Do neonates conceived after assisted reproductive technology require neonatal surgery more frequently? A 5-year single-center experience
Reprint request to: Dr Satohiko Yanagisawa, Department of Pediatric Surgery, Jichi Medical University, 3311-1 Yakushiji, Shimotuke, Tochigi 329-0498, Japan. Email: email@example.com
Assisted reproductive technology (ART) has increased the incidences of multiple gestations and low birth weights, which frequently warrant pediatric surgery. ART may have also increased the rate of birth defects. In this study, we aimed to determine whether infants conceived after ART required neonatal surgery more frequently compared with naturally conceived infants.
Material and Methods
Our study population comprised 1891 infants (160 ART (+) and 1731 ART (−)) who were admitted to our neonatal intensive care unit during a 5-year period (January 2006–December 2010); of these, 198 infants (9 ART (+) and 189 ART (−)), with diseases requiring surgery, were referred to pediatric surgeons (consultation cases). We examined the following: (i) factors potentially increasing the requirement for surgery; (ii) frequency of birth defects; and (iii) maternal factors that may increase the need for surgery.
A significantly higher incidence of multiple gestation and low birth weight was observed in the ART (+) group than the ART (−) group. However, ART did not yield a higher rate of surgery and birth defects: overall, the rate of surgery was 4% (7/160) in the ART (+) group and 8% (143/1731) in the ART (−) group. Of 198 consultation cases, the percentage of infants actually requiring surgery was approximately the same in the ART (+) group (7/9 [78%]) and the ART (−) group (143/189 [76%]).
Infants conceived after ART comprised a small proportion of neonatal surgery cases, and did not require surgery more frequently.
The practice of perinatal medicine requires a multidisciplinary team approach in which pediatric surgeons play an important role. Recent advances, especially in sonography, in prenatal diagnosis of various fetal diseases have enabled physicians to antenatally detect ‘high risk’ infants for neonatal surgery. Perinatal team members have the clinical impression that infants conceived after assisted reproductive technology (ART, ART infants) were more prone to having conditions that require neonatal surgery.
ART, including in vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI), has become widely available in developed countries, including Japan. ART infants currently account for approximately 2% of all infants born in Japan. While ART is a welcome option for infertile couples, it is associated with a few risks. ART increases the rate of multiple gestations, premature birth, and very low or extremely low birth weights.[2-6] ART also appears to increase birth defects;[4-6] however, there is no concrete evidence to support this. Thus, ART infants are more frequently admitted to the neonatal intensive care unit (NICU), and they occupy a large fraction of the NICU, which may create a social problem. Whether there is a similar effect of ART infants on neonatal surgery is yet unknown.
It is reasonable to assume that the increased rate of multiple gestations, low birth weights, and birth defects in ART infants would increase the need for neonatal surgery. Birth defects frequently require surgery. Prematurity accompanied either by low birth weight or by multiplicity may increase the risk of various intestinal diseases (including necrotizing enterocolitis), which also require surgery.[7-10] However, to our knowledge, no study has focused on whether ART infants require neonatal surgery more frequently. To address this issue, we performed a retrospective observational study in a single tertiary center.
Material and Methods
We retrospectively examined the medical charts of infants admitted to the NICU at the Center for Perinatal and Neonatal Medicine of Jichi Medical University between January 2006 and December 2010. Perinatal team members of our institute periodically meet to discuss all high-risk cases, especially cases that are expected to require pediatric surgical care. We retrieved records for infants who received consultation for pediatric surgery (consultation cases).
During this period, a total of 1891 infants were admitted to the NICU: 160 ART infants, 213 conventional infertility treatment (IFT) infants (controlled ovarian hyperstimulation, COH; or artificial insemination of husband's semen, AIH), and 1518 naturally conceived infants. We classified infants as ART (+) and (−); the ART (+) group comprised 160 infants and ART (−) comprised 1731 (213 + 1518) infants, with conventional IFT infants accounting for 12% (213/1518) of ART (−) infants. A total of 198 infants were referred for surgery (consultation cases); of these, nine, three, and 186 infants were ART, conventional IFT, and naturally conceived, respectively. Thus, the ART (+) and (−) groups had nine and 189 infants, respectively, showing that conventional IFT infants accounted for only 1.6% of ART (−) infants. When we excluded data from conventional IFT subjects and compared ART (+) to natural conception, the results were the same as when we compared ART (+) and ART (−). Therefore, for simplicity, we compared ART (+) and (−), with the conventional IFT group and naturally conceived group combined into the ART (−) group.
First, we examined the numbers of infants admitted to the NICU, and the number of consultation cases among those infants. Infants requiring cardiovascular surgery for congenital lesions were not considered consultation cases and were thus excluded from the present analysis.
Next, we examined factors that may be associated with the requirement for surgery: gestational weeks, birth weight, infant sex, diagnosis, surgical procedure performed, clinical outcome, chromosomal abnormalities, and associated malformations. These factors, as well as number of multiple gestations, were compared between the two groups.
Finally, we examined maternal factors that may influence the requirement for surgery: age at pregnancy, percentage of mothers over 35 years of age, underlying diseases, and poor pregnancy outcome. For statistical analysis, Fisher's exact test, Mann–Whitney U-test, and chi-square tests were used where appropriate, with P < 0.05 considered significant.
Table 1 presents the number of infants admitted to the NICU, comparing ART to ART (−) infants. Approximately 350–400 neonates were admitted to the NICU annually, and the number remained stable over 5 years. ART infants comprised 8.5% (160/1891) of NICU admissions. The rate of admitted ART infants was high in 2007 and 2008 (11.2% and 10.8%, respectively), but decreased and returned to the 2006 rate thereafter.
Table 1. Annual number of infants admitted to the NICU
Table 2 shows consultation cases among ART (+) and ART (−) infants. Total consultation cases numbered 198 (male 95, female 103; male/female = 0.92), and the number varied year-by-year (range, 20–52; average, 40). Of these, 150 infants (76%) actually required surgery (Table 3). The number of consultation cases did not increase throughout the study period. Of the 198 consultation cases, nine (4.5%; male two, female seven; male/female = 0.3) were of ART infants; the number varied from 0 to 3 annually and showed no increasing tendency. Among the consultation cases, ART infants (n = 9) included patients conceived with IVF-ET using fresh eggs and embryos (n = 6), IVF-ET using frozen embryos (n = 2), and ICSI (n = 1). Only three of the consultation cases (1.5%) were conceived after conventional IFT, and the remaining 186 (94%) infants were conceived naturally. Thus, ART infants did not exhibit higher rates of consultation for surgery.
Table 2. Annual number of consultation cases
Table 3. Diagnosis of infants needed surgery, total 150 cases
| 9||Esophageal atresia|
| 8||Hypertrophic pyloric stenosis, meconium obstruction|
| 6||Ovarian cyst|
| 5||Gastroschisis, omphalocele, necrotizing enterocolitis|
| 4||Intestinal atresia, inguinal hernia congenital diaphragmatic hernia|
| 2||Cloacal extrophy, purulent lymphadenitis, rectal polyp, adrenal tumor, tracheomalacia, biliary atresia congenital biliary dilatation|
| 1||Duplication cyst, gastric ulcer, intussusception, omphalomesenteric fistula, urachal remnant extrapulmonary sequestration, CCAM, CHAOS congenital tracheal stenosis, cervical cyst testicular torsion, infantile fibroadenoma sacrococcygeal teratoma, acute renal failure, cerebral palsy, hydrocephalus, spina bifida|
Characteristics of consultation cases are presented in Table 4. ART infants exhibited significantly higher incidence of multiple gestation (33% vs 6%, P = 0.018) and low birth weight (<2500 g; 78% vs 34%, P = 0.012). Regarding multiple gestations, all three cases were dichorionic twins conceived before 2008 and were premature (<36 weeks), including one extremely premature infant (<28 weeks). Other factors did not differ between the ART (+) and ART (−) groups. Of the 9 ART infants, one had necrotizing enterocolitis and two experienced meconium obstruction. Two (22%) IVF infants had trisomy 21 as a chromosomal disorder and 2 (22%) had ventricular septal defect as an associated anomaly. Thus, ART infants did not exhibit higher rates of anomalies or infantile intestinal diseases.
Table 4. Infant factors in consultation cases
|Extremely premature infant||1/9(11%)||7/189(4%)||0.310|
|Low-birth weight infant||7/9(78%)||65/189(34%)||0.012*|
|Extremely low-birth weight infant||3/9(33%)||19/189(10%)||0.064|
Final postnatal diagnosis of the 9 ART infants among the consultation cases were as follows: meconium obstruction (n = 2), necrotizing enterocolitis (1), esophageal atresia (1), duodenal atresia (1), intestinal atresia (1), anorectal malformation (1), anal polyp (1), and sacrococcygeal teratoma (1). Seven cases required surgery and two cases improved by conservative treatment. All surgeries were performed in the neonatal period. Clinical course was uneventful in seven of nine consultation cases, while two infants died because of underlying disease unrelated to the surgery.
Maternal data are presented in Table 5. ART (+) mothers were significantly older than ART (−) mothers. ART (+) mothers showed significantly higher incidence of poor pregnancy outcome and multiple gestations. Poor pregnancy outcomes in ART (+) mothers included premature delivery, dichorionic twins, fetal hydrops amnii, and fetal growth restriction.
Table 5. Maternal factors in consultation cases
|Average age at pregnancy(years)||34.2(30–41)||30.3(16–45)||0.045*|
|Mother over 35 years of age||4/9(44%)||55/189(29%)||0.683|
|Mother with underlying diseases||1/9(11%)||14/189(7%)||0.681|
|Poor pregnancy outcome||7/9(78%)||67/189(35%)||0.010†|
Our study clarified some questions concerning the influence of ART on perinatal outcomes. Infants conceived after ART accounted for 8.5% of all NICU admissions; however, ART infants accounted for only 4.5% of pediatric surgical consultations (9/198). ART infants account for only 2% of all neonates in Japan; therefore, the percentage of ART consultation infants (4.5%) is more than twice the expected rate. However, interpretation of this finding is not straightforward; in fact, the pediatric surgeons had dealt with only 9 ART infants during the 5-year period. While ART infants experienced significantly higher incidences of multiple gestations and low birth weight, other factors did not differ between ART (+) and (−). Thus, overall, our study showed that ART infants did not require neonatal surgery more frequently.
ART has become widely available in Japan. Increasing rates of employment in Japanese women has increased the age at which women decide to conceive a child. Fecundity gradually decreases with age, and thus, the number of couples seeking ART is expected to increase further in Japan.[1, 10, 11] ART gives infertile couples a chance to have a child. However, its risks are being increasingly discussed. ART is known to increase multiple gestations and low-birth weight infants; for example, in Canada, 28.5% of IVF infants were twins and 1.4% were triplets. Low birth weights, including those caused by multiplicity, lead to intestinal immaturity, causing necrotizing enterocolitis, and to meconium obstruction, such as meconium plug syndrome and meconium ileus,[9, 10] all of which usually require surgery. Chromosomal disorders and associated anomalies also sometimes require surgery. Birth defects may also increase after ART. Recent studies have shown a significantly higher incidence of birth defects among infants conceived with ART.[4-6] Rates of esophageal atresia, anorectal malformation, and cleft lip with or without cleft palate are higher in infants after ART. Since ART pregnancy rates have increased, possibly resulting in an increase in the number of ART infants requiring surgery, we thought that it would be reasonable to assume that ART is correlated with the increased need for surgery in ART infants.
However, this study negated our assumption and indicated no increase in ART infant admission to the NICU and no increase in ART infant consultation. Although ART infants exhibited significantly higher incidence of multiple gestation and low birth weight, this did not actually increase the requirement of surgery. Moreover, other factors did not differ between ART (+) and (−) infants and mothers. Why did these results differ from our clinical impressions?
First, we, as surgeons and perinatologists, may have been too strongly impressed by an individual patient, and this may be common in experienced doctors. We may have been deeply influenced by an impressive disease in an ART infant. We experienced 9 ART infants, who were candidates for surgery, which may have influenced our impression of their frequency. Second, through meetings or consultation, surgeons are likely to know the background of individual patients well before delivery. Surgeons know that the patient is an ART infant and that the parents waited months or years for his/her delivery, which also makes an impression. Third, some reports repeatedly emphasize the risks and drawbacks of ART pregnancy. Together, these influences may lead surgeons to be too cautious concerning ART infants and cause surgeons to overestimate the dangerous aspects of ART.
The present study demonstrated that ART did not significantly affect pediatric surgical practice. Furthermore, in 2008, the Japan Society of Obstetrics and Gynecology formally recommended that only one fertilized egg or blastocyst be transferred in utero, principally to avoid multiple gestations. This led to a decreased rate of twin pregnancy after ART, and may influence pediatric surgery practice. In fact, all three twin patients from ART in our study were born before 2008.
We, for the first time, have determined the influence of ART on pediatric surgery practice. Our study has two main limitations. First, our study population was obtained from a small residential area, and thus, it may not represent nationwide trends. Second, we analyzed short-term, and not long-term, data. Nationwide or worldwide studies examining both short- and long-term outcomes are necessary.
We declare no conflicts of interest.