Effects of assisted reproductive technologies in neonates with indications for surgery (2007

Abstract

PURPOSE:

Recently, the number of births using assisted reproductive technologies (ART) has increased. An associated increase in the incidence of congenital malformations in babies conceived using this technology has also been reported. Therefore, we aimed to investigate the rate of malformations in babies with neonatal surgical diseases, who were conceived using ART.

MATERIALS AND METHODS:

Between January 2007 and December 2016, 1737 patients were admitted to our hospital. We analyzed the incidence of congenital cardiac diseases, genetic anomalies, and congenital anomalies of the kidney and urinary tract (CAKUT) in neonates conceived by ART. The χ² test and logistic regression analysis were used to assess the odds ratios (ORs) for congenital malformations. A P-value < 0.05 indicated statistical significance.

RESULTS:

The OR for CAKUT was 16.94 for the first-birth neonates conceived using ART, [P < 0.05, AUC (area under the curve) = 0.86]. However, for non-surgery neonates, the OR for CAKUT was 5.99 (P = 0.15, AUC = 0.87), compared to 32.27 (P < 0.05, AUC = 0.93) for parallel conditions in surgery-neonates.

CONCLUSION:

Neonates conceived using ART are prone to develop CAKUT, which will need surgical treatment. Therefore, more management is necessary for associated malformations in these babies, particularly in cases with CAKUT.

Keywords

Neonate advanced age primipara assisted reproductive technology associated malformation congenital anomalies of the kidney and urinary tract (CAKUT)

1 Introduction

Recently, a survey showed that the number of deliveries in women with advanced age has increased in developed countries, such as the United States. Furthermore, in the UK, the number of primipara mothers aged 50 years or older is increasing. The same trend has been reported in Japan. Advanced age primipara is defined as first-time mothers aged 35 years or older. Before 1993, advanced age primipara was defined as first-time mothers aged 30 years or older, but owing to the increased number of first-time mothers aged 30 years or older, a new definition has been adopted by the WHO and in various countries. In 2014, the overall percentage of births by first-time mothers aged 35 years or older was 58.3% [1]. This was because of delayed marriage caused by an increase in the number of girls going to high school, college, etc., to become professionals, which has been reported to be the main cause of the shortened period of pregnancy after marriage [2]. This has triggered a decline in the birth-rate. However, advancements in medical technology have popularized assisted reproductive technologies (ART).

ARTs are broadly defined as procedures that aid in conception. They have evolved from miraculous to standard treatments in the 36 years since they were first reported [3]. Various ART procedures are available, such as intrauterine insemination (IUI), in vitro fertilization-embryo transfer (IVF-ET), intra-cytoplasmic sperm injection (ICSI), and transfer of thawed frozen embryo. The number of babies conceived using ART has exceeded 200,000 worldwide, and even the percentage of women aged 40 years or older who conceive by ART has been reported to be increasing [4]. Even in Japan, ART can is widely performed; however, the number of multiple pregnancies and low birth rate of high-risk fetuses are also increasing [5]. Apart from the low birth-rate, the risks of miscarriage, premature delivery, and pregnancy-induced diabetes mellitus have been reported to increase significantly in cases with multiple pregnancies compared with singleton pregnancies [6]. Therefore, single-embryo transfer is currently performed as a measure to reduce the risks in multiple pregnancies in many advanced countries, and the same measure has been adopted in Japan as well [7]. However, congenital malformations in fetuses due to ART are still observed.

Of late, we have started performing surgery on neonates conceived using ART at our hospital. In this study, we retrospectively investigated the correlation among sex, gestational age, birth-weight, age of the mother, age of the father, primipara or multipara, status of emergency maternal transport, congenital heart disease, genetic anomalies, congenital anomalies of the kidney and urinary tract (CAKUT); and the status of ART among neonates born at our hospital, for whom surgery was indicated.

2 Methods

Between January 2007 and December 2016, 1737 neonates were delivered at our hospital or other hospitals, including clinics, and were admitted in our hospital because they required in-hospital management. We investigated 865 first-birth neonates of 1550, with documentation on sex, gestational age, birth-weight, mother’s age, father’s age, status of emergency maternal transportation, congenital cardiac disease, genetic anomaly, and CAKUT (Fig. 1). A single mother who delivered multiple babies was counted as one.

Fig. 1

Screening design (January 2007 to December 2016).

For statistical analysis, the Chi-squared test (χ² test) and logistic regression analysis were used to assess the odds ratio (OR) for congenital malformations. The receiver operating characteristic (ROC) curve was used for area under the curve (AUC) analysis. JMP 12.2 software (SAS Institute Inc., Cary, NC, USA.) was used for statistical analysis, and a P-value < 0.05 indicated statistical significance.

3 Results

The number of neonates, that require hospitalization and surgery in the neonatal period, has hardly changed within the past 10 years (Fig. 2). Table 1(A) shows a summary of the primipara cases who conceived using ART and without using ART. Among the first-birth neonates, 36 were conceived by ART, and surgery was indicated for 9 of those (for esophageal atresia, duodenal atresia, anorectal malformations, omphalocele, sacrococcygeal teratoma). The mean age of mother (p < 0.05) and that of father (p < 0.05) tended to be higher in neonates conceived by ART. However, emergency maternal transport was not necessary for neonates conceived by ART, and non-surgery cases was indicated for many such neonates. Genetic anomalies occurred in 2.9% of non-ART cases, whereas in 5.6% of those conceived by ART (p < 0.05). CAKUT occurred in 1.2% of non-ART, while in 2.1% of those conceived by ART (p < 0.05).

Fig. 2

Neonatal patients (January 2007 to December 2016).

Table 1A

Primipara cases (January 2007 to December 2016)

	ART* (N = 36)	Non-ART* (N = 829)	P values
M:F	16:20 (36.3%: 63.7%)	468:361 (56.4%:43.6%)	−
Mean gestation period (week)	36.4±2.6	36.0±3.5	0.40
Mean birth weight (g)	2293.1±640.2	2232.6±760.4	0.64
Mean mother’s age (y)	37.4±4.2	31.1±5.1	<0.05
Mean father’s age (y)	39.0±5.5	32.7±5.9	<0.05
Emergency maternal transport	0	36(4.3%)	N/A
Congenital heart disease	3(8.3%)	42(5.1%)	0.71
Genetic anomaly	2(5.6%)	24(2.9%)	<0.05
CAKUT**	4(2.1%)	10(1.2%)	<0.05

ART: assisted reproductive technology.

CAKUT: congenital anomalies of the kidney and urinary tract.

Table 1(B) shows a summary of the primipara cases with surgery and without surgery. Among the non-surgery cases of infants conceived by ART, the mean ages of both mother (p < 0.05) and father (p < 0.05) were observed to be more advanced. Genetic anomalies occurred in 2.7% of non-ART cases, whereas in 3.7% of those conceived by ART (p < 0.05). On the other hand, CAKUT occurred in 1.1% of non-ART cases, whereas in 3.8% of those conceived by ART (p = 0.30). Even among the surgery cases of infants conceived by ART, the mean ages of both mother and father were observed to be more advanced. At the same time, genetic anomalies occurred in 6.0% of non-ART cases, while in 14.2% of those conceived by ART (p = 0.62). CAKUT occurred in 6.0% of non-ART cases, while in 33.3% of those conceived by ART (p < 0.05).

Table 1B

Primipara cases (January 2007 to December 2016)

	Non-surgery			Surgery
	ART* (N = 27)	Non-ART* (N = 781)	P values	ART* (N = 9)	Non-ART* (N = 48)	P values
M:F	12:15	438:343	−	4:5	30:18	−
(44.4%:55.6%)	(56.1%:43.9%)	(44.5%:55.5%)	(62.5%:37.5%)
Mean gestation period (week)	36.2±3.0	35.6±3.5	0.59	37.2±2.2	37.6±3.4	0.65
Mean birth weight (g)	2259.1±659.8	2191.9±757.1	0.72	2513.7±646.6	2646.3±699.3	0.32
Mean mother’s age (y)	37.1±4.1	31.2±5.1	<0.05	38.4±4.5	30.1±5.0	<0.05
Mean father’s age (y)	39.3±5.2	32.8±5.9	<0.05	38.2±6.5	32.0±46.2	<0.05
Emergency maternal transport	0	35(4.5%)	N/A	0	1(2.0%)	N/A
Congenital heart disease	2(7.4%)	38(4.9%)	0.85	1(14.2%)	4(8.0%)	0.95
Genetic anomaly	1(3.7%)	21(2.7%)	<0.05	1(14.2%)	3(6.0%)	0.62
CAKUT**	1(3.8%)	8(1.1%)	0.30	3(33.3%)	2(6.0%)	<0.05

ART: assisted reproductive technology.

CAKUT: congenital anomalies of the kidney and urinary tract.

Recently, a tendency of delayed marriage has been reported, and this fact has naturally resulted in a sudden increase in the age at which women have their first birth, which has been reported to be associated with an increase in number of low-birth-weight infants [8]. Furthermore, the increased number of low-birth-weight infants has been reported to be associated with an increased number of neonates hospitalized in the neonatal intensive care units (NICU), as well as with an increased number of cases of emergency maternal transport. Likewise, there has been a yearly increase in the number of low-birth-weight infants delivered by advanced age primipara in our hospital (Fig. 3). Thus, χ² test was used to investigate the birth-weights of first-birth infants delivered by advanced age women. There were 177 low-birth-weight infants born to mothers aged 35 years or older. The odds ratio (OR) for low-birth-weight infants delivered by mothers aged 35 years or older was 1.98 (P < 0.01) (Fig. 3). Emergency maternal transport was indicated for 82 cases and this number was found to decrease every year (Fig. 4). The cases of death after an emergency maternal transport were all related to non-surgery cases. In addition, surgery was indicated for 7 neonates and they all survived. Moreover, of these surgery cases, none were conceived by ART, and only 1 had a fatal diagnosis (Fig. 4).

Fig. 3

Low-birth weight infants from mothers aged 35 years or older primipara. (January 2007 to December 2016).

Fig. 4

Emergency maternal transport (January 2007 to December 2016).

Compared with infants conceived by spontaneous conception, those conceived by ART are known to be at a high risk for congenital malformations [9], such as chromosomal anomalies [10, 11], congenital cardiac diseases [12], and congenital renal anomalies [13]. Women who conceived by ART were found to be at relatively advanced age, and naturally, the age of the father was also higher. Therefore, we performed a logistic regression analysis in primipara cases on the age of mother, the age of father, congenital cardiac diseases, genetic anomalies, and CAKUT. Table 2(A) shows a summary of the statistical analysis on effects of ART in primipara cases. The odds ratio [OR] for the age of the mother was 895.34 (at 95% confidence interval [CI] of 40.71–26450.48, P < 0.05). The OR for genetic anomaly was 3.43 (at 95% CI of 1.01–10.26, P < 0.05). OR for CAKUT was 16.94 (at 95% CI of 3.00–83.41, P < 0.05). The value for the AUC analysis 0.86 was assessed by using the ROC curve. Table 2(B) shows a summary of the statistical analysis on effects of ART in primipara cases without surgery. The odds ratio [OR] for the age of the mother was 412.54 (at 95% confidence interval [CI] of 12.85–18882.87, P < 0.05). The OR for genetic anomaly was 8.43 (at 95% CI of 2.27–28.43, P < 0.05). The OR for CAKUT was 5.99 (at 95% CI of 0.26–51.89, P = 0.15). The value for the AUC analysis, which was assessed by using the ROC curve, was 0.87. Table 2(C) shows a summary of the statistical analysis on effects of ART in primipara cases with surgery. The OR for the age of the mother was 3429.19 (at 95% CI of 19.82–4377770, P < 0.05). The OR for CAKUT was 32.27 (at 95% CI of 1.40–1643.13, P < 0.05). The value for the AUC analysis was assessed by using the ROC curve, was 0.93.

Table 2

Statistical analysis: Logistic regression analysis

(A) Effects of ART in primipara case (AUC = 0.86)
	OR	CI	P values
Mother’s age (y)	895.34	40.71–26450.48	<0.05
Father’s age (y)	77.06	0.76–5949.73	0.06
Congenital heart disease	0.20	0.01–1.73	0.20
Genetic anomaly	3.43	1.01–10.26	<0.05
CAKUT*	16.94	3.00–83.41	<0.05
(B) Effects of ART in primipara case: non-surgery (AUC = 0.87)
	OR	CI	P values
Mother’s age (y)	412.54	12.85–18882.87	<0.05
Father’s age (y)	121.84	0.71–14204.48	0.06
Congenital heart disease	0.28	0.01–2.69	0.34
Genetic anomaly	8.43	2.27–28.43	<0.05
CAKUT*	5.99	0.26–51.89	0.15
(C) Effects of ART in primipara case: surgery (AUC = 0.93)
	OR	CI	P values
Mother’s age (y)	3429.19	19.82-4377770	<0.05
Father’s age (y)	10.87	0.01–7937.06	0.46
Congenital heart disease	0.34	7.32–27.74	0.75
Genetic anomaly	0.25	3.42–25.36	0.68
CAKUT*	32.27	1.40–1643.13	<0.05

CAKUT: congenital anomalies of the kidney and urinary tract.

4 Discussion

The incidence of advanced age delivery is increasing in developed countries. In Japan, the age of first-time mothers is also getting higher due to delayed marriage [1]. The higher the age of the women, the lower the fertility. Consequently, the rate of using ART also increases. The result is an increased number of births conceived by ART. When the maternal age gets to 35 years or older, the risk of delivering a low-birth-weight baby has been observed to increase [8]. The OR for the low-birth-weight babies delivered in our hospital, by first-time mothers aged 35 years or older is 1.98. Increased age of conception has been observed to be associated not only with an increased incidence of miscarriage, but also with an increased incidence of chromosomal anomalies [10, 11], such as Down syndrome; and congenital malformations, such as congenital cardiac diseases [12] and congenital renal anomalies [13]. Compared to the past, the advancements in prenatal diagnosis has allowed more patient-referrals approaching the hospitals in the early stage diseases. However, the rate of emergency maternal-fetal transportation has remained the same; although, the mortality of babies during the transportation has been reported to decrease [14]. The rate of emergency maternal transport at our hospital has shown a yearly decrease; however, this is because of the increased number of early case referrals, that is, before such conditions arise. In addition, all neonates requiring surgery who were transported to our hospital survived. This is because neonatal treatment has markedly advanced as compared to that in the past.

Considering the mother’s age at conception by ART and conditions for delivery, the age at which women can commonly be treated with ART ranges between 31 and 44 years. The overall percentage of those aged 40 years or older was 31.2% in 2007, but it gradually increased to 34.4% in 2009 [15]. On the basis of these findings, advanced age primipara will increase more and more in the future, which will be accompanied by an increase in the number of births conceived by ART. Compared to that among babies delivered after spontaneous conception, the risk of congenital malformations has been reported to be higher among babies conceived by ART [9, 16]. The results of this study showed that the risk of CAKUT is high among neonates conceived by ART with surgical diseases. Thus, stricter postoperative management is necessary for these babies. There is a wide spectrum of renal abnormalities, from mild hydronephrosis to more severe cases, such as an unformed kidney, horseshoe kidney, ureteral duplications, uretero-pelvic junction obstruction, etc. CAKUT is the cause of 40–50% of pediatric end-stage renal disease cases worldwide [17]. In Japan, CAKUT is the cause of 68.3% of pre-dialysis chronic kidney diseases [18]. Therefore, voiding management is required in many such cases. At the same time, there are also cases wherein life-time management is necessary for avoiding dialysis/renal transplantation. In addition, women who conceive by ART readily become anxious about possible multiple pregnancies, miscarriages, etc., and are even reported to become depressed [19]. Treatment applied to decrease anxiety has been reported to affect reproductive treatment outcome [20]. Furthermore, now, the age of the father is also being viewed as important. When the father is at an advanced age, the risk of developmental impairments, such as autism and attention deficit hyperactive disorder, increases in infants. Additionally, suicidal attempts, increased risk of drug dependency, and decreased IQ score have also been reported to be associated with increased paternal age [21]. Women treated with ART are at a more advanced age and, naturally, the father of the baby will also be at more advanced age. This study confirmed that the mothers and fathers of the babies conceived by ART are at a more advanced age. Thus, for advanced age primiparas, particularly those who conceive using ART, stricter long-term support than that previously will be necessary in the future, considering the health risks for such babies.

Our study has several limitations. Our study includes a historical cohort study. The neonates who were not transported to our hospital could not be investigated. In conclusion, strict treatment support is needed for infants delivered by mothers at advanced age. This study showed that the risk of CAKUT is high among neonates with surgical diseases, who were conceived using ART. Therefore, stricter medical support than that previously will be necessary for associated malformations, in particularly CAKUT, to prevent kidney disease progression and reduce complications in such neonates.

Disclosure statements

The authors have no conflict of interest.

Footnotes

Acknowledgments

We gratefully acknowledge the work of past and present members of our laboratory.

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Effects of assisted reproductive technologies in neonates with indications for surgery (2007–2016)

Abstract

PURPOSE:

MATERIALS AND METHODS:

RESULTS:

CONCLUSION:

Keywords

1 Introduction

2 Methods

Disclosure statements

Footnotes

Acknowledgments

References