Prenatal Assessment of Multiple Pregnancy

Isaac Blickstein, Louis G. Keith, Isaac Blickstein, Louis G. Keith

• Publisher: CRC Press
• Year: 2018
• ISBN:
  9781134223053
• Edition: 1
• Topic: Medicine
• Subtopic: Urology

Following on from the success of their previous standard textbook on Multiple Pregnancy, the authors have refocused their attention on prenatal assessment in multiple pregnancy and come up with condensed and revised material in a free-standing text. Multiple pregnancies are associated with higher levels of morbidity and fetal distress, and so effective and rapid diagnosis of problems is paramount. Those clinicians who would not have a practical application for all the aspects covered comprehensively in the earlier work will find this volume a clinically orientated and extremely useful addition to their working library.

1
How is multiple pregnancy defined?

Introduction

According to Cicero, a renowned Roman orator and statesman, Hippocrates (a preeminent physician of ancient Greece) suspected that a pair of brothers were twins.¹ Hippocrates reached this conclusion because they both became ill at the same time, and their disease progressed to a crisis and subsided in the same length of time for each of them. Hippocrates’ conclusion was not accepted by the astrologer Posidonius the Stoic who challenged this diagnosis and explained this coincidence by the fact that the two brothers were conceived and born under the same constellation.

Centuries later, in the first edition of his book Inquiries into Human Faculty and its Development, Francis Galton (1883) commented:²

The reader will easily understand that the word ‘twins’ is a vague expression, which covers two very dissimilar events – the one corresponding to the progeny of animals that usually bear more than one at a birth, each of the progeny being derived from a separate ovum, while the other event is due to the development of two germinal spots in the same ovum. In the latter case they are enveloped in the same membrane, and all such twins are found invariably to be of the same sex.

This definition represents a considerable part of the foundation of modern medical thinking, and remained in use, albeit in a refined nature, until the end of the 20th century.

The Effect of Infertility Treatment

An important observation about the twinning process was made during the late 19th century, when Hellin described the mathematic relationship between the rates of twins and higher-order multiples. This relationship, the so-called Hellin’s law, suggests that if the twinning rate is X, then the triplet rate is X², the quadruplet rate is X³, and so forth. Hellin’s law is an approximation, however, for naturally occurring multiples when tested in a population at large. As such, it disregards secular trends in twinning rates as well the effect of maternal age and race.

The first recorded deviation from Hellin’s law, that is, the difference between the expected and observed numbers of multiples in a given population, did not occur until the last two decades of the 20th century – the era of iatrogenic multiple pregnancies. Figure 1.1 shows the comparison between the expected (based on Hellin’s law, from the twin birth rate) and the observed triplet birth rates in the United States during three distinct periods: (a) before the availability of ovulation induction agents; (b) at the beginning of the 1980s – the start of the epidemic of multiple gestations; and (c) at the late 1990s – the peak of the epidemic. The difference between the expected and observed rate of triplets was negligible in the era of natural twinning before the use of ovulation induction and obeyed quite neatly Hellin’s law. However, with the increasing number of iatrogenic multiples, either from ovulation induction or from assisted reproduction technologies (ART), the deviation from natural twinning is increasingly evident. A similar conclusion was reached by Fellman and Eriksson, who studied secular data from Finland for 1881–1990 and from Sweden since 1751.³

Figure 1.1 Expected (by Hellin’s Law) vs observed triplets rate, before, in the middle and at the peak of the ‘epidemic’ of multiple pregnancies

The frequency of twins and higher-order multiples is not the only change that occurred following the widespread implementation of infertility treatment over the past two decades. Another major change is the ratio between dizygotic (DZ) and monozygotic (MZ) twins. In spontaneous conceptions, MZ twins comprise about one-third and DZ two-thirds. In contrast, MZ comprise about 5% of all twin births following iatrogenic pregnancies and DZ the remainder. Table 1.1 is derived from the East Flanders Prospective Twin Survey (EFPTS), in which zygosity is known for all twins, and shows the frequency of MZ twins by mode of conception. As was shown in East Flanders and in other studies, MZ twinning is increased following ovulation induction as well as following in vitro (IVF) procedures. An evaluation of a population-based dataset of single embryo transfers following IVF found an incidence of 2.3% monozygotic twins, a figure 6 times higher than after spontaneous pregnancies as quoted in the literature.⁴ The largest series with complete zygosity assessment derives from the EFPTS and confirms that the overall frequency of MZ twinning following all assisted conceptions – 4.5% – is 10 times the spontaneous rate (0.45%). Interestingly, the frequency of MZ twinning following ART procedures (2.6%) was 6-fold the spontaneous rate, in full accord with estimates derived from single embryo transfer pregnancies.⁵

The advent of infertility treatment radically changed the definition of twinning, as conceptualized based on spontaneous conceptions. To appreciate this change, one may imagine how Cicero and Galton (cited above) would consider the so-called ‘Angela’ case.⁶ This Italian woman was at the same time and in one pregnancy a surrogate mother for two unrelated couples, and when she delivered unlike-sexed twins, postnatal blood typing (confirmed by DNA fingerprinting) allowed identification of each baby’s genetic parents. This is presumably the first time in which the twins were not genetically related to each other, nor was there any genetic relationship to the mother. Thus, at the present time, simple definitions of twinning are unsuitable to encompass the whole spectrum of multiple gestation as seen by modern, technologically capable clinicians.

Superfetation and Superfecundation

Superfecundation, defined as the fertilization of two or more ova released during the same menstrual cycle by sperm from separate acts of coitus, is frequently and erroneously confused with superfetation. In superfetation, which is an entirely different phenomenon, the fertilization and creation of another conceptus is assumed to take place when the female is already pregnant. In humans, superfetation has been discarded by scientific arguments, namely the arrest of subsequent ovulation after the initial ovulation and the inability of sperm to reach the fertilization site in the Fallopian tube. However, modern infertility treatment can theoretically circumvent these obstacles in one of two manners. The first is

Table 1.1 Zygosity of spontaneous and iatrogenic twin and triplet maternities (1964–2000)

transfer of sperm directly to the Fallopian tube by a procedure characterized as gamete intrafallopian transfer (GIFT). If this procedure is performed when the patient is already pregnant, and follicles are pushed to ovulate under the influence of hCG, a ‘retrograde’ fertilization may occur. Obviously, such a gestation is likely to develop in the Fallopian tube because the preceding gestational sac blocks the uterine cavity.⁷

A second possibility arises from the fertilization of oocytes in vitro, a routine procedure in ART. Once created in vitro, zygote transfer directly to the Fallopian tube by a procedure known as zygote intrafallopian transfer (ZIFT) and performed inadvertently during an early gestation may create a heterotopic superfetation.⁸

It is questionable if the ovulatory-inhibitory effect of an intrauterine pregnancy is the same in the presence of an extrauterine pregnancy. Indeed, it is speculated that the latter produces a lesser quantity of progesterone because of a smaller quantity of trophoblastic tissue and a diminished effect on the corpus luteum. In such circumstances, it is therefore possible that an ovarian follicle might escape the progesterone-induced ovarian suppression. This may be the reason why heterotopic superfetations are repeatedly mentioned in the older⁹ as well as in the more recent literature.^10,11

The diagnosis of superfetation is often conjectured and speculative. In contrast, the diagnosis of superfecundation, especially the heteropaternal pregnancy – when the twins are of different color or racial phenotype – is usually unquestionable. In the human, the best examples are those in which the twins born to the same woman are of different colors. Gould and Pyle cited a long list of prominent medical authorities that described such cases, the earliest of which was from 1714.⁹ Interestingly, most cases in the past, but certainly not all of them, described black women (many of whom were servants) who acknowledged that shortly after being with their respective husbands, they had intercourse with a white man.⁹ In recent years, the effect of modern infertility technologies also resulted in some form of superfecundation. A mix-up at a Leeds in vitro fertilization (IVF) clinic in 2002 resulted in the delivery of twins of different colors to an infertile white patient. The blunder could have been at either the fertilization stage (using sperm of a different father, i.e. heteropaternal pregnancy) or the embryo transfer stage (using an embryo from a different couple, i.e. heterologous pregnancy).¹² DNA fingerprinting confirmed the former possibility. However, in its ‘pure’ sense, these heteropaternal twins were not a result of superfecundation because they were produced by inseminating retrieved eggs of the same ovulation cohort. Heteropaternal superfecundation seems to be an anecdotal and rare occurrence; however, Wenk and colleagues¹³ identified three cases in a parentage-test database of 39 000 records and quoted a frequency of 2.4% heteropaternal superfecundations among DZ twins whose parents were involved in paternity suits. James¹⁴ has suggested that about one pair in 400 is heteropaternal in the population of DZ twins born to married white women in the USA.

Superfecundation is by no means equivalent to heteropaternity, however. Estimates from the Galton Institute in London¹⁴ suggest that at least one dizygotic twin maternity in 12 is preceded by superfecundation, with varying frequencies depending on the population’s coital rates and rates of double ovulation. Monopaternal super-fecundation may also occur in assisted reproduction. Amsalem and colleagues¹⁵ reported the transfer of two embryos on day 3 and the development of five separate embryonic sacs. Genetic analysis of the twin pregnancy and of the three embryos that were reduced confirmed monopaternal superfecundation.

The Definition

In order to formulate the most appropriate definition of twinning, it is necessary to consider the following:¹⁶

• (1) The definition should include multiple gestations that do not end with more than one fetus/neonate. Thus, cases of singletons following embryonic or fetal demise, or following spontaneous or iatrogenic reduction, should be considered as a multiple gestation. The registration of singletons that had a missed (‘vanished’) twin or are delivered along with a fetus papyraceous is also important. For example, Pharoah and Cooke¹⁷ pointed out that registration of such cases as singletons does not permit a true evaluation of single fetal demise on the prevalence of cerebral palsy in twins. This definition should also include combinations of a fetus and a complete hydatidiform mole, a circumstance that is clearly a twin pregnancy.
• (2) A pregnancy should be defined as intracorporeal rather than intrauterine to include multiple gestations of the hetero-topic type. These are encountered much more frequently following assisted reproduction. The definition should exclude twins produced by cloning, but may include monozygotic (MZ) twins in whom zygotic splitting occurred in vitro.
• (3) The number of zygotes at the beginning of gestation should be considered in the definition in order to include cases of conjoined twins, and inclusion of a set of MZ twins among a higher-order multiple pregnancy. This, however, is not always possible.
• (4) The production time of the zygote(s) should be incorporated in the definition to include case...