Intern seminar Assisted reproductive technology and perinatal risk Supervisor 謝旻玲醫師

Outline Case with congenital anomaly Discussion Introduction of ART ART induced perinatal risk Outcome of ART baby ART = Assisted reproductive technology 人工生殖技術 IVF = In Vitro Fertilization 體外人工受孕

Basic information - Name : 吳x融 - Age : 0 day-old - Chart No : 180XXX83 - Sex : male - Admission : 2017/03/01

Chief complaint - Prematurity 34 weeks with congenital heart disease and respiratory distress after birth

Mother hospital course Prenatal examination at 奇美(IVF) -> Twin A single umbilical artery Twin B suspected fetus CHD (pregancy GA 23 weeks) Cell-free DNA testing (NIPT): low risk trisomy 13,18,21 12/15 Right upper quadrant pain, susp. acute cholecystitis Premature uterine contraction Pre-eclampsia 02/06 02/13 Discharge

Mother hospital course Abdominal pain, vaginal bleeding Sent to NCKU ER -> admission 02/28 03/01 Caesarean section

Present illness Subcostal retraction, air hunger without obvious cyanosis after birth

BP: 64/39 mmHg Saturation: 90% BP: 62/42 mmHg Saturation: 86% BP: 71/44 mmHg Saturation:93% BP: 80/53 mmHg Saturation: 90%

Vital Signs : T: 36.6°C P: 158/min R: 62/min BP: 80/53mmHg Chest : Clear breath sound No crackles, Regular heart beats Pansystolic murmur grade 2/6 Skin : No petechiae or ecchymosis, hypospadias, imperforate anus

Past history - Birth History: - Growth and Development: G1P1, C/S (twin, twin A breech), GA: 34+0 weeks, BBW:1598g, DOIC(-), PROM(-) Apgar score: 7 -> 8 - Growth and Development: BW: 1598g (3rd%, asymmetric SGA) BH: 43.5cm (23th%) HC: 30cm (15th%)

Family history Mother: Type 1 DM for 10++ years under insulin

Decreased lung marking Decreasing lung marking

EKG tall P waves, left axis deviation with a superior axis (>30°), LV hypertrophy, and diminished RV forces Tall P-waves in lead II indicate right atrial enlargement, and ventricular forces are notable for left axis deviation and diminished right ventricular forces (small or absent R-waves in precordial leads V1–V3)

RV LV RA LA

LA RA LV ASD RV

PA Ao PA 前 AO 後 -> NO TGA

RV LV RV hypoplasia

Lab data

Problem and plan Tricuspid atresia, type 1B with pulmonary stenosis, VSD, large ASD and PDA, RV hypoplasia 6 m/o for 1st OP Imperforate anus with cutaneous fistula Consult pediatric surgeon for operation Hypospadias with bilateral mild hydronephrosis Consult urologist for operation (> 6 months) - Prematurity 34 weeks

WHY ? Congenital anomaly - IVF ? - Maternal DM ? - Chromosomal ?

Discussion Assisted reproductive technology and perinatal risk

Louise brown in 1978 - First ART baby - Oldham hospital

In Vitro Fertilization Step 1: Control Ovarian Hyperstimulation (COH) Step 2: Egg Retrieval  Step 3: Fertilization Step 4: Embryo Culture & Embryo Quality Step 5: Embryo transfer Assisted reproductive technologies (ART)代表所有在體外對oocyte做的事情。 其中，IVF是ART中的老祖宗，也是現今最常用的一種方式。 三步驟: 排蛋抓蛋受精蛋 排蛋Monitoring and stimulating a woman's ovulatory process 抓蛋Removing ovum or ova from the woman's ovaries 受精蛋Letting sperm fertilize them in a liquid in a laboratory.

In Vitro Fertilization Factor which believed increase perinatal risk underlying causes of infertility - aspects of the ART procedures the medications used, culture media composition, length of time in culture, freezing and thawing of embryos, altered hormonal environment at the time of implantation, the manipulation of gametes and embryos or a combination of these.

Introduction Infertility 10-15% over world (50% female, 30% male, 20% unknown) ART induced perinatal risk Preterm birth LBW, SGA birth Birth defect Vertical transmission of genetic diseases ?

ART and Preterm birth Statistically significant about 20% increase in the relative risk of preterm birth in IVF twins Estimated two-fold increased risk of preterm birth in IVF singletons Reason ? McDonald SD, Han Z, Mulla S, Murphy KE, Beyene J, Ohlsson A. Preterm birth and low birth weight among in vitro fertilization singletons: a systematic review and meta-analyses. Eur J Obstet Gynecol Reprod Biol 2009;146:138–48

ART and LBW birth Both singleton and twin IVF pregnancies demonstrate an increased risk of low birth weight compared with naturally conceived (RR about 1.5) the relative risk of babies being SGA is also increased about 40–60% McDonald SD, Han Z, Mulla S, Murphy KE, Beyene J, Ohlsson A. Preterm birth and low birth weight among in vitro fertilization singletons: a systematic review and meta-analyses. Eur J Obstet Gynecol Reprod Biol 2009;146:138–48

ART and Birth defect Between 2% and 3% of all infants are diagnosed with a congenital anomaly soon after birth. IVF is associated with a 30–40% increased risk of major congenital anomalies compared with natural conceptions. pre-auricular tags, tongue tie, undescended testicles, unstable hips, single umbilical artery (www.eurocat-network.eu) Hansen M, Bower C, Milne E, de Klerk N, Kurinczuk JJ. Assisted reproductive technologies and the risk of birth defects – a systematic review. Hum Reprod 2005;20:328–38

ART and Vertical transmission of genetic diseases Microdeletions of the long arm of the Y chromosome (Yq), in particular the AZF region, can also cause spermatogenic failure and either oligo- or azoospermia ART imprinting syndrome ??? Beckwith-Wiedemann syndrome (BWS), Angelman syndrome (AS) and, more recently, maternal hypomethylation syndrome 本科張旭陽、蔡孟穎醫師(1997年)曾針對68位南台灣的這些罹患無精子或精子稀少症的男性分析，發現有6位( 9%)的確有這方面基因的缺陷。  Amor DJ, Halliday J. A review of known imprinting syndromes and their association with assisted reproduction technologies

Long-term outcomes for children The physical, neurological and developmental health of children born after IVF is normal Cerebral palsy ??? Carson C, Kurinczuk JJ, Klemetti R, Redshaw M, et al. Cognitive development following ART: effect of choice of comparison group, confounding and mediating factors. Hum Reprod 2010;25:244–52.

Long-term outcomes for children ART parents - Expressed greater warmth towards their child, - interacted more with their child - less stress associated with parenting Golombok S1, Brewaeys A, Cook R, Giavazzi MT, The European study of assisted reproduction families: family functioning and child development. Hum Reprod. 1996 Oct;11(10):2324-31.

Future ART Technique WE

Take home message IVF pregnancies are at increased risk of adverse perinatal outcomes, it is also the case that the majority of the children born following IVF will have a normal outcome Recommend complete pre-natal examination for IVF birth

Reference In Vitro Fertilisation: Perinatal Risks and Early Childhood Outcomes, Scientific Impact Paper No. 8 May 2012 Hansen M, Bower C, Milne E, de Klerk N, Kurinczuk JJ. Assisted reproductive technologies and the risk of birth defects – a systematic review. Hum Reprod 2012;20:328–38. 成大婦產部陳達生醫師

Thank you ANY QUESTIONS ?

Brain echo showed mild PVE and follow-up brain echo showed normal on 03/16 He tried room air since 03/29 and able to use N/C, transferred to level 2 Advance feeding gradually, family train double-barrel colostomy care , MBD on 4/5