Monochorionic diamniotic quadruplet pregnancy: physical models from prenatal three‐dimensional ultrasound and magnetic resonance imaging data

Monozygotic (MZ) twins are relatively rare, with an incidence worldwide of about 0.40–0.45% after non-stimulated in-vivo conception1. The rate of MZ twinning after assisted reproductive technology (ART) is estimated to be between two and 12 times higher than for natural conception2. Higher-order multiple pregnancies carry significantly increased risks of fetal morbidity and mortality compared with the baseline risks of a twin pregnancy. Additional risks are also associated with monochorionicity. Simultaneous division of two transferred embryos in ART is a rare event (< 0.16% of all pregnancies) and only a few cases have been reported in the literature3. Several reports refer to higher-order multiple pregnancies as a result of the increasing use of ART in recent years, including quadruplet pregnancies4. However, embryo reduction is performed in most cases and good outcomes in higher-order multiple pregnancies from ART are scarcely reported. We present here a case of successful pregnancy after simultaneous division of two transferred embryos, resulting in two sets of monochorionic diamniotic twin pregnancies. Three-dimensional (3D) virtual and physical models of the pregnancy were created using prenatal ultrasound and magnetic resonance imaging (MRI) data. A 32-year-old Caucasian woman with an unremarkable medical history, who failed to conceive after 3 years of trying, was diagnosed with bilateral endometrioma, peritoneal endometriosis and right tubal dilatation on MRI. The couple was offered ART. In the first cycle of in-vitro fertilization (IVF), eight oocytes were collected. This first attempt was unsuccessful and embryo transfer resulted in miscarriage after 4 weeks. A new attempt at IVF was made 6 months after the first cycle. Eight oocytes were obtained and fertilized, resulting in three embryos. Two blastocysts were transferred. Beta-human chorionic gonadotropin was 1612 IU 13 days after transfer. Transvaginal ultrasound examination at 6 weeks showed two intrauterine sacs, each containing two embryos. The couple was informed on the maternal and fetal risks of a quadruplet pregnancy and counseled on the possibility of fetal reduction, which was declined. During first-trimester ultrasound examination, anatomy of all four fetuses was apparently normal (Figure S1 and Videoclips S1–S3). Cervical cerclage was performed at 16 weeks for the prevention of preterm delivery and vaginal progesterone was prescribed at 24 weeks. MRI was performed at 26 weeks (Figure 1a and Videoclip S4) due to difficulty in evaluating complete fetal anatomy with ultrasound, and 3D virtual and physical models were constructed using the data (Figure 1b–d and Videoclips S5 and S6). Cesarean section was performed at 32 weeks due to uterine contractions and dyspnea, delivering four male babies (Table 1). Apgar scores at 1 and 5 min were 9 or 10 in all neonates. Two neonates were discharged from the hospital 34 days after delivery and the other two at 36 days after delivery (Figure S2). MZ twinning following IVF was first reported in 19845 and numerous studies have since demonstrated an increased occurrence associated with ART. From 127 977 ART procedures performed in the USA in 2004, 49 458 infants were born, with 50% being a multiple-birth delivery and 6% being triplets or higher-order multiples6. Data from 365 103 ART cycles in Europe in 2003 indicated that twin and triplet pregnancies accounted for 22% of all resulting deliveries7. The rate of triplet delivery varied between countries, from 0–4.4%. In many studies, the rate of MZ twinning is based on the number of monochorionic twins detectable by ultrasound, and thus, MZ dichorionic twins have been labeled inaccurately as dizygotic, which results in underrepresentation of the actual rate of MZ twinning8, 9. Multiple factors are associated with the increased risk of MZ twin pregnancy after ART, including ovarian stimulation, manipulation of the zona pellucida, blastocyst transfer, suboptimal culture conditions and maternal age2. Simultaneous division of more than one transferred embryo is rare and few cases are reported. To our knowledge, there are three reports in the literature of quadruplet pregnancies consisting of two sets of monochorionic diamniotic twins, each with different outcomes. Carrillo-Vadillo et al.10 reported a case of two sets of monozygotic twins after implantation of two embryos, fertilized by intracytoplasmic sperm injection and transferred on day 2. On day 36, the presence of two gestational sacs with two embryos each was observed. In the 11th week of pregnancy, fetal reduction was performed to reduce the pregnancy from quadruplets to one pair of monochorionic diamniotic twins. The patient presented intense bleeding in the 13th week of pregnancy, confirming the complete loss of the pregnancy. However, the successful outcome of a quadruplet pregnancy after ART and fetal reduction was reported by Wehbe et al.11. In their case, four embryos were transferred on day 3. On day 35, two intrauterine sacs were identified and, 1 week later, two poles were observed in both gestational sacs. Fetal reduction was performed at 12 + 5 weeks' gestation. An uncomplicated vaginal delivery of healthy monozygous twins occurred at 36 weeks. 3D postprocessing technology is a recent development that may be added to conventional imaging to improve accuracy of prenatal diagnosis. Rapid physical prototyping may be performed using scanning measurement data12 obtained from 3D ultrasound volumes, computed tomography or MRI13-16. This advanced digital application has been used to study normal anatomy and to display multiple fetal malformations, such as Chiari II malformation17. 3D virtual and physical prototypes produce a new visualization model and could therefore be added into medical training programs to improve understanding and knowledge of congenital anomalies. In addition, 3D physical models have been shown to enhance the parental bonding process. Its relationship with the bonding process was explored recently in six fetuses with serious congenital anomalies in pregnancies of blind parents18. Notwithstanding, virtual prototypes have been employed recently to generate physical models of the fetal skull in cases of microcephaly due to congenital Zika virus infection19, 20. In the current case, 3D virtual models greatly improved knowledge of the intrauterine spatial relationships between the quadruplets, with prenatal imaging quality that resembled reality. 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