Overview. In Vitro Fertilization: a Success Story

Transcription

1 Does IVF cause adverse perinatal outcomes? Paolo Rinaudo *, MD PhD Rebecca A. Jackson %, MD Departments of Ob/Gyn & *Center for Reproductive Sciences & % Epi/Biostats University of California, San Francisco Overview 1. Background (success and risks of in vitro fertilization) 2. Meta-analysis results ( Dr. Jackson) 3. Potential mechanisms & Barker hypothesis 1. In Vitro Fertilization: a Success Story 2 million children conceived through IVF one in babies born in the world is conceived by IVF estimated annual number of IVF cycles worldwide: ~ 500,000 Pregnancy rate/cycle 35% SART data

2 ART Pregnancy Complications Early pregnancy: Ectopic (3-5%), heterotopic (0.5-1%) Ovarian hyperstimulation Multiple gestation (20-30%) Real problem: multiple gestations Twins vs. 10 x higher rate of PTD 7X higher rate of PTD <32 wks 2X higher rate of PNM Increased pre-eclampsia, GDM Higher rates of malformations Longer hospital stay The 2002 Revolution Stromberg Sweden, Sweden, Lancet 359:461, 2/2002 incidence of neurological sequalae: OR 1.7 Hansen Australia, NEJM 346:725, 3/2002 incidence of major birth defects: OR= 2 Hansen Schieve CDC CDC, NEJM 346:731, 3/2002 incidence of low birth weight in singleton: RR 2.6 Bonduelle, Belgium Hu Reprod 16:671,2002 ~ incidence of major birth defects comparing ICSI vs. IVF: 3.4% vs. 3.8% Problems with the literature No RCT s (not ethical) Most studies are not controlled for age and parity Many studies include various types of ART in one group (IVF, ICSI, IUI, ovarian stimulation). Many studies are small 2

3 2. The question is.. Do IVF pregnancies have worse perinatal outcomes than naturally conceived pregnancies even when controlled for age, parity and number of gestations? 3 meta-analyses Studies included slightly different as a result of differing inclusion criteria 1. Jackson: only studies matched for age and parity 2. Helmerhorst: matched and unmatched 3. McDonald: matched for age Analyses slightly different All 3 came to same conclusions with similar odds ratios ; Helmerhorst, BMJ, 2004, McDonald, J Ob- Gyn Canada; 2005 Inclusion Criteria Singleton gestations resulting from IVF and/or GIFT. Comparison group=spontaneous conception Controlled for at least age and parity Primary Outcomes: PNM, PTD, LBW, SGA 15 studies met inclusion criteria comprising 12,283 IVF singletons and 1.9 million spontaneous conceptions Study Designs of Included Studies All retrospective All unblinded (obstetricians knew IVF status) Most controlled only for age and parity. A few also adjusted for demographics, smoking and obstetric history. All cohort design (3 traditional, 8 matched, 4 external comparison) Jackson, Obstet Gynecol, 2004 Jackson, Obstet Gynecol,

4 Perinatal Mortality IVF Spontaneous Odds ratio Odds ratio Study n n (95% CI) (95% CI) Cohort Gissler , Matched cohort Dhont Koudstaal Reubinoff Verlaenen Westergaard External comparison Howe Tanbo Tottal l 102//5199 ((19..6/1000)) Absolute risk 1271/ /192,,993 ((6..6//1000)) (( )) Jackson, Obstet Gynecol, 2004 Preterm Delivery (<37 wks) IVF Spontaneous Odds ratio Odds ratio Study n n (95% CI) (95% CI) Cohort Bergh % 1.7 Gissler , Von During , Matched cohort Dhont Koivurova Koudstaal Reubinoff Verlaenen Wang Westergaard External comparison Howe Tan Tanbo Wang 465 9% 1.8 Tottal l 1399/ /12,114 % 11..5% 221,,947/410, (( )) 5..3% Favors IVF Favors spontaneous Jackson, Obstet Gynecol, 2004 Low Birth Weight (<2500g) IVF Spontaneous Odds ratio Odds ratio Study n n (95% CI) (95% CI) Cohort Bergh % 1.2 Gissler , Matched cohort Dhont Koivurova Koudstaal Reubinoff Verlaenen Westergaard External comparison Tan Tanbo VLBW (<1500g) IVF Spontaneous Odds ratio Odds ratio Study n n (95% CI) (95% CI) Cohort Bergh % 2.6 Gissler , Von During , Matched cohort Dhont Koivurova Verlaenen Westergaard External comparison Tanbo Total % 957/10,096 (9.5%) 7371/195,342 (3.8%) 1.8 ( ) Total 240/9577 (2.5%) 4213/427,382 (0.99%) 2.7 ( )

5 SGA (<10%) Additional outcomes: caution! IVF Spontaneous Odds ratio Odds ratio Study n n (95% CI) (95% CI) Matched cohort Koudstaal Maman Reubinoff Verlaenen External comparison Howe Tan Wang % 1.6 Fewer studies Outcomes not as clearly defined or vary from study to study Total % 275/1889 (14.6%) 198/2208 (8.9%) 1.6 ( ) More antenatal outcomes More L&D outcomes Number IVF Spont Odds Ratio Odds Ratio Outcome Studies % % (95% CI) (95% CI) Antepartum Delivery <32-33 weeks ( ) Gestational diabetes ( ) Malpresentation ( ) Placenta previa ( ) Preeclampsia ( ) Preterm delivery after spontaneous labor ( ) Stillbirth ( ) Vaginal bleeding ( ) Labor and delivery Number IVF Spont Odds Ratio Odds Ratio Outcome Studies % % (95% CI) (95% CI) Labor induction ( ) Spontaneous labor ( ) Operative vaginal delivery ( ) Cesarean delivery ( ) Elective Cesarean ( ) Emergent Cesarean ( )

6 More neonatal outcomes Is the risk real? Number IVF Spont Odds Ratio Odds Ratio Outcome Studies % % (95% CI) (95% CI) NICU admission ( ) Neonatal death ( ) Same results despite differing populations & study designs Most odds ratios are >2 Higher quality studies found higher OR s Or is it bias? Hard Outcomes These are not RCT s and so are fraught with bias (information bias, treatment bias, selection bias, recall bias etc) Treatment bias AKA precious pregnancy : Higher rates of prenatal visits & procedures, antepartum hospitalization, elective C/S, and induction in IVF group. Are these indicated or due to patient and MD worry? These interventions could lead to iatrogenic increases in PTD and LBW. Could treatment bias explain our results? IVF Spontaneous Odds ratio Odds ratio Outcome % % (95% CI) (95% CI) PNM ( ) SGA ( ) VLBW ( ) VPTD (<32 wks) ( ) Placenta Previa ( )

7 Additional risks: Malformations, CP, development and imprinting disorders Major malformations Meta-analysis of Major Malformations (MM) CAUTION! Data from individual studies (not metaanalyses) These outcomes are difficult to define and their definition varies from study to study These outcomes could be higher in the IVF group because they are looking harder for them (ascertainment bias) OR 1.29 ( ) (IVF/ ICSI) Limited by: Heterogeneous definitions of MM Heterogeneous study design Some studies controlled for maternal age, plurality, and other important factors, others did not Rimm, J Asst Repro Gen, 2004 Cerebral Palsy Two large population based cohort studies Significantly increased risk of CP in IVF group (RR of 1.6 to 2.8) before adjusted for PTD 1. Stromberg showed continued increased risk after adjustment for PTD whereas 2. Hyidtjorn showed no increased risk of IVF after adjustment for PTD Nonetheless, overall rate of CP is higher in IVF because of higher rate of PTD Stromberg, Lancet, 2002: Hvidtjorn, Pediatrics, 2006 Developmental Delay (DD) Difficult to define, many different measures Most studies very small: n= Most show no difference but a few showed lower mental development scores and/or more developmental delay in ICSI children compared with spontaneous conceptions Largest study (5680 IVF), Stromberg, showed increased DD with RR of 2.8 for singles + twins even after adjust for PTD and other factors. Non-significant increase (RR-2.6) in singletons alone. Stromberg, Lancet,

8 Imprinting Disorders Imprinting 2 paternal sets of chromosomes: Hydatiforme Mole 2 maternal copies sets of chromosomes: Teratoma Beckwith-Widemann Syndrome Macroglossia Visceromegaly Macrosomia Omphalocele Microcephaly Embryonal Tumors Angelman Syndrome Developmental delay Speech impairment Ataxia Happy demeanor Microcephaly Seizures. 3. Why ART pregnancies might have worse outcomes? 1. The Patient 2. The Procedure(s) 3. The Obstetrician 8

9 Patient Related Risk Factors Low Birth Weight Age Nulliparity Prior poor pregnancy outcomes? Infertility 56 yo British woman with twins Infertile patients with spontaneous conception Modified from Olivennes et al., 2002 Author Odds Ratio Year Wilson Funderbunk Berkowitz Olsen Varma Tuck Ghazi Bhalla Very Low birth Weight The Procedure ODDs Ratio Control Subfertile no RX Subfertile and Rx McElrath et al,

10 Methylation and Expression Methylation changes during preimplantation development 1. DNA methylation 2. genomic imprinting 3. histone modification Could it be placentation? Controlled studies show more abnormal morphologies in IVF singleton placentae Higher incidence of placenta previa and abruption Higher incidence of preeclampsia and growth restriction: both of which may be related to abnormal placental function Role of Obstetric Management The worry factor or precious pregnancy bias causes increased interventions More prenatal visits and procedures More antepartum hospitalizations More labor inductions and cesarean sections 10

11 Twins Meta-analysis Things in perspective: the twins data PNM: 1.4 ( ) PTD: 1.6 ( ) LBW: 1.1 ( ) SGA: 0.9 ( ) Maternal hospitalization 4.7 ( ) Cesarean: 1.3 ( ) NICU: 2.2 ( ) McDonald, AJOG, 2005 Increased risk in singletons but not twins? Could be a sample size problem (confidence intervals wider for twins meta than for singles meta) The added risk of IVF/infertility has a marked impact on a low risk singleton pregnancy but this added risk is not detectable in the already high risk twin pregnancies Role of Obstetric Management ACOG Committee Opinion: 2005 Advise counseling about 1. obstetric risks especially for twins but also for singletons, 2. possible chromosomal abnormalities following ICSI in severe male factor cases, 3. and genomic imprinting modifications. Note that absolute risk to IVF babies is small The single most important health effect of ART for the offspring remains iatrogenic multiple fetal pregnancy supports efforts to decrease multiples 11

12 Summary 1. 3 meta-analyses analyses revealed worse perinatal outcomes for IVF singletons, independent of age and parity. 2. The etiology for these adverse outcomes is unknown but may be related to abnormal placentation and/or infertility 3. IVF twins seem to be at slightly higher or no higher risk than spontaneous twins Conclusions New technological solutions offer unprecedented hope to infertile couple, with excellent success. The risks of the procedures are not yet clearly defined/ understood and deserve further evaluation. 4. The quality of the evidence is Level II-2 ( well-designed case-control control or cohort studies ) Does IVF cause adverse perinatal outcomes? Paolo Rinaudo *, MD PhD Rebecca A. Jackson %, MD rinaudop@obgyn.ucsf.edu Departments of Ob/Gyn & *Center for Reproductive Sciences & % Epi/Biostats University of California, San Francisco 12