Neonatal and maternal outcomes after fresh blastocyst and cleavage stage embryo transfer in their first assisted reproductive technology

Received: 30-Oct-2017 Accepted Date: Oct 31, 2017; Published: 15-Nov-2017

Citation: Du M, Wang X, Zhang J, et al. Neonatal and maternal outcomes after fresh blastocyst and cleavage stage embryo transfer in their first assisted reproductive technology. J Reprod Biol Endocrinol. 2017;1(2):19-22.

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Abstract

BACKGROUND: Blastocyst culture became a significant technology now. But it provided not only advantages but also disadvantages. Although prolonged in vitro exposure may cause damage to the embryo, but it would choose better embryo to transfer. Our purpose was to probe neonatal and maternal outcomes after blastocyst transfer versus cleavage stage embryo transfer.

METHODS: This is a retrospective cohort study from a single center (1477 singleton birth).

RESULTS: There was a high risk of preterm birth after blastocyst transfer versus cleavage stage embryo transfer (9.9% vs. 5.7%, p=0.02). But we did not find any difference in low birth weight, small for gestational age, large for gestational age, very preterm birth, very low birth weight, antepartum haemorrhage, placental abruption, placenta previa, post-partum haemorrhage and premature rupture of membranes, birth defects, perinatal mortality, APGAR score <7 at 5 min and gestational diabetes. Binary logistic regression indicated that body mass index is an important factor in small for gestational age (COR 0.86, 95% CI 0.80- 0.92; AOR 0.86, 95% CI 0.80-0.92, P=0.00) and large for gestational age (COR 1.17, 95% CI 1.11-1.22; AOR 1.15, 95% CI 1.10-1.21, P=0.00). And the type of infertility, years of unwanted childlessness and parity also influenced large for gestational age.

CONCLUSION: Neonatal and maternal outcomes after cleavage stage embryo transfer were similar with blastocyst transfer except preterm birth. And body mass index played an important role in large for gestational age. Types of ectopic pregnancies so to preserve the woman’s potential fertility.

Keywords

Blastocyst; Cleavage stage embryo; Neonatal outcomes; Maternal outcomes

Abbreviations

LBW Low birth weight; LGA Large for gestational age; SGA Small for gestational age; VLBW Very low birth weight; ART Assisted reproductive technology; ICSI Intracytoplasmic sperm injection; IVF In vitro fertilization; PA Placental abruption; PP Placenta previa; PPH Post-partum hemorrhage; PROM Premature rupture of membranes; OR Odds ratio; CI Confidence interval

Recently, assisted reproductive technology (ART) was applied to more and more people [1]. According to a report by the International Committee for Monitoring Assisted Reproductive Technologies World, the percentage of babies born from ART was estimated to increase by an average of 9.1 percent per year between 2008 and 2010 [2]. In America, a total of 169,568 ART resulted in 56,028 live-birth deliveries and 68,782 infants born in 2014 [3].

With the increment of ART ratio, the neonatal and maternal outcomes were paid more and more attention. For instance, which one has a preferable neonatal and maternal outcome, blastocyst embryo transfer or cleavage stage embryo transfer? Numerous professors probed into this area at one time. Some studies pointed out that there was no significant difference in neonatal and maternal outcomes in different duration of in vitro culture [4-7]. But other studies considered that there was an increased risk of preterm birth after blastocyst embryo transfer [8-10]. And a recent meta-analysis found that the blastocyst embryo transfer was associated with risks of neonatal death, preterm birth, very preterm birth and large for gestational age [11]. The closest meta-analysis indicated that the risk of preterm birth and very preterm birth decreased with cleavage stage embryo transfer in fresh cycle. However, there is no difference in frozen cycle [12].

The primary outcome was aim to investigate the neonatal and maternal outcomes for example preterm birth, low birth weight, small for gestational age, large for gestational age in different duration of in vitro culture. And we also compared very preterm birth, very low birth weight, sex ratio, antepartum haemorrhage, placental abruption, placenta previa, postpartum haemorrhage and premature rupture of membranes, birth defects, perinatal mortality, APGAR score <7 at 5min and gestational diabetes between two groups.

Methods

Study design

This was a single-center retrospective study. All of data was provided by The Reproduction Center, The Third Affiliated Hospital of Zhengzhou University between January 2013 and August 2016. We collected data in our database. Women who underwent their first IVF/ICSI embryo transfer cycle were included. And we excluded patients who aged more than 35 years old to avoid age factor. If patients had intrauterine lesions and uterine malformation, we also eliminated them. We also only chose fresh embryo transfer to eliminate the biases. Data only included if the infants born after twenty weeks of gestation. Stillbirth also excluded in this study. Patients who underwent preimplantation genetic diagnosis (PGD)/preimplantation genetic screening (PGS) were excluded. Likewise, patients with donor oocytes were also excluded. We excluded it too by transvaginal ultrasound performed 30 days after transplantation to avoid vanishing twins [13]. In total, 1477 singletons born after fresh embryo transfer.

Patients with GnRH agonist to ovulate, when 1-3 follicular diameter ≥ 20 mm or 60% dominated follicle ≥ 18 mm and serum luteinizing hormone (LH), estrogen (E2), progesterone (P) level were appropriate, 250 ug of Recombinant Human Chorionic Gonadotropin (Merck, Darmstadt, Germany) were injected. After trigger 36-38 h, oocyte retrieval underwent under ultrasonography. According to the stage of embryo, transplant surgery underwent after 3, 5 or 6 days after ovulation. Luteal support added the time after oocyte retrieval. We had two choices for patients. One was 60 mg im qd Progesterone Injection (Xianju, Zhejiang, China) and 20 mg po bid Dydrogesterone Tablets (Abbott, Illinois, America), the other was 90 mg Intravaginal administration qd Progesterone Sustained-release Vaginal Gel (Merck, Darmstadt, Germany) and 20 mg po bid Dydrogesterone Tablets (Abbott, Illinois, America). The luteal support continued to 45 days after transplantation.

Study and outcome factors

The original outcomes were preterm birth (PTB, <37 weeks), very preterm birth (VPTB, <32 weeks), low birth weight (LBW, <2500 g), very low birth weight (VLBW, <1500 g). Then, large for gestational age (LGA, >90th percentile) and small for gestational age (SGA, <10th percentile) were evaluated by percentile charts for Chinese newborns [14]. Calculating standard deviation score (also known as Z-score) for IVF/ICSI infants by the equation Z=(x-μ): σ [15]. x was the infant’s birth weight, μ, was the mean birth weight at the same gestational age and gender in reference group. And sex ratio, antepartum haemorrhage, placental abruption, placenta previa, postpartum haemorrhage and premature rupture of membranes, birth defects, perinatal mortality, APGAR score <7 at 5 min and gestational diabetes were also discussed.

Statistical analysis

We compared the neonatal and maternal outcomes of IVF/ICSI pregnancy after blastocyst embryo transfer vs. cleavage stage embryo transfer by SPSS (Statistical package for the social sciences) software 22.0. For categorical variables, we used chi-square tests. If more than 20% cells have expected count less than 5, we used Fisher’s exact test. For continuous variable, we used Student’s t-test or Mann-Whitney test. And we also used binary logistic regression to analysis PTB, LBW, LGA and SGA. According to papers, these factors were analysis in binary logistic regression. Maternal age (categorical: ≤ 30 years, >30 years), Male age (continuous variable), Method of treatment (categorical: IVF, ICSI), type of infertility (categorical: primary infertility, secondary infertility), Years of unwanted childlessness (continuous variable), Parity (categorical: 0, ≥ 1), Body mass index (continuous variable), Reason for infertility (categorical: Male factor, Tubal factor, Others), Number of retrieved oocytes (continuous variable), Delivery mode (caesarean section, spontaneous delivery), Endometrial thickness (continuous variable), Stage of embryos transferred (categorical: cleavage stage embryos or blastocyst) and transplanting time (categorical: weekday, weekend). We did not analysis smoke for the reason that only 2.4% women smoked in China [16].

Results

In the aggregate, 1477 live deliveries after blastocyst transfer (191, 12.9%) or cleavage stage transfer (1286, 87.1%) between January 2013 and August 2016.

In Table 1, a high risk of sex ratio imbalance to male was discovered (p=0.01). And in Table 2, we found that there was a high risk of preterm birth after blastocyst (9.9% vs. 5.7%, p=0.02) transfer. However, in Z score, very preterm birth, low birth weight, large for gestational age, small for gestational age, very low birth weight, birth defects, perinatal mortality and Apgar score <7 at 5 min, there was no difference after cleavage stage embryo transfer. Table 3 revealed that blastocyst group and cleavage stage group had semblable maternal outcome for instance preeclampsia, placental abruption, placenta previa, postpartum haemorrhage, premature rupture of membranes and gestational diabetes.

Table 1: Patient characteristic in blastocyst or cleavage stage group

Table 2: Neonatal outcome in blastocyst or cleavage stage group

Table 3: Maternal outcome in blastocyst or cleavage stage group

For the sake of probing the factors exhaustively which influenced preterm birth, low birth weight, large for gestational age and small for gestational age, binary logistic regression was used. In term of preterm birth, blastocyst transfer had an adverse outcome compared with cleavage stage embryo transfer (COR 1.86, 95% CI 1.10-3.17; AOR 2.19, 95% CI 1.15-4.18, P=0.02). To low birth weight, patients who had long years of unwanted childlessness would had high risk (COR 1.11, 95% CI 1.01-1.22; AOR 1.16, 95% CI 1.03- 1.30, P=0.01). As for small for gestational age infants, we found that thin patients were more likely to born infants like that (COR 0.86, 95% CI 0.80- 0.92; AOR 0.86, 95% CI 0.80-0.92, P=0.00). In the end, five factors and large for gestational age infants was relevant. Secondary fertility (COR 1.03, 95% CI 0.76-1.40; AOR 0.59, 95% CI 0.40-0.89, P=0.01), short duration of infertility (COR 0.98, 95% CI 0.92-1.04; AOR 0.92, 95% CI 0.85-0.99, P=0.02), women who had 0 parity (COR 1.78, 95% CI 1.14-2.77; AOR 1.89, 95% CI 1.09-3.28, P=0.02) and thin patients (COR 1.17, 95% CI 1.11-1.22; AOR 1.15, 95% CI 1.10-1.21, P=0.00) had a low risk of delivering a large for gestational age infant. And large for gestational age infants would have a large ratio of caesarean section (COR 3.08, 95% CI 2.08-4.57; AOR 2.79, 95% CI 1.86-4.19, P=0.00) Table 4.

Table 4: Unadjusted and adjusteda risk for outcomes in singleton birth after IVF/ICSI

Discussion

In our study, we only found that there was an increased risk of preterm birth after blastocyst transfer. After adjusting potential confounding factors, we also discovered high risk of preterm birth with blastocyst transfer. Some studies also demonstrated this opinion. A recent meta-analysis revealed that there was a high risk of preterm birth especially in fresh embryo transfer [12]. Kalra et al. compared 14743 singleton born after blastocyst and 32351 singleton after cleavage stage embryo transfer [9] and revealed that cleavage stage embryo transfer had a decreased risk of preterm birth (AOR: 1.39, 95% CI 1.29-1.50, P=0.00). And other studies also concluded a coincident result [8,11,17-20]. In other neonatal and maternal outcomes, we did not find any difference in two groups especially. Although many researches also pointed that duration of in vitro culture do not influence birth weight [4,5,12,20,21], one study found that there was a low risk of low birth weight after blastocyst transfer [22]. Moreover, Zhu et al. indicated that the duration of in vitro culture make a difference in birth weight [16]. As for very preterm birth, some studies found that outcome was similar [4,5,7,20,23]. However, a recent meta-analysis indicated that blastocyst had been worse [11]. In our study, we did not found any advantage in very preterm birth after cleavage stage transfer. Almost all studies pointed that there was no difference between two groups in very low birth weight and we were no exception [4,8,23].

For large for gestational age, we did not find a risk after blastocyst. Furthermore, a binary logistic regression analysis indicated that large for gestational age was associated with the type of infertility, years of unwanted childlessness, parity, delivery mode and body mass index. Some studies also proved this opinion. Makinen et al found that body mass index, parity and culture had a significant effect on large for gestational age [15]. Similarly, a low body mass index mother had a high risk of small for gestation age in our research. A large number of studies have revealed that the body mass index is related to gestational age [15,24-26]. The exact reason for this was not clearly. Some scholar pointed that it may be related with lifestyle, maternal metabolism, insulin resistance, glucose homeostasis, fat oxidation and amino acid synthesis [27-29]. And parity also made an influence on gestational age. Some meta-analysis also indicated that [30,31]. Ng et al. found that previous pregnancy (AOR=2.03, 95% CI 1.08-3.81), caesarean section (AOR=1.98, 95% CI 1.10-3.55) and married mothers (AOR=1.85, 95% CI 1.00-3.42) had a high risk of large for gestational age babies [26].

In a recent meta-analysis, a higher male-female ratio after blastocyst transfer compared with cleavage-stage embryo transfer (OR:1.29, 95% CI 1.10-1.51) was found [32]. Some professors also demonstrated that [33,34]. Dumoulin et al. showed that higher mean log cell number of trophectoderm cells in ICSI male embryos compared with female in blastocyst [35]. It might interfere with the process of imprinted X-inactivation. The other professor thought that a decrease in trophectoderm cells in female would cause female mortality in long duration of in vitro culture [36,37]. So it made an influence on sex ratio.

We found that many articles had discussed this method. But in our study, we optimized the inclusion criteria and exclusion criteria to get a better result. We only included the first cycle of patient to avoid confounding factors and repetition. And we excluded the intrauterine lesions and uterine malformation for instance bicornuate uterus, unicornuate uterus, septate uterus, endometrial tuberculosis and so on. Even so, we had some limitations. The sample in blastocyst transfer was small compared with cleavage stage transfer. And this study was a retrospective cohort study from a single center. Part of diagnoses was made in primary hospital, so it may cause an error.

Conclusion

In summary, we found that there was a high risk of preterm birth after blastocyst transfer. And the body mass index was an important factor in gestation age. The type of infertility, years of unwanted childlessness, parity, delivery mode and body mass index were related to large for gestational age. Finally, a higher male-female ratio after blastocyst transfer compared with cleavage-stage embryo transfer was showed.

Funding

This study was funded by Henan Province Health Department.

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