Twins, Premies and Sex

1. Twins, Premies and Sex Eric S. Shinwell Department of Neonatology Kaplan Medical Center, Rehovot Hebrew University, Jerusalem Israel

2. Epidemic of Multiple Births • 1980-97: High-order Multiples up >400%Twins up >50% • Twins still rising, slightly less triplets • Multiples: now 3-4% of all births Guyer: Pediatrics 1999; Hoyert. Pediatrics 2001; Reichman 2007

5. Israel VLBW Neonatal Database VLBW <1500 gr.

6. Risks for Multiples • Mortality • Morbidity • Short term • Long term

7. Infant Mortality/1000 live births Luke B, et al: J Reprod Med 1992;37:661

8. Average CP rate / 1000 survivors (number of studies) Blickstein 1999

9. GA by plurality Alexander 1998

10. Birth Weight (50%ile) Alexander 1998

11. MultiplesMore Prematurity+More Intra-uterine Growth RetardationCorrection for GA?

12. Haklai, 2008

13. Neonatal MortalityPediatrix, USA, 124 NICUs, 23-35 wks

14. Canadian Neonatal Network, 2005 • 24 NICUs, n=3242, <32 weeks • Singletons=2284, Multiples=958 • Multiples – higher GA, older mothers, more maternal HBP, more CS, more prenatal care, less drugs, tobacco, alcohol, less abortions. • Mortality ≤26 wks: multiples 30%, singletons 20%. • Multivariate - More RDS (1.3) less ROP (0.5). Qiu X, et al. Obstet Gynecol 2008;111:365

15. Morbidity and Mortality in VLBW Singletons, Twins and Triplets

16. Study Sample • Israel National VLBW Infant Database • 28 NICU’s • 1995-99 • Live-born • All singletons + all complete sets of twins and triplets N=7047

17. Hypertension Maternal Age Ethnic Origin Antenatal Care Antenatal Steroids Mode of Delivery Plurality Gestational Age SGA Sex Resuscitation in DR Apgar at 5’ Risk Factors

18. Plurality and Poor Outcome

19. Conclusions • VLBW Triplets have increased risk for death. • Perhaps effect in twins diluted by larger infants 1000-1500 grams with low mortality rates?

20. Effect of Gender

21. Conclusions 2Risk Factors for poor outcomes • Lack of Antenatal Care • No Antenatal Steroids • Vaginal Delivery • SGA • Male • Need for Resuscitation at birth • RDS

22. Twin, Male sexRisk factors, 22-25 weeks NICHD Network, NEJM 2008

23. Death: Singleton Male - Female

24. Death: Multiples Male - Female

25. Conclusions • 22-25 weeks • Increased risk of Death or Neuro-Developmental Impairment • Male • Multiples

26. Male DisadvantageorFemale Advantage?Role of Androgens or other factors?

27. Effect of Male on Female co-twin • Compare Birth Weight in sets of twins • MM, FF, MF • Females in MF pairs weigh significantly more than females in FF pairs • Endocrine / Paracrine / Other factors? • Glinianaia, Int J Epidemiol 1998 • Blumrosen, J Perinat Med 2002 • Goldman, Twin Research 2003

28. Effect of Intrauterine PositionAnimals Male X Male Female X Female MM FF

29. Testosterone • Higher in MM than FF • Transfer between fetuses • Via blood • Via Amniotic Fluid

30. Masculinizing effectsin Animals • Physiologic • Morphologic • Behavioral

31. Physiologic • inhibition of pulmonary surfactant production • later vaginal opening • later mating and impregnation • more male offspring in the next generation • increased sensitivity to testosterone • changes in neurotransmitters (GABA) and metabolic activity (cytochrome oxidase) in the hypothalamus and limbic system

32. Morphologic • increased anogenital distance • larger testes and seminal vesicles • smaller prostate glands • larger sexually dimorphic nucleus in the adult rat brain

33. Behavioral • increased likelihood to mount females • more parental behavior • more aggression

34. Masculinizing in Human FemalesUnlike-sex twin pairs • decreased hearing, increased myopia • reduced finger length (2D:4D) ratios • increased tooth size • increased functional cerebral lateralization • behavioral effects • Long Term • more infertility • more Polycystic Ovary Disease

35. Accelerate Glucocorticoids Estrogens Inhibit Androgens Alveolar Type II cell Development Direct Effect Via Fibroblasts

36. GENDER DIFFERENCESINMULTIPLE PREGNANCIES Shinwell ES1, Reichman B2, Lerner-Geva L2, Boyko V2, Blickstein I1, in collaboration with the Israel Neonatal Network 1Kaplan Medical Center, Rehovot, Hebrew University, Jerusalem, 2Women and Children Health Research Unit, Gertner Institute, Sheba Medical Center, Tel Hashomer Israel Pediatrics, 2007;120:e447

37. Hypothesis • If the male disadvantage in incidence of RDS and its complications is mediated via factors that may inhibit Type II cell development and surfactant production,and • If the effect of males on female co-twins is mediated via such factors (eg androgens)

38. Hypothesis (2) • Then, the incidence of RDS and its complications in females from unlike-sex pairs should be significantly closer to that of their male twins, when compared to female singletons or from FF pairs • i.e. transfer of “male disadvantage” not “removal of a female advantage”?!

39. Objective • To compare the incidence of major morbidity and mortality in Very Low Birth Weight (VLBW; <1500 gr.) infants in 5 different groups. Twins Singletons M F MM FF MF

40. Inclusion BW 500-1500 grams GA 24-34 weeks Singletons+ Full sets of Twins Study Sample Exclusion • Major Congenital Malformations • Induced Termination of Pregnancy

42. IVH III+ PVL ROP 3+ Outcome Variables • RDS • Pneumothorax • BPD at 36 weeks • Mortality Should show effect No effect? ?

43. IVF Antenatal Care Antenatal Steroids Presence of Labor PROM Chorioamnionitis Cesarean section Tocolysis Abruptio Placentae GA Ethnic origin DR Resuscitation Confounding Variables Univariate and Multivariate Analyses

44. BW by GA – z-score

45. Mortality

47. RDS

48. Pneumothorax

49. BPD at 36 weeks GA

50. By Comparison!