestation. More recently, a cervical pessary was proposed to help in cases of preterm birth in twins.³³ Expecting mothers of multiples are frequently asked to leave work and to conduct a more sedentary lifestyle. Box 22-1 lists the most common maternal complications during multiple gestations.²³

Box 22-1

Maternal Complications More Frequently Seen in Multiple Gestations

Hypertensive diseases

• Preeclamptic toxemia

• HELLP syndrome

• Acute fatty liver

• Pregnancy-induced hypertension

• Chronic hypertension

• Eclampsia

Anemia

Gestational diabetes mellitus

Premature contractions and labor

• Complications associated with tocolysis

Delivery-associated complications

• Cesarean section

• Operative delivery

• Premature rupture of membranes

• Postpartum endometritis

• Placental abruption

HELLP, Hemolysis, elevated liver enzymes, low platelets.

Adapted from Blickstein I, Smith-Levitin M. Multifetal pregnancy. In: Petrikovsky BM, ed. Fetal disorders: diagnosis and management. New York: John Wiley & Sons; 1998:223.

Fetal and Neonatal Consequences

Animal models, similar to humans, show an inverse relationship between litter size and gestational age and birth weight. In humans, the average gestational age at birth is around 40 weeks for singletons, 36 weeks for twins, 32 weeks for triplets, and 29 weeks for quadruplets. Although multiple gestations exhibit many specific complications, the consequences of prematurity are the most common.

Malformations

Most texts cite a two- to threefold increased risk of malformations among multiples. It seems that the increased risk is primarily related to MZ twinning, however, and that the malformation rate of DZ twins is similar to that of singletons.⁶ The higher malformation rate among MZ twins is explained by the hypothesis of a common teratogen; that is, the one that causes the split of the zygote is also responsible for the malformation.

Malformations among multiples are grouped into four types (Table 22-1).⁶ The first type includes malformations that are more frequent among multiples, notably malformations affecting the central nervous and cardiovascular systems. The second type involves malformations related to MZ twinning, such as twin reverse arterial perfusion sequence and the various forms of conjoined twins. The third type relates to consequences of placental malformations, in particular the MC placenta, resulting in the twin-twin transfusion syndrome (TTTS). Finally, the fourth type involves skeletal (postural) deformities (e.g., clubfoot, dolichocephaly, brachycephaly) that are caused by intrauterine fetal crowding.

TABLE 22-1

Categories of Structural Defects in Twins

Category	Defect
Malformations more common in twins than in singletons	Neural tube defects Hydrocephaly Congenital heart disease Esophageal and anorectal atresias Intersex Genitourinary tract anomalies
Malformations unique to monozygotic twins	Amniotic band syndrome TRAP sequence Conjoined twins Twin embolization syndrome
Placental malformations	Single umbilical artery Twin-twin transfusion syndrome Velamentous cord insertion
Deformations owing to intrauterine crowding	Skeletal (postural) abnormalities

TRAP, Twin reverse arterial perfusion.

Some malformations can have a major impact on the properly formed twin. In the twin reverse arterial perfusion sequence, the circulation of the severely anomalous acardiac-acephalic twin is entirely supported by the normal (pump) twin. Sooner or later this cardiac overload leads to cardiac insufficiency of the apparently normal twin. Another example is the case in TTTS whereby both twins might be completely normal, but the anomalous transplacental shunt of blood can cause serious morbidity in both twins. The most striking example is the case of single fetal demise in MC twins, whereby the surviving fetus might die in utero soon after the death of the first twin. Alternatively, the surviving twin can be seriously damaged (see Embryonic and Fetal Demise).

In contrast to structural malformations, chromosomal anomalies are not more frequent among multiples. Each member of the multiple gestation has the same maternal age–dependent risk for trisomy 21. By probability calculations, the risk for a mother that one of her twins will have trisomy 21 is greater, however, than that of a mother of a singleton who is at the same age. A 32-year-old mother of twins has approximately the same risk of one infant with trisomy 21 as a 35-year-old mother of a singleton.⁴⁰

Because multiples are commonly seen in older mothers, and invasive cytogenetic procedures (amniocentesis or chorionic villus sampling) carry a much higher risk of pregnancy loss when performed in multiples, there is a genuine utility to maternal screening of aneuploidy to minimize the need for invasive procedures in these premium pregnancies. Screening tests such as the triple or quadruple test (second-trimester maternal serum human chorionic gonadotropin or free β-human chorionic gonadotropin, α-fetoprotein, and unconjugated estriol, with or without PAPP-A or inhibin) have a significantly lower prediction for trisomy 21 in multiples compared with singletons.²³ Thus at present the basic screening for aneuploidy is the nuchal translucency thickness measurement.

Most structural anomalies can be detected by a comprehensive ultrasound scan. In addition, echocardiography and Doppler velocimetry can detect structural and functional cardiovascular anomalies. This ability raises the question of reduction of the anomalous twin. In multichorionic multiples, reduction is accomplished by ultrasound-guided intracardiac injection of potassium chloride. Because of the risk to the survivor in MC sets, however, highly invasive procedures are used to interrupt the umbilical circulation of the anomalous twin.

All invasive procedures (amniocentesis, chorionic villus sampling, and reduction methods) are associated with the risk of 5% to 10% of membrane rupture and loss of the entire pregnancy. When an invasive procedure is considered during the second trimester, the risk of extremely preterm birth of the normal twin is apparent. This situation is exemplified in discordant lethal malformations. When one twin is anencephalic, the risk of reducing this twin should be weighed against the risk of endangering the normal fetus by preterm birth.

Embryonic and Fetal Demise

From the early days of sonography, it was clear that there are more twin gestations than twin deliveries. The early loss of one twin was eventually designated “vanishing” twin syndrome to denote the disappearance of an embryonic structure during the first trimester.³⁵ Many authorities consider this spontaneous reduction the natural equivalent of intentional multifetal gestation (numerical) reduction. The true frequency of vanishing twin syndrome is unknown because many twin gestations remain unnoticed unless sonography is performed at an early stage. One estimate of frequency of vanishing twin syndrome comes from iatrogenic conceptions: Spontaneous reduction of one or more gestational sacs or embryos occurred before the 12th week of gestation in 36% of twin, 53% of triplet, and 65% of quadruplet gestations.²⁸ Pinborg and co-workers found that 1 in 10 singletons after IVF started as a twin pregnancy.⁴⁵ Interestingly, case-control studies on plurality-dependent spontaneous embryonic loss rates after assisted reproduction found that twin pregnancies have a two to five times lower miscarriage rate of the entire pregnancy compared with singletons.³⁹

Single fetal death occurring beyond the first trimester is also more common in multiples. In DC twins, it is believed that the risk to the surviving twin is extremely low, and present only if there is an external insult such as maternal disease. Fetal death in MC twins is a totally different story.

Historically it was believed that some ill-defined thromboplastin-like material is transfused from the dead to the live fetus—the twin embolization syndrome. The theory was that these emboli might cause fetal death or result in end-organ damage, such as brain and kidney lesions. In the early 1990s, after meticulous postmortem examinations, the embolic theory was replaced by the ischemic theory, which postulates that blood is acutely shunted from the live twin to the low-resistance circulation of the deceased fetus, causing acute hypovolemia, ischemia, and end-organ damage in the survivor. The chance of serious damage in the survivor is significant and estimated to be 20% to 30%, although more recent estimations suggest lower figures.⁴⁴

The diagnosis often is made some time after single fetal death, however, and the question arises whether prompt delivery is indicated to reduce the risk for the survivor. Data suggest that acute blood loss occurs just before the time of death of the surviving twin, and it is unlikely that immediate delivery of the surviving twin could decrease the associated high mortality and morbidity rates.⁴³ It is prudent to suggest conservative management in such cases, especially remote from term, and to use ultrasound and magnetic resonance imaging (MRI) to exclude brain lesions. MRI should be performed at 32 weeks’ gestation, when white matter lesions can be better visualized.

Only gold members can continue reading. Log In or Register to continue