ACOG update: Letrozole is the first line therapy for ovulation induction in PCOS

The American College of Obstetricians and Gynecologists (ACOG) now recommends Letrozole (aromatase inhibitor) as the first-line treatment for ovulation induction in women with Polycystic Ovarian Syndrome (PCOS) due to data demonstrating increased ovulation rates, clinical pregnancy rates and live-birth rate vs clomiphene citrate. The guidelines are published as Practice Bulletin No. 194 in the June issue of Journal Obstetrics and Gynecology.

This replaces the Practice Bulletin Number 108, published October 2009, which recommends letrozole as first-line therapy for ovulation induction only in women with PCOS and a BMI greater than 30.

It is estimated that polycystic ovary syndrome (PCOS) affects 1 in 10 women of childbearing age and it is the most common cause of ovulatory infertility. If lifestyle modifications and weight loss are unable to achieve conception, currently clomiphene citrate (CC) is usually prescribed as the first-line treatment for ovulation induction.

  

The gonadotropin-stimulating action of letrozole has been used off-label in the treatment of patients with ovulatory dysfunction, such as polycystic ovary syndrome.

The results of recent double-blind, multicenter trial show that letrozole was associated with higher live-birth (27.5% vs 10.1%) and ovulation rates (61.7% vs 48.3%) among infertile women with the polycystic ovary syndrome as compared to CC.

Women on letrozole also had a 40% higher clinical pregnancy rate (OR 1.40 95% CI, 1.18-1.65) and 64% increased live birth rate (OR 1.64 (95% CI, 1.32-2.04) as compared to CC.

If prescribing letrozole, the starting dose is 2.5 mg/day for 5 days typically starting on day 3, 4, or 5 after a spontaneous menses or progestin-induced bleed. If ovulation does not occur, the dose can be increased to 5 mg/day for 5 days with a maximum dose of 7.5 mg/day. Doses higher than 7.5 mg/day have been associated with thinning of the endometrium as seen with clomiphene citrate.

Lifestyle modification and weight loss are strongly encouraged along with letrozole therapy.

Several studies have also shown that letrozole is also the drug of choice in clomiphene non-responders with 50–80% women ovulating on letrozole.

Letrozole and clomiphene citrate are pregnancy category X drugs, and studies have demonstrated similar rates of congenital malformation in mothers who achieved pregnancy because of ovulation induction using these drugs.

When prescribing letrozole for ovulation induction, patients should be counseled that unlike clomiphene citrate, letrozole is not approved by the U.S. Food and Drug Administration for ovulation induction.

More recent papers on PCOS:

Fresh or frozen-embryo transfer results in similar pregnancy rates in women without PCOS

The therapeutic dilemma in PCOS patients not desiring pregnancy: A systematic review and meta-analysis

Clomiphene compared with other drugs in terms of ovulation, EMT, pregnancy and live births: systematic review and meta-analysis

Stair-step clomiphene protocols shorten time to ovulation in women with PCOS

Preconception IGT in PCOS results in adverse pregnancy outcome, independent of BMI

New study quantifies the risk of developing type 2 Diabetes in women with PCOS

Polycystic ovarian syndrome increases the risk of subsequent early ovarian aging later in life

PCOS is often underdiagnosed as the common cause of Abnormal Uterine Bleeding in Adolescents

Letrozole does not increase the risk of adverse pregnancy or neonatal outcomes and major congenital anomalies in patients conceived by ARTs

ACOG calls upon all obstetrician-gynecologists to screen PCOS patients for metabolic abnormalities.

Current options for ovulation induction in Polycystic Ovarian Syndrome (PCOS)

PCOS and Infertility: Pretreatment Weight loss hikes the live birth and ovulation rate in overweight and obese patients. 

PracticeBulletin No. 194

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WHO updates its guidance on Tranexamic Acid for the Treatment of Postpartum Hemorrhage

WHO has recently updated their guidelines for use of Tranexamic acid for treatment of Postpartum Hemorrhage: TXA should now be included in the treatment regimen for PPH along with other drugs, irrespective of the cause of hemorrhage.  

In 2012, WHO recommended Use of TXA  for the treatment of PPH if oxytocin and other uterotonics fail to stop the bleeding or if it is thought that the bleeding may be partly due to trauma.

Globally, PPH accounts for 25% of all maternal deaths and in most low-income countries it is the leading cause of maternal deaths. And minutes count when treating postpartum hemorrhage with tranexamic acid: for every 15-min delay, there's a 10% reduction in effect.

The key recommendations from WHO are:

• The World Health Organization (WHO) recommends early use of intravenous tranexamic acid (TXA) within 3 hours of birth in addition to standard care for women with clinically diagnosed postpartum hemorrhage (PPH) following vaginal birth or caesarean section.
• Administration of TXA should be considered as part of the standard PPH treatment package and be administered as soon as possible after onset of bleeding and within 3 hours of birth. TXA for PPH treatment should not be initiated more than 3 hours after birth.
• TXA should be used in all cases of PPH, regardless of whether the bleeding is due to genital tract trauma or other causes.
• TXA should be administered at a fixed dose of 1 g in 10 mL (100 mg/mL) IV at 1 mL per minute (i.e., administered over 10 minutes), with a second dose of 1 g IV if bleeding continues after 30 minutes.
• TXA should be administered via an IV route only for treatment of PPH. Research on other routes of TXA administration is a priority.

ACOG also has recently updated its practice bulletin on Postpartum Hemorrhage, based on the results of The WOMAN (World Maternal Antifibrinolytic) trial published in May 2017, in The Lancet.

The researchers concluded that “Tranexamic acid reduces death due to bleeding in women with post-partum hemorrhage with no adverse effects. When used as a treatment for postpartum hemorrhage, tranexamic acid should be given as soon as possible after bleeding onset.”

ACOG says, “Although the generalizability of the WOMAN trial and the degree of effect in the United States is uncertain, given the mortality reduction findings, tranexamic acid should be considered in the setting of obstetric hemorrhage when initial medical therapy fails.” (Level B evidence)

WHO Update

WOMAN trial full text in Lancet

ACOG practice bulletin postpartum hemorrhage abstract

ACOG resources on obstetric hemorrhage

AWHONN video on Quantification of Blood Loss