Early Multifetal Pregnancy Reduction Outcomes: Non- Chemical-Based Method Yield Improved Pregnancy Rates and Minimized Risks
Abstract
Objectives: Multifetal pregnancies increase the risk of maternal and perinatal mortality and reducing to a lower-order pregnancy attenuates this risk. We assessed a non-chemical-based procedure for multifetal pregnancy reduction.
Methods: A single-arm prospective study was conducted between December 2013 and September 2018 on patients with trichorionic triamniotic pregnancies (n=296). Multifetal pregnancy reduction was performed between gestational weeks 5 and 10. Using the same equipment for transvaginal ultrasound-guided oocyte recovery, an echo-tipped needle (17 Cook medical ovum aspiration needle) was inserted into the embryo’s cardiac area until the absence of fetal heartbeat. Afterward, the needle was extracted, and the hemostasis/vitality of the remaining embryos was verified. Patients were followed until delivery, where the birth weight was recorded as well as any complications.
Results: None of the women presented or indicated any surgical-related complications. Three patients lost their pregnancies (1.0%); however, 89.9% maintained the remaining two gestational sacs and 9.1% retained one gestational sac. The live birth rates were 95.1% for the two gestational sacs (birth weight: 2135±586 grams) and 96.3% for one gestational sac (birth weight: 2546±636 grams). The birth weight was significantly better in pregnancies that resulted in one gestational sac (p=0.001). There was a significant difference in the low birth weight rate (two sacs: 26.9% v one sac: 58.4%) but not with the very low birth weight rate (two sacs: 9.1% v one sac: 7.7%).
Conclusions: Here, we demonstrate that a non-chemical method can successfully reduce the number of embryos avoiding complications and allowing pregnancy.
Keywords: Embryo reduction; High-order multiple pregnancies; Pregnancy outcomes; Selective termination; Trichorionic triplet pregnancy
Introduction
Procedures to increase the success of achieving a clinical pregnancy include implanting multiple embryos; however, this has had many unforeseen risks [1]. The risk of spontaneous pregnancy loss is 25% for quadruplets, 15% for triplets, and 8% for twins [2]. Moreover, multifetal pregnancies increase maternal and perinatal morbidity and mortality [3]. Maternal risks of multifetal pregnancies include hypertension, preeclampsia, gestational diabetes, and postpartum hemorrhage [4,5]. Implementing multifetal pregnancy reduction during assisted reproduction technologies when three or more fetuses are present has become a common practice.
According to Liu, et al. the optimal strategy for multifetal pregnancy reduction has not been elucidated [6]. Multifetal pregnancy reduction is typically scheduled between 11 and 14 weeks of gestation, known as late reduction, with most common procedures requiring the use of chemical substances, such as potassium chloride (KCl), as an adjuvant or gestational sac aspiration to improve the embryo reduction success rate [7]. Even though these procedures have improved assisted reproduction technology outcomes, under certain circumstances, these procedures present with significant complications, ranging from increased miscarriage rates to abdominal pain to maternal distress [8-10]. The proposed mechanisms postulated for these effects include procedure-related trauma, infection, over-activation of the maternal immune system due to the resorbing of dead fetoplacental tissue, feticide-promoted hemorrhage leading to the death or impaired development of the remaining fetus(es), or that the KCl from the injection transfers to another fetus via the intertwine placental vascular anastomoses [11,12,9,13]. Lastly, when late reduction could be or is not possible, alternative techniques, such as early reductions, should be considered. Certain circumstances include but are not limited to cervical ectopic pregnancy, placental complications, compromised embryo development, in which all implantations may suffer from prolonged intervention. With more unsatisfactory results associated with early reductions compared to late reductions concerning procedure-related fetal or pregnancy loss, augmented miscarriage rates, preterm delivery, and birth weight [14,15], the early reduction techniques need improvement. Therefore, we present a non-chemical-based method for fetal reduction, performed during early gestation.
Materials and Methods
Patients and study approval
Between December 2013 and September 2018, patients with trichorionic triamniotic triplets were asked to participate in this single-arm prospective study. To be included in the study, women had to be attending the Ingenes Institute for advanced maternal age without any other cause of female infertility and underwent a standardized in vitro fertilization (IVF) protocol. Exclusion criteria were an ectopic pregnancy, not willing to accept the procedure, or monetary issues. Options were explained to the patients and presented with embryo reduction as an alternative. They were explained the potential problems with the procedure.
IVF and pregnancy evaluation
All patients underwent a 10-day controlled ovarian stimulation with gonadotropin-releasing hormone agonists and antagonists. Ovarian response was assessed by monitoring follicular development by ultrasound examination and measuring serum estradiol levels. Oocyte retrieval was conducted 36 h after human chorionic gonadotropin (hCG) administration (10,000 IU Choragon Ferring Laboratories or 6500 IU Ovidrel, Merck Laboratories, Naucalpan de Juárez, Estado de México, México). At the end of hormonal stimulation, oocyte collection was performed under general anesthesia. To follow and locate mature follicles, transvaginal ultrasound was used. Ovulation was induced with hCG. Using a specialized suction system, 3–5 ml of follicular fluid containing the oocytes was extracted.
Samples were analyzed using a stereoscopic microscope to locate the oocytes, which were kept at 37.5 °C in an 8.3% CO2 atmosphere until fertilization. Only the highest quality embryos were transferred, and pregnancy was diagnosed by β-hCG values >10 mUI/ml (Day 14) as well the presence of a fetal heartbeat, confirmed by ultrasound at 6–8 weeks. An embryologist monitored and recorded information about embryo development, embryo morphology, transfer, and pregnancy. Low birth weight was defined as a delivery weight below 2,500 grams and very low birth weight below 1,500 grams. Using the World Health Organization criteria, preterm births were categorized as either extremely preterm (less than 28 weeks), very preterm (28 to 32 weeks), moderate to late preterm (33 to 37 weeks)[16]. Birth weight discordance was calculated using the formula: (birth weight of the larger twin – birth weight of the smaller twin)/birth weight of the larger twin [17]. Pregnancy loss due to the procedure was defined as a loss of pregnancy within three weeks of the procedure as indicated by Evans, et al. [18] and Timor- Tritsch, et al. [19], whereas miscarriages were defined as a pregnancy loss before 24 weeks and abortion was defined as a pregnancy loss after 24 weeks.
Embryo reduction
Patients without spontaneous pregnancy reduction were counseled about multifetal pregnancy reduction at our facilities. The probable complications of multiple fetal pregnancies and the risks and benefits of multifetal pregnancy reduction were explained. The doctors gave advice about which embryo should be reduced according to the embryos’ condition and position. Final decisions about whether to undergo multifetal pregnancy reduction and retained embryos were made by the patients, depending on their religious beliefs and personal preference.
Before the procedure, an ultrasound scan was performed using a 5.0 MHz transducer (Panavista-VA GM-2600A, Matsushita, Japan) to determine the location of the pregnancy and the size of the fetus and gestational sac. The embryos were observed, and an embryo was chosen for reduction based on its proximity to the cervix as well as the presence of an unfavorable prognosis. Fetal heartbeats were confirmed for each fetus before starting the procedure. Under general anesthesia, after patients had been placed into the lithotomy position, the vagina was prepared with 10% povidone-iodine and thoroughly rinsed with sterile saline solution. Prophylactic antibiotic (2.0g Cefalotin, intravenous injection) was administered one h before the procedure. Under on-screen sonographer guidance, the fetus was approached transvaginal through the anterior fornix with a 17-gauge COOK needle (COOK Medical, Bloomington, IN, USA) for embryo reduction. A cardiac puncture was performed. The transuterine puncture was carried out until reaching the fetus’s heart. From there, a direct intracardiac puncture was performed, where the needle was repeatedly rotated 90 degrees or by making continuous punctures in the cardiac area until evidence of cessation of the cardiac activity. After ensuring that no fetal heartbeat occurred, the needle was withdrawn. There was no need for suction. Ultrasonic graphic presentation of the procedure is presented in Figure 1. Following the procedure, vaginal hemostasis revision was performed. Patients were followed until delivery and the birth weight was recorded as well as any complications.
Statistical analysis
The Shapiro-Wilk test was used to determine if the data were normally distributed. Either the Chi2 test, Mann–Whitney U test, or Student’s t-test was used to examining differences between groups. P-values <0.05 (two-tailed) were considered significant. All analyses were carried out with the Statistical Package for the Social Sciences software v26.0 (IBM Corp., Armonk, NY, USA).
Results
For this proof of principle study, we only approached patients with three gestational sacs (trichorionic triamniotic), which were reduced down to two. Two hundred ninety-six patients agreed to participate out of 407. The characteristics of the participants are presented in Table 1. For the women who choose not to proceed, the top reasons were personal reasons/choices, religious beliefs, and economic causes. Embryo reduction typically took place during the 7th week (range: 5-10.5 weeks). The procedural time was 15 minutes. None of the women presented or indicated any complications due to the surgery.
After the procedure, three patients lost their pregnancy (1.0%) due to the procedure (within three weeks); however, 89.9% maintained the remaining two gestational sacs and 9.1% for one gestational sac. The live birth rates were 95.1% for the two gestational sacs and 96.3% for one gestational sac (Table 1). There was no difference in the live birth rate (p=0.784). Even though there was no difference in the gestational age at birth, the one gestational sac group had more full-term deliveries, and the two gestational sacs group had more moderate to late preterm deliveries. Interestingly, there was no difference between the groups with respect to preterm deliveries <33 weeks. For patients in which the reduction led to 1 gestational sac, there was a significant benefit concerning birth weight (p=0.001). When the birth weight was stratified into normal, low, and very low, there was a significant difference in the low birth rate but not the very low birth weight (Table 1). The most common fetal complication for the two gestational sacs group was the pregnancy that required neonatal intensive care unit intervention (4.5%), whereas for the one gestational sac group was the restriction of intrauterine growth (14.8%, Table 2).
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