Improving Reproductive Outcomes: Rationale, evidence and models for interconception care

1. Improving Reproductive Outcomes:Rationale, evidence and models for interconception care Anne L. Dunlop, MD, MPH Emory University School of Medicine Department of Family & Preventive Medicine Global Collaborating Center in Reproductive Health

2. Disclaimer Funding for this activity was made possible in part by the HHS, Office on Women's Health. The views expressed in written materials or publications and by speakers and moderators at HHS-sponsored conferences, do not necessarily reflect the official policies of the Department of Health and Human Services; nor does the mention of trade names, commercial practices, or organizations imply endorsement by the U.S. Government.

3. Objectives Following this presentation, learners will be knowledgeable of: • The definition of ‘Interconception Care’ (ICC); • The historical context and rationale for ICC; • Review of evidence supporting ICC: • Evidence-based recommendations for content of ICC; • Models for the delivery of ICC.

4. ICC: Definition(s) • Medical & psychosocial care provided from the birth of one child through a subsequent pregnancy to improve health and modifiable risk factors in order to promote subsequent healthy pregnancy and family outcomes. (LA Best Babies, 2003) • A subset of preconception care that addresses continuity of risk from one pregnancy to the next.(Kotelchuck, 2006)

5. Historical Context: Limits of Prenatal Care • Prenatal care has improved in reach, access, and utilization, and disparities in utilization have narrowed in the US while… • Preterm and low birth weight rates have increased overall; • Racial/ethnic disparities in preterm and low birth weight rates have widened. • No compelling literature links comprehensive prenatal care with improved birth outcomes. • No impactful breakthroughs in the content of prenatal care • Debate around topic of 17-hydroxy-progesterone End of era viewing prenatal care as the public health strategy for improving birth outcomes and reducing disparities (Atrash, 2006)

6. Historical Context: Preconception Care • If prenatal care is not the answer then  ‘preconception care’ • Initially, focus upon a single preconception visit, however… • Poor utilization (no “demand”, attitude of providers, no payment) • Unplanned pregnancies • Those at elevated risk less likely to seek or receive services • Next, emphasis upon preconception care for women with specific chronic medical conditions (e.g., diabetes) • Later, ‘preconception health’ broadened to encompass: • Inter-relationship between women’s health and pregnancy outcomes (two-way interaction in which pregnancy conceptualized as a key life health event) • Life-course perspective (Kotelchuck, 2003; Lu, 2003)

7. Rationale: Interconception Care • Women known to the health care delivery system • Over 95% have some prenatal care and most delivered in hospital • All live/still births identifiable by state-filed certificates • Most with miscarriages or abortions receive medical care • Care-seeking for infant is typically high • Many seek family planning services (Klerman, 2005) • Women with demonstrated reproductive potential, with small children in the home • Goal: Achievement of wanted, planned, well-spaced pregnancies • Goal: Achievement of well-being of woman, children, and family • Repeatability of birth outcomes in subsequent pregnancies • Preterm birth, fetal growth restriction, miscarriage, stillbirth

8. ICC: Evidence to Support • Birth planning, birth spacing • Specific interconception strategies • Gaps in evidence • ‘Packaged’ interconception interventions

9. A. Evidence for planning & spacing • Unintended (mistimed or unwanted) pregnancies: • Increased detrimental prenatal behaviors1 • Increased risk of preterm and low birthweight delivery2 • Negative health & social outcomes for mother and child1 • Short interpregnancy intervals (< 18-months): • Increased risk preterm, low birthweight, SGA births3 1 Brown & Eisenberg. National Academy Press: Washington, D.C., 1995. 2 Orr, et al. Paediatric and Perinatal Epidemiology 2000; 14: 309-313. 3Conde-Agudelo, et al. JAMA 2006; 295: 1809-23.

10. B. Evidence for Specific Interventions • For those with prior Neural Tube Defect: • Folic acid (4 mg qd)  71% reduction in recurrence1 • For those with Binge Alcohol Use: • Brief motivational interviewing among pre- and interconception women  > 2-fold reduction in risk of alcohol-exposed pregnancy2 • For those with Gestational Diabetes or Diabetes: • Intensive lifestyle intervention (diet and exercise)  58% reduction in incidence of type 2 diabetes3 • Cohort study of PCC/ICC for women with diabetes on-going(Conry, Kaiser Permanente CA) 1 MRC Vitamin Study Research Group. Lancet 1991; 338: 131-7. 2 Floyd et al. Am J Prev Med 2007; 32: 1-10. 3Kitzmiller et al. Diabetes Care 1996;19:514–41.

11. Evidence Against Specific Interventions • For those with Prior Spontaneous Preterm Birth occurring< 34 weeks’ gestation: • Azithromycin + metronidazole (vs. placebo) q. 4 months until conception of a subsequent pregnancy • NO difference in subsequent PTB1 (with lower birth weight and gestational age in treatment arm) 1 Andrews, et al. Am J Obstet Gynecol. 2006; 194: 617-23.

12. C. Gaps in Evidence Related to ICC • Bacterial Vaginosis (BV) • Observational studies: association between BV & PTB (RR 1.4-6.9), PPROM (RR 2.0-7.3), & SpAb (RR 1.3-2.0); Very early screening and treatment (< 14 wks’) associated with reduced LBW and very PTB1 • Cochrane review: early screening and treatment (< 20 wks‘) may reduce the risk of PTB; and, among women with a previous PTB treatment is associated with a decrease in PPROM2 • Periodontal disease: • Extent of periodontal disease linked with PTB although RCT of prenatal treatment NOT associated with reduced occurrence3 • Psychosocial Stress: • Stress linked with PTB;4 observational study of IC social support associated with reduction in VLBW & very PTD5 1Koumans, et al. Syracuse Healthy Start . MCH Epidemiology Conference 2006. 2 McDonald, et al. Cochrane Database of Systematic Reviews 2007. 3Offenbacher, et al. Ann Periodontol 2001;6:164-74. 4Dunkel-Scheter. Perinatal & Neonatal Medicine 1998; 3: 39-42. 5 Willis, et al. J Natl Med Assoc 2004; 96: 315-24.

13. D. Evidence for ICC ‘Packages’ • For those with Social & Biobehavioral Risks: • Limited evidence based upon observational studies (Healthy Start) • Limited evidence based upon RCT(CePAWHS) • For those with Prior Adverse Outcome: • Limited evidence based upon observational (Denver) and observational cohort (Grady) studies. • No evidence (yet) based upon RCT (Drexel University ICC study)

14. Magnolia Healthy Start Program • Design: Participants (n=206) vs. Medicaid-eligible matched group (n=412) for period 2000-2005 • Participants: Low-income African American women 15-44 yrs (pre- and interconception) • Intervention: Case management of health and social risks using the Healthy Start model • Outcomes: • Proportion experiencing STI • Proportion experiencing pregnancy within 24 months • Change in low birth weight rate pre-post program implementation • Change in infant mortality rate pre-post program implementation Livingood. Maternal and Child Health Journal 2009.

15. Magnolia Healthy Start Program • Results (Healthy Start Clients vs. matched Medicaid controls): • Proportion experiencing no STI: 78.8% vs. 70.4% (p=0.02) • Proportion pregnant within 24 months: 12.9% vs. 13.7% (p=0.88) • Change in low birth weight rate : -10.9% vs. +3.2% (p=0.066) • Change in infant mortality rate: -45.6% vs. -10.3% (p=0.92) Livingood. Maternal and Child Health Journal 2009.

16. Central PA Women’s Health Study (CePAWHS) • Design: Randomized controlled trial • Participants: Low-income rural women 18-35 years of age (with and without prior pregnancy) • Intervention: Six group sessions addressing biopsychosocial risks for preterm and low birthweight • Reproductive planning, reproductive tract infections • Stress • Physical activity, Nutrition • Tobacco smoke (including 2nd-hand), substance abuse • Outcomes: • Health literacy, behavior change skills, self-efficacy in regard to targets of intervention above • Actual behavior change Downs. Maternal Child Health Journal 2009.

17. Central PA Women’s Health Study (CePAWHS) • Results: • Improved self-efficacy with regard to childbearing • Improved nutrition label reading • Improved intake of folic acid multivitamin • Statistically significant difference in mean weight loss at 6- and 12-mo post-intervention (of about 4 lb) between treatment and control group women Downs, et al. Maternal and Child Health Journal 2009.

18. Denver Interconception Health • Design: Demonstration project, compared participant outcomes to non-participants. • Participants: Low-income women with a LBW delivery • Intervention: Case management & home visitation x 3 years • Focus on maternal role, medical & reproductive health, contraception, and life course. • Outcomes: • Compliance with medical care and family planning • Pregnancy spacing, and repeat LBW delivery

19. Denver Interconception Health • Results: Women participating for at least 6-months in the program (vs. women who did not so participate) had: • Improved compliance with medical care & family planning • Improved pregnancy spacing • Improved use of prenatal care in subsequent pregnancy • 34% fewer subsequent LBW infants Loomis LW, The Interconception Health Promotion Initiative. Final Report to the Colorado Trust, Denver, CO, 2003.

20. Grady IPC Program • Design: Prospective-retrospective cohort • Participants: Low-income African-American women with a previous VLBW delivery • Intervention: Coordinated primary care and social support via group process for 24-months following VLBW delivery • Reproductive planning • Folic acid, dietary and activity counseling • STD prevention, screening, treatment • Care for chronic problems and substance abuse • Outcomes: • No. of pregnancies within 9- & 18-months of index VLBW • No. of adverse pregnancy outcomes

21. Grady IPC: Care Package • Definition of an individualized IPC plan to address 7 areas epidemiologically linked to low birth weight/preterm delivery: • Reproductive planning(assistance in achieving intendedness and spacing) • Prevention, screening and treatment forsexually-transmitted infections • Micronutrient supplementation& screening/treatment for nutritional deficiencies • Prevention, screening and treatment for periodontal disease • Management of chronic disease • Treatment and referral for substance abuse • Screening and treatment fordepression, psychosocial stressors, & domestic violence • Provision of health and dental services in accordance with the IPC plan for 24 months; • Community outreach via a trained Resource Mother.

22. Grady IPC: Provision of Care • Contact with a multidisciplinary team: • Family nurse practitioner, family physician, periodontist, nurse case manager, social worker, and Resource Mother; • Primary care visits occurred every 1 -3 months (dependent upon extent of health problems) in a group setting with integration of group educational experiences according to the Centering Pregnancy Model of prenatal care; • Home visits and telephone contact by the Resource Mother monthly to address psychosocial issues. Rising SS. J Nurse Midwifery 1998.

23. Grady IPC Care Program • Results: • Women in the control cohort had, on average, • 2.6 times (95% CI: 1.1-5.8) as many pregnancies within 18-months • 3.5 times (95% CI: 1.0-11.7) as many adverse pregnancy outcomes • Cost-analyses revealed: • Program Cost per Participant per 24-Months: $4,197 (x 29 = $121,713) • Cost per subsequent LBW averted: $55,576 (x 5 = $277,880) • Cost savings per 29 participating women: $100,591 • Conclusions: Primary health care and social support for low-income African-American women following a VLBW delivery mayenhance achievement of a subsequent 18-month interval, reduce recurrence of adverse pregnancy-related outcomes, and result in cost savings. Dunlop et al., Maternal Child Health Journal 2007.

24. Drexel U Preterm Prevention Project • Design: Randomized controlled trial • Participants: Philadelphia women with PTB < 34 weeks’ • Intervention: Targets infection, smoking, stress, depression, weight, and delaying repeat pregnancy. • Outcome: Repeat PTD • Results: Very poor participation of women Limited data upon which to draw conclusions

25. Clinical Content of Interconception Care:Evidence-based Recommendations

26. Outline • Recommended PCC/ICC strategies for all women • Recommended ICC strategies for risk conditions • Prior preterm birth • Prior growth-restricted fetus • Prior miscarriage • Prior stillbirth • Prior pregnancy affected by GDM, Preeclampsia, NTD

27. General PCC/ICC Recommendations

28. CDC National Summit on Preconception Care:Ten Recommendations for Improving Preconception Health Recommendation 1. Individual responsibility across the life span. Encourage each woman and every couple to have a reproductive life plan. Recommendation 2. Consumer awareness. Increase public awareness of the importance of preconception health behaviors and individuals’ use of preconception services using information and tools appropriate across varying contexts. Recommendation 3. Preventive Visits As a part of primary care visits, provide risk assessment and counseling promotion advice to all women of childbearing age to reduce risks related to the outcome of pregnancy. Recommendation 4. Interventions for identified risks. Increase the proportion of women who receive interventions as follow up to preconception risk screening, focusing on high priority interventions (i.e., those with high population impact and sufficient evidence of effectiveness). Recommendation 5. Interconception care. Use the interconception period to provide intensive interventions to women who have had a prior adverse pregnancy outcome (e.g., infant death, LBW, preterm).

29. CDC National Summit on Preconception Care:Ten Recommendations for Improving Preconception Health Recommendation 6. Pre-pregnancy check ups. Offer, as a component of maternity care, one pre-pregnancy visit per pregnancy. Recommendation 7. Health coverage for low-income women. Increase Medicaid coverage among low-income women to improve access to preventative women’s health, preconception, and interconception care. Recommendation 8. Public health programs and strategies. Infuse and integrate components of preconception health into existing local public health and related programs, including emphasis on those with prior adverse outcomes. Recommendation 9. Research. Augment research knowledge related to preconception health. Recommendation 10. Monitoring improvements. Maximize public health surveillance and related research mechanisms to monitor preconception health.

30. General Preconception Interventions • The Select Panel recommends key clinical interventions because of their high population impact and sufficient evidence of effectiveness (detailed in following table).

31. * CDC/Select Panel Recommendation 4: Interventions for Identified Risks

32. Continued…. * CDC/Select Panel Recommendation 4: Interventions for Identified Risks

33. * CDC/Select Panel Recommendation 4: Interventions for Identified Risks

35. * CDC/Select Panel Recommendation 4: Interventions for Identified Risks

36. Specific Interconception Interventions • The Select Panel recommends that providers use the interconception period to provide intensive interventions to women who have had a prior adverse pregnancy outcome or complication: a. Prior preterm birth b. Prior growth-restricted fetus c. Prior miscarriage d. Prior stillbirth e. Prior pregnancy affected by Neural Tube Defect f. Prior pregnancy affected by Gestational Diabetes g.Prior pregnancy affected by Preeclampsia

37. Prior Preterm Birth (PTB) • Burden: Other than multiple gestation, previous PTB is the single most important risk factor for another PTB among multiparous women. • Recurrence: Women who have had a PTB have increased risk for subsequent PTB. • The earlier in gestation the prior PTB, the greater the risk for another. • The risk of recurrence increases with each prior PTB: • One PTB < 35 weeks  16% risk of a 2nd PTB; • Two PTB < 35 weeks  41% risk of a 3rd PTB; • Three PTB < 35 weeks  67% risk of a 4th PTB.

38. Prior Preterm Birth (PTB) • Other risk factors for recurrence: • African American ethnicity • Low maternal BMI (<19.8 kg/m2) • Large inter-pregnancy weight loss (more than 5 kg/m2) • Cigarette smoking • Short inter-pregnancy interval • History of cervical insufficiency or short cervix on transvaginal ultrasound • Presence of inflammatory changes in the placenta of the prior preterm pregnancy.

39. Prior Preterm Birth (PTB) • Evidence base for interconception interventions: • No well-designed studies address the outcome of recurrence of PTB specifically; • However, studies support that addressing key risk factors (e.g., maintaining appropriate body weight, smoking cessation, and achievement of at least 18 months between pregnancies) improve pregnancy outcomes in general.

40. Prior Preterm Birth (PTB) • Evidence base for prenatal interventions: • Most evidence supports that cervical cerclage during pregnancy is NOT beneficial. • However, in one meta-analysis the risk of recurrent PTB was reduced by cerclage for women with a prior PTB and a short cervix by ultrasound. • Significant reduction in recurrent PTB is found for women with a prior PTB treated with 17-hydroxyprogesterone from 16-36 wks’. • Reductions in neonatal death, respiratory distress syndrome, bronchopulmonary dysplasia, intraventricular hemorrhage, and necrotizing enterocolitis in the progesterone-treated group.

41. Prior Preterm Birth (PTB) • ICC Recommendation:†Women with a history of PTB should be evaluated for remediable causes to be addressed before the next pregnancy. Strength of recommendation: A; Quality of the evidence: II-2 • ICC Recommendation:†Women with a previous spontaneous PTB should be informed of the potential benefit of treatment with progesterone in a subsequent pregnancy. Strength of recommendation: A; Quality of the evidence: I-a † Stubblefield et al. The clinical content of preconception care: reproductive history. Am J Ob Gyn 2008.

42. Prior Fetal Growth Restriction (FGR) • Recurrence: Risk of recurrent FGR is about 20%, depending upon etiology. • Etiology: Etiology of FGR is complex, and divided into 3 broad categories with different risk factors: • Maternal: • Low pre-pregnancy weight, malnutrition, poor weight gain • Maternal age younger than 16 years or older than 35 years • Short inter-pregnancy interval • Smoking and substance abuse • Chronic maternal vascular disease such as hypertension, renal insufficiency, diabetes mellitus, and the collagen vascular diseases (especially when complicated by preeclamsia) • Also Fetal and Placental causes

43. Prior Fetal Growth Restriction (FGR) • Evidence base for interconception interventions: • No well-designed studies addressing the outcome of recurrence of FGR specifically; • However, studies support that addressing key risk factors (e.g., maintaining appropriate body weight, smoking and illicit substance use cessation, achievement of at least 18 months between pregnancies, and addressing maternal chronic conditions) decrease the risk of FGR.

44. Prior Fetal Growth Restriction (FGR) • ICC Recommendation:† Women with a history of a growth-restricted fetus should be evaluated for remediable causes to be addressed before the next pregnancy. Strength of recommendation: A; Quality of the evidence: II-2 † Stubblefield et al. The clinical content of preconception care: reproductive history. Am J Ob Gyn 2008.

45. Prior Spontaneous Abortion (SpAb) • Burden: • Sporadic pregnancy loss occurs at random throughout reproduction in 10-15% of clinically recognized pregnancies. • Recurrent pregnancy loss (defined as ≥ 3 consecutive SpAb) occurs in about 1% of fertile couples. • Etiology: • Uterine factors(anomalies, leiomyomata, adhesions, endometrial defects) • Immunologic factors(antiphospholipid syndrome, others) • Thrombophilias & fibrinolytic factors • Endocrine factors(luteal phase defect, PCOS, hyperprolactinemia, diabetes, thyroid disease) • Genetic factors(aneuploidy, chromosomal rearrangements, other) • Other (sperm aneuploidy, celiac disease, other)

46. Prior Spontaneous Abortion (SpAb) • Recurrence: • Patients with sporadic pregnancy loss have good prognosis for future pregnancies. • When no cause is identified, couples with recurrent pregnancy loss (RPL) can be reassured that a successful next pregnancy occurs in a 50-75% of women; otherwise, recurrence risk related to underlying cause.

47. Prior Spontaneous Abortion (SpAb) • Evaluation of Recurrent Pregnancy Loss:†Women with recurrent early loss should have a work-up to include: • measurement of anti-phospholipid antibodies (lupus anticoagulant (LA) and anti-cardiolipin antibody (ACA) • parental karyotyping • imaging of the uterus (ultrasound or hysterosalpingogram) • No randomized controlled studies have shown any benefit from measuring infectious agents, antinuclear antibody (ANA), paternal leukocyte antigens/anti-paternal antibodies, or their associated treatments and thus cannot be recommended. • No recommendation can be made about thyroid testing, glucose tolerance or luteal phase defects as data are not conclusive about their association with RPL (not recommended by ACOG, but are recommended by European Society for Human Reproduction). † Stubblefield et al. The clinical content of preconception care: reproductive history. Am J Ob Gyn 2008.

48. Prior Spontaneous Abortion (SpAb) Evidence base for prenatal recommendations: • Although no randomized controlled studies exist, psychological support has been shown to improve outcomes in RPL patients: • 86% rate of successful pregnancy with specific counseling and support versus 33% with no specific care • SpAb rates of 26% vs. 51% for those with and without supportive therapy. Evidence base for interconception recommendations: • For those with elevated anti-phospholipid antibodies, two small trials found pregnancy loss reduced by 54% for treatment with heparin and aspirin versus aspirin alone. Therapy must start early in pregnancy, so antiphospholipid syndrome should be identified preconceptionally. • Those diagnosed with a uterine septum on imaging can undergo preconception resection of the septum via hysteroscopy with reported rates of live births of 70-85% based on case series data. • Removal of uterine fibroids is an option when they are identified and felt to be contributing to RPL, such as a large submucous fibroid, which deforms the cavity. All surgical treatments are largely based on case series, so the actual treatment effect is unclear.

49. Prior Spontaneous Abortion (SpAb) • ICC Recommendation:† • Women with sporadic early pregnancy loss should be reassured of a low likelihood of recurrence and offered routine preconception care. • Those with three or more early losses should be offered a work-up to identify a cause. Therapy based on the identified cause may be undertaken. For those with no identified cause, the prognosis is favorable with supportive care. Strength of recommendation: A; Quality of evidence: I-a. † Stubblefield et al. The clinical content of preconception care: reproductive history. Am J Ob Gyn 2008.

50. Prior Stillbirth (SB) • Recurrence:The risk of recurrent stillbirth is increased 2-10 fold for women with a history of prior stillbirth(s) over the risk for women with no such history. A history of stillbirth also increases the risk of a range of other adverse pregnancy outcomes in the subsequent pregnancy. • Recurrence risk depends upon maternal race and characteristics of the prior stillbirth, including etiology, gestational age, and the presence of fetal growth restriction.