Medical Conditions and IVFObesity, thyroid, depression and hypertension

Marcelle I. Cedars, M.D.Professor and DirectorDivision of Reproductive Endocrinology and InfertilityUCSF

Impact of weight

Impact of obesity• Thum MY (J Obstet Gynecol 2007) - 8145▫ No decline in clinical pregnancy rate.

Statistically increased SAB rate (53% vs. 23%) lower LBR (18.4 % vs. 29.2%)

Impact of obesity

• Luke Fertil Steril 2011▫ Increased cycle cancellation for low

response▫ Increased odds of treatment failure (1.03

for overweight to 1.53 for BMI > 50kg/m2)

▫ Pregnancy rate decline from BMI 18.5 to > 50kg/m2 = 43% to 36%

▫ BUT pregnancy rate with BMI 30-35 - 41%

Impact of obesity

• Luke Hum Reprod 2011▫ Higher BMI associated with increased

failure to achieve a clinical pregnancy▫ BUT pregnancy at normal weight – 44.7% ▫ and with BMI > 40: 37.4%

▫ Early studies - No decrease in pregnancy rate with use of oocyte donor

Impact of obesity

Moragianni VA (Fertil Steril 2012) – 4609No statistically significant decline in LBR until BMI > 40

Live birth rates following IVF in different age groups by BMI

Koning AMH, Hum Reprod 2012

Impact of obesityegg or endometrium

• OD model–Bellver – (Hum Reprod 2007) n=2656 –

no statistically significant difference–trend for decreasing ongoing rate with increasing BMI

–Luke et al. (Fertil Steril 2011) n=9366 - no impact increasing BMI

Impact of ObesityOD model

Bellver J, Fertil Steril 2013

Impact of ObesityOD model

Jungheim ES, 2013

Impact of obesity – male/female

Schliep KS 2015

Role of Paternal Obesity

And decreased blastocyst formation, clinical pregnancy

Male obesity

• Is there an independent impact from maternal obesity?

• No impact on embryo quality up to day 3 (Merhi ZO: 2014; Bakos HW 2011)• Decrease blast formation (Bakos HW 2011)• Decrease in clinical pregnancy rate (Keltz J

2010; Bakos HW 2011; Merhi ZO 2014▫ IVF but not ICSI▫ ? Changes in the embryo epigenome with IVF

from “exposed” sperm

Additional risks of obesity

• Increased very early pre-term (twins, singletons) – Dickey 2012

• Increased risk for gestational diabetes• Increased risk for IUGR• Increased long-term risk for offspring

• In spontaneous conceptions – no difference in loss past 9 weeks.

Obesity - summary

• Implantation, pregnancy and live birth rates decrease with increasing BMI• Strong evidence for oocyte impact• New data suggest endometrial defect• Acute weight loss does not improve outcome• Decrement in outcome is “minimal”▫ What should criteria for dis-allowing

participation in ART be?• Pregnancy outcome is complicated with

increased childhood risk

Cellular impact of obesity

• Maternal and paternal obesity impact alters molecular composition with potential for epigenetic changes leading to long-term implications for offspring• Maternal obesity▫ Alterations in oocyte mitochondrial function▫ Altered metabolic fingerprint of human

embryos • Paternal obesity▫ Increased sperm DNA damage

Peri-conceptual trans-generational impact

• 1st wave of epigenetic change solely driven by maternal “machinery”▫ Altered mitochondrial function ▫ Maternal nutrition and metabolic state▫ Paternal obesity and nutrition impact

histone acetylation

Strategies for weight loss

• Physical activity▫ Even without weight loss – benefits obese

women (Palomba 2014)• Weight loss▫ Severe caloric restriction has a negative impact

(Tsagareli 2006)• Bariatric surgery▫ Lower doses of gonadotropins; but no change

in other oocyte/embryo parameters (Tsur A, 2014)

▫ Still high risk pregnancy

Very low weight Hypothalamic dysfunction

• Leptin▫ Produced primarily by adipose tissue▫ Regulates metabolism and reproduction

(hypothalamus)• Kisspeptin – GnRH secretagogue▫ Potential new therapeutic agent• Genes – not only KAL1 but also FGFR1,

PROKR2, GNRHR

Functional hypothalamic amenorrhea

• Treatment – weight gain, exercise reduction and appropriate psychological counseling• Exercise – decrease activity ▫ needn’t stop• Treatment with SSRI in conjunction with

specialized eating disorder clinic for anorexia• Assure adequate nutrition prior to ovulation

induction▫ Lower success rates▫ Fetal risk (IUGR), preterm delivery

Are markers of ovarian reservereliable?

Tran et al. JCEM 2011

Hypothalamic dysfunction

• Cautions▫ Agonist trigger Will not respond OD on long-term OCPs may respond as if

hypogonadotropic hypogonadism▫ LP support Do well with hCG (if not at risk for OHSS) If at risk for OHSS – need both estradiol and

progesterone

Hypothyroidism

• Overt hypothyroidisim▫ Known Reproduction Impact Infertility Miscarriage Adverse obstetric and neonatal outcomes

• Subclinical hypothyroidism (untreated)▫ Reproductive Impact Infertility Miscarriage Adverse obstetric outcomes Fetal neurodevelopment risk

Subclinical Hypothyroidism

• Definition▫ TSH > upper limit of normal (4.5-5.0 mIU/L)▫ Normal free T4▫ Incidence: 2-4% reproductive-age population• Normal values▫ NHANES – Median 1.5 mIU/L 2.5 and 97.5 percentiles of 0.41 and 6.10 95% healthy population < 2.5mIU/L Additional 11 – 14% of the population

Assessment of Auto-antibodies

• Not part of the definition for SCH• Positivity increases likelihood for

development of thyroid dysfunction• Only anti-TPO antibodies of clinical

significance• 10-12% population positive (NHANES)

10 20 30 40

TSH mIU/L

Weeks Gestation

0.03

1.5

0.5

2.5

3.5

4.5

1st. Trimester 2nd. Trimester 3rd. Trimester

0.4

3.5

1.2

0.4

3.5

1.2

Median and 95% TSH confidence limits (Hong Kong)

Panesar et al, Ann Clin Biochem 38:329, 2001

2.3

0.03

0.8

3.1

0.03

1.1

3.5

0.13

1.3

TSH levels during pregnancy

Infertility

• Possible increased incidence of SCH in infertility women ▫ Primarily among women with ovulatory

problems▫ No evidence for increase risk of infertility

with SCH

Miscarriage Risk

• Few good studies with TSH measured prior to pregnancy• Negro 2010▫ Compared pregnancy outcome in women

with TSH < 2.5 vs. 2.5 – 5.0▫ SAB rate increased 3.1% - 6.3%• FASTER▫ Pregnant subjects enrolled at 10- 13weeks▫ No difference in SAB rate

Adverse Obstetrical Risks

• Placental abruption, pre-term birth, fetal death and PPROM• Studies limited as rare outcomes and

largely retrospective• FASTER trial with increased risk for

PPROM if antibodies positive

Childhood Development

• Fetal thyroid does not produce hormone until 10-13 weeks of pregnancy• Maternal hypothyroidism (low free T4) is

associated with cognitive impairment• SCH diagnosed during pregnancy

increases risk• No association with SCH diagnosed prior

to pregnancy (TSH 2.5 – 4.0 mIU/L)

Thyroid Replacement

• For TSH > 4.0 mIU/L▫ Improvement in pregnancy chances▫ Reduction in miscarriage

• For TSH 2.5 – 4.0 mIU/L▫ No evidence of benefit

Anti-thyroid Antibodies

• Increased risk of miscarriage• Treatment with thyroid replacement (for

TSH > 2.5 mIU/L) improves outcome• No specific “autoimmune” treatments of

benefit

Progression to clinical hypothyroidism

• With TSH > 2.5 AND presence of anti-TPO antibodies▫ 4% per year• With TSH > 2.5 only▫ 2-4%/year• With + ATA only▫ 1-3%/year

Thyroid function and pregnancy

• Negro R (JCEM 2010)▫ Low risk women with TSH > 2.5 with +

anti-peroxidase Ab (without treatment) had an increased risk of adverse pregnancy outcomes (including pregnancy loss and preterm labor)

What about antibody negative?• Negro R 2010 JCEM -4123 women with

TSH > 5; negative anti-peroxidase antibodies

▫ Increased risk for SAB (6.1% vs. 3.6%, P= 0.006)

Pregnancy risks with SCH

• Miscarriage▫ Non-significant reduction (+ATA) with

treatment• Pre-term labor▫ Evidence that treatment (+ATA) for

reducing pre-term birth• PPROM• Pre-eclampsia• Placental abruption• NNICU admissions

FASTER trial

Cleary‐Goldman et al, Obstet Gynecol  2008

SCH and ART outcome

Mikalakis KG, et al. Fertil Steril 2011

Clinical outcomes based on TSH level

Reh Fertil Steril 2010

SCH and neurological function in offspring

• Lazarus JH NEJM 2012• No difference in IQ at age 3 with treatment or

no treatment

• BUT average gestational age for institution of thyroid supplementation was 13 weeks▫ ? Too late• Mean TSH levels considered for treatment -

3.8mIU/mL (1.5-4.7)• Crude assessment for neurological

compromise at age 3

Subclinical hypothyroidism

• Data inconclusive• Upper limit of normal for TSH still under

debate

• Most large systematic reviews and randomized trials fail to show benefit to identifying those with subclinical hypothyroidism• Universal screening is not recommended▫ Although recent (Disiou, JCEM 2012) found

even universal screening cost effective

Recommended patient profiles for targeted screening• Women over 30 years of age• Women with a family history of autoimmune thyroid

disease and/or hypothyroidism• Women with a goiter• Women with thyroid antibodies (anti-TPO)• Women with symptoms suggestive of hypothyroidism• Women with type I DM or other autoimmune disease• Women with infertility• Women with a prior history of preterm delivery• Women living in an area of presumed iodine deficiency• Women with prior therapeutic head or neck radiation or

prior thyroid surgery• Women receiving levothyroxine replacement

Thyroid - summary• Screen with TSH• If 2.5-5mIU/mL - check anti-TPO

antibodies

• If positive - treat• If negative - repeat in early first

trimester - treat if TSH > 5mIU/mL

Treatment during pregnancy

• Alexander EK, et al, NEJM 2004• Increase dosing immediately by 30% and

then follow TSH (average required increase 50%)▫ Equivalent to increasing by 2 tablets/week

Depression

• 10-25% lifetime risk• Women: Men 2-3:1• Peak incidence – reproductive years

Depression during Pregnancy

• Yonkers 2014• Prevalence 10-20%• >50% of pregnant women will take

prescription medication • Increased antidepressant use during

pregnancy• SSRI's are the most frequent

antidepressants taken▫ sertraline and fluoxetine

Depression and Anxiety in the Infertility Population

• Rate of depression similar to those of chronic illness population (Domar et al 1993)

• Greatest rate of depression between years 2-6 of treatment (Domar et al 1992)

Depression/Anxiety and IVF

• Depression the most common disorder in men (5%) and women (11%) (Volgsten et al. 2008)

• 30% of women, 10% of men >1 psychiatric diagnosis

• Up to 60.5% of women and 53.3% of men with psychiatric disorders reported previous history of depression

Depression/Anxiety and IVF

• Women with history of anxiety or unipolar depression show more distress during ART treatment (Zaig et al. 2013)

• Higher levels of depressive symptoms and state anxiety at baseline persisted over time, including when pregnancy achieved (Varahtian et al. 2011)

SSRI and ART

• Decreased pregnancy rates among IVF patients treated with SSRIs (Klock et al 2004)

• Higher cycle cancellation rate among SSRI users due to poor response, no difference in pregnancy rate or live birth rate per cycle (Friedman et al 2009)

• IVF outcome measures not adversely affected by fluoxetine (folic acid –placebo) (Serafini et al 2009)

Treatment during Pregnancy

• Past psychiatric history: severity, duration, recurrence, treatment response history, self-care or self-harm behaviors when not treated

• Maternal/Fetal Outcomes with and without treatment-risk/benefit discussion• Patient’s risk assessment of outcomes

Maternal Outcomes of Untreated Depression

• Ongoing/worsening clinical illness• Risk of negative health behaviors

leading to poor fetal outcomes• smoking, drug and alcohol use, poor self

care, poor neo-natal care• Prenatal depression a significant risk

factor for PPD

Obstetrical/Neonatal Risks

• Increased risk for Cesarean section delivery• +/-Hypertension/Pre-eclampsia• Gestational diabetes• Increased risk of pre-term birth (<37

weeks gestation) (Grote et al 2010)

• +/-LBW (<2500gm)

Infant OutcomesUntreated Depression

• Increased risk for irritability, decreased activity and attentiveness, fewer facial expressions (Chaudron 2013)

• Poor motor and regulation skills (Stein et al 2014)

• Concern about fetal programming and adult health in children exposed to prenatal stress-schizophrenia, cardiovascular disease (Glover 2013)

Childhood/Adolescent OutcomesUntreated Depression• Cognitive, behavioral, and psychological

problems that might persist into adulthood▫ Lower levels of general cognitive

development▫ Increased risk for internalizing behaviors

(symptoms of depression, anxiety) (Stein et al 2014)

▫ Independent association with offspring depression at 18 years (Stein et al 2014)

Anti-depressant Usage in Pregnancy• Limitations of studies▫ Cannot do randomized controlled trials in

pregnant women▫ Methodologies other than RCT have drawbacks▫ Limited number prospective naturalized

studies• Diagnostic accuracy• Medication adherence• Confounding factors▫ Women who take antidepressants are more

likely to have confounding factors• Timing/duration/dosage of exposure ill defined

Miscarriage Risk

• 7-11% in general population• 11-17% rate of miscarriage in

pregnancies exposed to SSRI, SNRI, TCA's (Yonkers 2014)

Fetal Death/Congenital Anomalies

• Fetal Death – no increase• Congenital Anomalies• 2-3% rate of major congenital malformations

in the general population; heart defects the most common▫ Conflicting results for TCA's, SSRI's,

venlafaxine, and bupropion▫ Majority of evidence suggests that

antidepressants are not major teratogens

Birth DefectsAnti-depressant usage

• Paroxetine▫ Conflicting results▫ Atrial and ventricular septal defects▫ FDA Category D

Fetal GrowthAnti-depressant usage

• Pre-term birth-<37 weeks gestation▫ Occurs at a higher rate among women who

take antidepressants▫ Overall risk modest with gestation shortened

by 3-5 days (Yonkers et al 2012)

• Low Birth Weight (<2500gm)/Small for Gestational Age▫ Small effect, 74gm difference, if any▫ Not a major concern

Neurodevelopment OutcomesAnti-depressant usage• No clinical evidence of risk with serotonin

manipulation (Gur et al 2013)

• Subtle effect on motor development and control in exposed infants (Yonkers et al 2012)

• No effect: IQ, temperament, language development in a group of exposed children age 16-86 months (Nulman et al 2002)

• No effect comparing exposure to SSRI's, venlafaxine, or untreated depression (Nulman et al 2012)

• Maternal mood more predictive of child behavior problems

Autism Spectrum DisorderAnti-depressant usage

• Increased risk of ASD in children exposed to antidepressants (OR=2.2) (Croen et al 2011)

• Increased risk of ASD with exposure to maternal depression and antidepressants (Rai et al 2013)

• Case control design may overestimate risk, lack of control for maternal illness severity and other exposures

Neonatal Behavior SyndromeAnti-depressant usage

• Symptoms: irritability, jitteriness, trouble feeding, tremor, agitation, hypertonia, hyper-reflexia, respiratory distress, seizures, vomiting, and excessive crying (Yonkers et al 2014)

• Onset within 1-2 days of delivery, resolve by 2 weeks• Self limited with supportive care in most

instances• Occurs in 15-30% of infants• Etiology: Toxicity vs. withdrawal

Neonatal Behavior SyndromeAnti-depressant usage• Positive association with any

antidepressant• Agents most commonly implicated:

fluoxetine, paroxetine, venlafaxine• Greater risk with poly-pharmacy• More likely to occur with 3rd trimester

exposure• Decreasing dose or discontinuation more

than 2 weeks prior to delivery did not ameliorate syndrome; may increase risk to mother (Meltzer-Brody 2011)

Risk of Untreated Depression

• Mother's illness and function• Obstetrical and neonatal• Child and adolescent behavior• PPD

Risk of Anti-depressants

• Miscarriage-modest increase• Physical Anomalies▫ Not major teratogens as a class; avoid

paroxetine▫ Slight increased risk of PPHN; extremely low

absolute risk• Increased risk of PTB (<37 weeks)-small effect• Neonatal behavioral syndrome-increased risk▫ Short-lived, self-limited symptoms, low risk

for specialized care, no evidence of long-term negative effects

• LBW not a major concern

Risk of Anti-depressant

• Neurodevelopment▫ No long-term negative effects on

neurodevelopment▫ Maternal mood more predictive of

neurodevelopment problems than AD exposure

▫ Autism Spectrum Disorders: needs more study

• Lactation-Generally considered safe

Depression

• Women (39%) – and men (15%) – with infertility have higher rates of major depressive disorder (MDD) than the general population

• Pre-treatment presence of MDD predicted risk for MDD during treatment

Holley SR 2015

Depression• Negative impact on outcome▫ Seijbaek CS 2013; Quant HS 2013; An Y 2013 Longer stimulation Lower fertilization rate Lower clinical pregnancy rate

Most stressful time: egg retrieval and day of pregnancy test

Increase in cortisol and norepinephrine

• No effect▫ Anderheim L 2005; Pasch 2012▫ BUT depression prior to treatment – more

likely for MDD after treatment

Postpartum Depression

• Lynch CD 2014• No increased risk in women treated for

infertility

Where should our attention be directed?• Reducing/treating depression prior to

treatment▫ Consider screening all new patients for

depression▫ No evidence use of anti-depressants increases

success rates▫ Anti-depressants are associated with increased

miscarriage, birth defects, preterm birth, newborn behavioral syndrome, and possible longer term neurobehavioral effects

▫ Cognitive therapy and physical exercise reduce stress in depression; should be explored more in infertile populations

Where should our attention be directed?

• Reducing stress during the process –especially around the retrieval, during the “waiting period” and at the pregnancy test• Increasing support in the face of failed

cycles

Hypertension

• Increased risk during pregnancy▫ Pre-eclampsia▫ Gestational hypertension▫ Fetal growth restriction• Long-term health risks▫ Hypertension▫ Stroke▫ Cardiovascular disease

Hypertension during pregnancy

Opdahl S 2015

Hypertension during pregnancy

• Propensity score matched study – 2014▫ 3,084 pregnant women (NICHD) seen

prior to 20 weeks 474 (15.4%) IVF vs. 2610 (84.6%) non-IVF

conception Pre-eclampsia: 3.2% v. 1.2% (OR 2.72 – CI

1.46-5.08) After propensity matching (27 maternal and

paternal variables): OR 2.5 CI 0.49-12.89

Hypertension – oocyte source

• Case-control study• Risk of pre-eclampsia 27% vs. 5.6% (p=

0.0024)▫ Maternal age, BMI, parity and prevalence of

twins• Oocyte donor women higher pre-pregnancy

risk profile▫ Pre-existing hypertension

• Risk of pre-eclampsia (adjusted) 10.7% vs. 1.85% (p= 0.09)

Simeone S 2012

Hypertension in PregnancyAre there high risk groups?

• Diminished ovarian reserve▫ Increased risk Woldringh GH 2010 Yarde F 2013

▫ No impact vanDisseldorp J 2010

Long-term hypertension risk

• Swedish National Registry 2014▫ HTN: HR = 1.27 (CI 1.13-1.41)▫ CVA: HR = 1.27 (CI, 0.96-1.68)▫ no difference coronary heart disease or

DM• Nurses’ Health Study – Cohort II 2015▫ HTN: RR = 1.01 (CI 0.94-1.07)

Are there preventative treatments?

• Lambers MF 2009▫ Small study suggested baby ASA as

protective• Haapsamo M 2010▫ RCT – no impact• Groeneveld E 2014▫ Individual patient data meta-analysis▫ No impact

Hypertension risk to offspring

• 194 4-year olds following fertility treatment▫ COH-IVF▫ Modified natural cycle IVF▫ Spontaneous conceptions• Higher SBP with ovarian hyper-

stimulation▫ (preliminary analyses)

LaBastide-van Gemert S 2014

What is the maternal environment?

The Brain – hypothalamic‐pituitary axis‐ Weight gain, behavioral tx, remember biology

Thyroid‐ Check TSH, possibly ATA

BMI‐impact of age and time

CV system– no need for intervention if baseline levels normal

The Brain ‐Depression‐ Early screening and intervention