document_title: The Handmaid's Tale (TV series)

question_text: how many eps in handmaids tale season 2

question_tokens: how many eps in handmaids tale season 2

text: The Handmaid's Tale (TV series)

text: Plot[edit]

text: In the near future, fertility rates collapse as a result of sexually transmitted diseases and environmental pollution.[4] With this chaos, the totalitarian, theonomic government of "Gilead" establishes rule in the former United States in the aftermath of a civil war.[5][6][7] Society is organized by power-hungry leaders along with a new, militarized, hierarchical regime of fanaticism and newly created social classes, in which women are brutally subjugated, and by law are not allowed to work, own property, handle money, or read.[7] Worldwide infertility has resulted in the conscription of the few remaining fertile women in Gilead, called "Handmaids", according to an extremist interpretation of the Biblical account of Bilhah.[7] They are assigned to the homes of the ruling elite, where they must submit to ritualized rape by their male masters in order to become pregnant and bear children for those men and their wives.

text: Alongside the red-clad Handmaids, much of society is now grouped into classes that dictate their freedoms and duties. Women are divided into a small range of social categories, each one signified by a similarly-styled plain dress in a specific color: Handmaids wear red, Marthas (who are housekeepers and cooks, named after the biblical figure) wear green, and Wives (who are expected to run their households) wear blue. Econowives, the lower-class women who still have minimal agency, are a sort of mixture of all these categories, and they wear gray (a departure from the book in which Econowives wear clothing striped with the aforementioned colors). Women prisoners are called Unwomen and are worked to death clearing toxic waste in the Colonies. Another class of women, Aunts (who train and oversee the Handmaids), wear brown. Additionally, the Eyes are a secret police watching over the general populace for signs of rebellion, Hunters track down people attempting to flee the country, and Jezebels are prostitutes in secret brothels catering to the elite ruling class.

text: June Osborne, renamed Offred (Elisabeth Moss), is the Handmaid assigned to the home of the Gileadan Commander Fred Waterford (Joseph Fiennes) and his wife Serena Joy (Yvonne Strahovski). Offred is subject to strict rules and constant scrutiny; an improper word or deed on her part can lead to brutal punishment. Offred, who is named after her male master ("Of Fred") like all Handmaids, can remember the "time before", when she was married and had a daughter, a job, a bank account, and her own name and identity, but all she can safely do now is follow the rules of Gilead in hopes that she can someday live free again and be reunited with her daughter. The Waterfords, key players in the rise of Gilead, have their own conflicts with the realities of the society they have helped create.

text: Cast and characters[edit]

text: Main[edit]

text:
Elisabeth Moss as June Osborne / Offred, a woman who was captured while attempting to escape to Canada with her husband, Luke, and daughter, Hannah. Due to her fertility, she is made a Handmaid to Commander Fred Waterford and his wife, Serena Joy, and is named "Offred".
Joseph Fiennes as Commander Fred Waterford, a high-ranking government official and June's master. Both he and his wife played an instrumental role in Gilead's founding. He wishes to have more contact with June outside of what is lawful between a Handmaid and her master, and starts inviting her to play nightly games of Scrabble.
Yvonne Strahovski as Serena Joy Waterford, Fred's wife and a former conservative cultural activist. She appears to have accepted her new role in a society that she helped create. She is poised and deeply religious, but capable of great cruelty and is often callous to June. She is desperate to become a mother.
Alexis Bledel as Emily / Ofglen / Ofsteven, June's shopping partner. Although June is initially wary of her, it is revealed Ofglen is not as pious as she seems, and the two become friends. Ofglen had a wife and son, and was a university lecturer in cellular biology. Being homosexual is punishable by death in Gilead, and most university professors are sent to labour camps, but Ofglen was spared and made a Handmaid, due to her fertility. She is later captured and punished for her relationship with a Martha, and is sent to another household where she becomes "Ofsteven". She is involved with a resistance movement called "Mayday".
Madeline Brewer as Janine / Ofwarren / Ofdaniel, a Handmaid who entered the Red Center for training at the same time as June and considers June a friend due to her kind treatment. Initially non-compliant, Janine's right eye is removed as a punishment. She becomes mentally unstable due to her treatment and often behaves in temperamental or childlike ways. She gives birth to a child for Warren and Naomi Putnam, whom they name "Angela", but Janine insists the baby's name is "Charlotte". Janine is later reassigned and becomes "Ofdaniel". She was temporarily assigned to the Colonies until a bombing at the new Rachel and Leah Center.
Ann Dowd as Aunt Lydia, a woman in charge of overseeing the Handmaids in their reeducation and duties. She is brutal and subjects insubordinate Handmaids to harsh physical punishment, but she also cares for her charges and believes deeply in the Gileadean mission and doctrine. She appears to have a soft spot for Janine, and even goes so far as to address her by her given name on occasion. Showrunner Miller has suggested that Aunt Lydia was a schoolteacher before Gilead, and Dowd has said this, and her own upbringing as a student at Catholic schools, informs her performance.[8]
O. T. Fagbenle as Lucas "Luke" Bankole, June's husband from before Gilead. Because he and June began their relationship before his divorce from his first wife, their union is considered invalid in the new society. June is considered an adulteress and their daughter, Hannah, is considered illegitimate. Initially, June believes he has been killed, but it is later revealed Luke managed to escape to Canada.
Max Minghella as Nick Blaine, Commander Waterford's driver and a former drifter from Michigan who has feelings for June. June and Nick develop an intimate relationship and she eventually discovers that he is an Eye, a spy for Gilead.
Samira Wiley as Moira / Ruby, June's best friend since college. She is already at the Red Center when June enters Handmaid training but escapes before being assigned to a home. She is recaptured and becomes "Ruby", a Jezebel. She seems to have given up hope of ever being free, but on meeting June again regains the conviction to escape.
Amanda Brugel as Rita, a Martha at the Waterford home. She had a son who died fighting in the civil war when he was 19 years old.[9]

tag: ul

text: Recurring[edit]

text:
Ever Carradine as Naomi Putnam, Commander Warren Putnam's wife. She views her baby largely as a status symbol and has no sympathy for the Handmaids.
Tattiawna Jones as Lillie Fuller / Ofglen No. 2, who replaces Emily in the position after Emily is captured by the Eyes. She initially follows the rules and does not wish to upset the status quo, but this is because she believes her life as a Handmaid is better than the difficult, impoverished life she led prior to Gilead, rather than out of religious piety.
Nina Kiri as Alma / Ofrobert, another Handmaid who trained at the Red Center with June, Moira, and Janine. She is frank and chatty, and often trades gossip and news with June. She is also involved with Mayday and becomes June's first contact with the resistance group.
Jenessa Grant as Dolores / Ofsamuel, a local Handmaid with a friendly and talkative nature.
Bahia Watson as Brianna / Oferic, another local Handmaid who is friends with June.
Jordana Blake as Hannah Bankole, June and Luke's daughter.
Erin Way as Erin, a young mute woman who was being trained to become a Handmaid but managed to escape to Canada.[10]
Sydney Sweeney as Eden Spencer (season 2), a pious and obedient girl who dreams of one day being a Commander's wife.[11]
Bradley Whitford as Commander Joseph Lawrence (season 2), the architect of Gilead's economy, who is gruff and intimidating, with a disheveled mad genius vibe. His sly humor and flashes of kindness make him a confusing, mysterious presence for his newest Handmaid.[12]
Greg Bryk as Commander Ray Cushing (season 2)
Rohan Mead as Isaac (season 2), a Guardian assigned to the Waterford home.

text: Guest[edit]

text:
Kristen Gutoskie as Beth (season 1), a Martha at Jezebel's. She has an arrangement with Nick whereby she trades illegal alcohol and other contraband for drugs, which the Jezebels use. She has a casual sexual relationship with him and is aware that he is an Eye.
Marisa Tomei as Mrs. O'Conner (season 2), a Commander's wife who is sent to the colonies as punishment for having sex with another man.[13]
Cherry Jones as Holly Maddox (season 2), June's mother, an outspoken feminist.[14]
Clea DuVall as Sylvia (season 2), Emily's wife.[15]
Yahya Abdul-Mateen II as Omar (season 2) a man who helps June attempt to escape.
John Carroll Lynch as Dan (season 2), Emily's boss at the university where she worked.
Kelly Jenrette as Annie (season 2), Luke's ex-wife.
Rebecca Rittenhouse as Odette (season 2), a Doctor and Moira's fiancee.
Sam Jaeger as Mark Tuello (season 2), a mysterious stranger who Serena encounters in Canada.

text: Episodes[edit]

text: Series overview[edit]

text:
Season
Episodes
Originally released

First released
Last released

1
10
April 26, 2017 (2017-04-26)
June 14, 2017 (2017-06-14)

2
13[16]
April 25, 2018 (2018-04-25)
July 11, 2018 (2018-07-11)[16]

tag: table

text: Season 1 (2017)[edit]

text:
No.
overall
No. in
season
Title
Directed by
Teleplay by
Original release date

1
1
"Offred"
Reed Morano
Bruce Miller
April 26, 2017 (2017-04-26)

A family is pursued by a group of armed men. The woman is caught, and separated from her young daughter and husband as shots are fired in the distance. She is now known as Offred, the Handmaid to Commander Fred Waterford. While walking with another Handmaid, Ofglen, they pass by a wall on which men have been hanged for crimes such as being gay, working in an abortion clinic, and being a Catholic priest.[17] In a flashback, various women are indoctrinated into their Handmaid roles by Aunt Lydia, and Offred notices Moira, a woman she knew in college. Handmaid Janine taunts Aunt Lydia and is shocked with a cattle prod, later her right eye is removed as punishment. In the present, Commander Waterford tries to impregnate Offred during "the Ceremony" as she lies in the lap of his wife, Serena Joy. The next day, the Handmaids are encouraged to beat a man to death after Lydia announces he raped a pregnant Handmaid. Janine tells Offred that her friend Moira is dead. On the way home, Ofglen tells Offred that she had a wife and son, and warns her there is an Eye in the Waterford house. Offred affirms to herself that her true name is June and that she intends to survive to find her daughter.

2
2
"Birth Day"
Reed Morano
Bruce Miller
April 26, 2017 (2017-04-26)

Offred and Ofglen go shopping, and they reveal more personal information about themselves to each other. While they are walking, they see St. Paul Catholic Church, their local church, being destroyed by the new régime.[18][17] Ofglen tells Offred that the régime also bulldozed St. Patrick's Cathedral in Manhattan to try to "erase" the fact that it ever existed. When Offred asks how Ofglen knows this information, she reveals that she is part of a resistance movement against the government, but Offred declines to join.[19] Commander Waterford's driver, Nick, tells Offred that the Commander wants to see her alone later that night, which is forbidden, and warns her that Ofglen is dangerous. Offred and other Handmaids visit a home to witness the birth of Ofwarren (Janine)'s child, named Angela by the Puttnams, but Charlotte by Ofwarren. In flashbacks, June (Offred) remembers the birth of her and Luke's daughter, Hannah. At that time healthy births were already rare, and a woman who tried to kidnap baby Hannah was arrested. Warily, Offred goes to the Commander's office, but he just wants to play Scrabble, to her relief. The next day, when Offred prepares to tell Ofglen what happened that night, a different woman introduces herself as Ofglen.

3
3
"Late"
Reed Morano
Bruce Miller
April 26, 2017 (2017-04-26)

In flashbacks, the rise of Gilead is detailed. June and all the other women at her office were fired, and the government froze women's bank accounts and ruled they could no longer own property. In the present, Serena takes Offred to see Ofwarren and the baby, and Offred fears Ofwarren is delusional. Back home, Offred is interrogated by an Eye and Aunt Lydia about her knowledge of Ofglen. Offred eventually reveals she knew Ofglen was gay and for this, Aunt Lydia shocks Offred with a cattle prod. Before she can leave the room, Offred quotes one of the Beatitudes from the Bible, which would have earned her a much more serious beating, but Serena intervenes, believing that Offred is pregnant. When Offred later tells Serena that she's not pregnant, Serena angrily locks her in her room. In a flashback, June and Moira attend a protest against the new laws amidst automatic gunfire and explosives. In the present, Ofglen and the Martha she's in a relationship with are charged with "gender treachery". The fertile Ofglen receives a lesser sentence, but the Martha is executed by hanging as Ofglen watches, sobbing and horrified. Later, Ofglen (now referred to by her "old" name, Emily), to her grief and anger, undergoes female genital mutilation surgery as explained by Aunt Lydia.

4
4
"Nolite Te Bastardes Carborundorum"
Mike Barker
Leila Gerstein
May 3, 2017 (2017-05-03)

Banished to her room, Offred retreats to her closet where she finds what appears to be a Latin phrase, Nolite Te Bastardes Carborundorum, scratched discreetly into the wall. When Rita, the Commander's housekeeper, finds Offred lying on the closet floor, Offred tells her that she fainted. Serena then has Offred sent to the hospital for a check-up. During the examination the physician remarks that the Commander is most likely sterile, as is common. He offers to personally impregnate her but she declines. In flashbacks, Aunt Lydia teaches the Handmaids about The Ceremony in which a Commander endeavours to fertilize a Handmaid. Later, June and Moira assault Aunt Elizabeth, and Moira takes Elizabeth's outfit. June and Moira plan to escape via train to Boston, which has safe houses. Moira manages to catch the train without June, who lets Moira know it's okay. June is later caught and punished by having her feet whipped. Commander Waterford has an unsuccessful Ceremony night with Offred, but later that night, they have another game of Scrabble. She asks him about the Latin phrase, and he tells her it means, Don't let the bastards grind you down. When she inquires about the previous Offred, he tells her that she committed suicide because life was unbearable. He then releases Offred from her solitary confinement.

5
5
"Faithful"
Mike Barker
Dorothy Fortenberry
May 10, 2017 (2017-05-10)

Serena suggests to Offred that she have sex with Nick in case Commander Waterford is sterile. Later that day, Serena leads Offred up to Nick's room and waits by the door while Offred and Nick have detached sex. Flashbacks detail Luke and June's first meeting and courtship. At the grocery store, Offred talks to the original Ofglen, now called Ofsteven, but Ofsteven is not as responsive as she used to be. During a Ceremony night, the Commander touches Offred's thigh, which she later tells him never to do again. In their ensuing conversation, the Commander admits that while they thought they were building a better world, they knew that "better never means better for everyone." Nick reveals to Offred that he is indeed an Eye. At an open-air market, Offred questions Ofsteven about the resistance group called Mayday. Ofsteven jumps behind the steering wheel of a security car and drives erratically around the plaza. She hits a guard, and is caught and put into a black van. Offred returns to Nick's coach house alone, and they have passionate sex.

6
6
"A Woman's Place"
Floria Sigismondi
Wendy Straker Hauser
May 17, 2017 (2017-05-17)

Mexican trade delegates visit the Commander's home to evaluate the effects of the Gilead cultural movement. The female head of the delegation questions Offred about her experience, but she lies, saying that she is happy. Offred visits the Commander's office later, but there is tension. She reluctantly obeys his demand to kiss him, but ferociously brushes her teeth afterward. The Handmaids and children are then taken to a function to demonstrate Gilead's success. Offred's friend remarks that the delegates are only interested in fertile women. The next day, as the delegates are leaving, Offred tells them the brutal truth about Gilead. She pleads for their help, but in response, the Mexican ambassador explains her own country's dire situation. However, the ambassador's assistant quietly claims June's husband is alive and that he can deliver a message to Luke. A flashback details Serena and Fred's life at the beginnings of the Gilead movement when Serena was a conservative cultural activist with passion and intelligence equal to her husband's. Serena Joy wrote a book about her beliefs, titled A Woman's Place. However, after the takeover, she is completely shut out of the new government planning and accepts her new limited role in the society she helped create. A copy of her book is seen being thrown out with the trash.

7
7
"The Other Side"
Floria Sigismondi
Lynn Renee Maxcy
May 24, 2017 (2017-05-24)

A flashback chronicles Luke's story after he becomes separated from his wife and daughter. Luke is shot by Gileadan guards, but he escapes when the ambulance crashes, and he takes some medical supplies. He reaches a small abandoned town and, after passing out from his wounds, is rescued by a resistance group traveling to Canada. These survivors included a Roman Catholic nun, a seemingly mute escaped Handmaid, a homosexual man, and a daughter of a US Army soldier.[20] Initially reluctant, Luke joins them after one of the survivors, Zoe, shows him that Gileadan authorities hung townspeople from the rafters of their church for resisting.[21][22] As they board a boat, Gileadan guards open fire, killing several members of the group, but Luke and Erin, the escaped Handmaid, survive. A further flashback shows Luke, June, and their daughter Hannah before they were separated. June and Luke are helped by Mr. Whitford, a man who knew June's mother. He leaves them at a secluded cabin in the woods while he arranges documentation for them to escape to Canada. Later, a local hunter tells them Whitford has been caught and hanged, but the hunter helps them cross the border. Three years later, in the present, Luke and Erin live safely in "Little America", based in Toronto, Ontario. While in the main administrative office, Luke receives the letter from June, which reads "I love you so much. Save Hannah."

8
8
"Jezebels"
Kate Dennis
Kira Snyder
May 31, 2017 (2017-05-31)

Commander Waterford gifts Offred with makeup and a dress as he is taking her out for the night. Nick drives them to Boston to an underground brothel, where prostitutes (known as "Jezebels") work. Offred spots Moira working in the club, and they briefly reunite. Nick trades drugs and pregnancy tests for alcohol with one of the brothel's Marthas. Offred goes to see Moira again, and she explains to Offred how Quakers tried to help her escape but were caught.[23][24] Moira had the choice of being sent either to the colonies or one of the brothels.[24] Moira tells Offred, "Forget about escaping. This is Gilead. No one gets out." Offred reveals to Moira that she knows Luke is alive. Flashbacks detail how Nick got involved with the Gilead movement and how he became an Eye after reporting a Commander for breaking protocol with his Handmaids. There are other flashbacks to the suicide of the previous Offred, with Serena pointedly saying to her husband, "What did you think was going to happen?" In the present, after Nick drives Waterford and Offred home, he ends his relationship with Offred, which upsets and angers her. Offred receives a gift from Serena, a music box. The episode closes with Offred etching "You are not alone" into the closet wall.

9
9
"The Bridge"
Kate Dennis
Eric Tuchman
June 7, 2017 (2017-06-07)

Ofwarren's daughter is handed over to Commander Putnam and his wife, and Ofwarren is transferred to another couple and renamed Ofdaniel. However, Offred is worried about Ofwarren/Ofdaniel's mental state. During the first Ceremony night with her new Commander, Ofdaniel forcefully stops it. At the market, Alma pulls Offred aside, tells her that she is involved with the resistance group Mayday, and requests that Offred retrieve a package from the bar at Jezebel's. Offred convinces Waterford to take her to Jezebel's again that night. After Offred and Waterford have sex in their room, Waterford presents Moira, as he believes they have a sexual attraction. Offred asks Moira to retrieve the package, but she refuses, seemingly resigned to her fate. The next day Offred is taken to a bridge where Ofdaniel is standing on the edge with baby Charlotte, while Gileadan guards, the Putnams, the Waterfords, and Aunt Lydia stand fearfully by. Ofdaniel shouts that Commander Putnam promised to leave his wife for her. Offred convinces Ofdaniel to give her the child, and Ofdaniel then jumps into the icy water below. Later, while Ofdaniel lies comatose in hospital, Commander Putnam is led away by guards. When Serena Joy tries to offer comfort to Mrs. Putnam, she reminds Serena of the first Offred's fate, causing Serena to doubt her husband's loyalty. At the market, Offred is given a package by the butcher, sent by Moira from Jezebel's. At the brothel, Moira kills a client and takes his clothes, then jubilantly drives off in his car.

10
10
"Night"
Kari Skogland
Bruce Miller
June 14, 2017 (2017-06-14)

A flashback shows June's capture and indoctrination by Aunt Lydia at the Red Center. After Serena discovers Fred's trips to Jezebel's, she slaps Offred hard and forces her to take a pregnancy test. It is positive. Serena then angrily accuses her husband, telling him the child is not his. Upon learning the news, Nick shares a brief, tender moment with Offred. Serena takes Offred to where Hannah now lives, but Offred is kept in the car, and unable to attract her daughter's attention. Serena warns Offred that Hannah will be cared for as long as the unborn child is safe. Fred participates in Commander Putnam's trial advocating leniency, but Mrs. Putnam wants the harshest punishment possible, and ultimately Putnam's left arm is amputated at the elbow. The package from Jezebel's contains letters from women who have lost family members and been enslaved in the Gilead takeover. Later, an emotional Aunt Lydia gathers the Handmaids for the execution of Janine/Ofdaniel. The Handmaids hesitate, and Ofglen No. 2 is brutally beaten when she voices her angry refusal. Offred, then the other Handmaids, drop their stones. The guards prepare to kill them all, but Aunt Lydia saves them, although assuring them that there will be consequences. Not long afterward, a black van comes for Offred. Nick urges her to trust him and go with them. Offred's transfer is unusual, as neither of the Waterfords have any idea this would be happening. As Offred leaves, she whispers to Rita where to find the hidden letters. In a side story, Moira reaches Canada and is reunited with Luke.

text: Season 2 (2018)[edit]

text:
No.
overall
No. in
season
Title
Directed by
Teleplay by
Original release date

11
1
"June"
Mike Barker
Bruce Miller
April 25, 2018 (2018-04-25)

Offred and other handmaids are taken to Fenway Park where they are made to believe they will be hanged, but it turns out to be a ruse to frighten them. During another punishment, Offred is freed after Aunt Lydia is told of her pregnancy. When she rejects a meal Aunt Lydia gives her, she is shown a pregnant handmaid, Ofwyatt, chained in a prison room due to her attempt to kill herself with drain cleaner. Offred agrees to eat, and during her meal Aunt Lydia, who had told her that her friends would be punished for their disobedience but her pregnancy would mean that she would be exempted, brings the other handmaids into the room, and one by one they are burned with a gas flame. Later, Offred is at a pregnancy check-up, where she is visited by Fred and Serena, but afterwards finds a key in one of her boots, which she uses to escape to a van parked underneath the hospital. The van drops her off to a safe house in Back Bay where she meets Nick, while Fred authorizes a highly resourced search for her. He tells her to change out of her handmaid outfit, and to cut her hair. After stripping off her handmaid's dress, she burns it, before cutting the red cattle tag out of her ear. In flashbacks throughout the episode, Hannah is admitted to the hospital for having a fever while in school; June is questioned by one of the hospital workers about giving Hannah medication to bypass the school's fever policy, as well as questioning June and Luke's fitness as parents. Later, they arrive home to a news story about the Capitol Building and the White House being attacked.

12
2
"Unwomen"
Mike Barker
Bruce Miller
April 25, 2018 (2018-04-25)

June has been transported to the former headquarters of The Boston Globe, another safe place arranged by Mayday.[25] Emily has been taken to the Colonies, where disobedient and lower-class infertile women ("unwomen") are forced to dig on highly toxic land.[26] Many of the unwomen are falling sick, and Emily is doing what she can to help them. A commander's wife arrives at the Colonies and is not welcomed by the unwomen: Emily befriends her and finds that she was taken to the colonies for committing a "sin of the flesh". Emily gives her tablets that turn out to be poison, which leads to her death. Emily blames her for "holding a woman down while her husband rapes her".[25] The unwomen are warned that there will be consequences for this death. Janine arrives at the Colonies, where she is briefly greeted by Emily. Nick visits June and she gets upset when he tells her she needs to wait for several weeks before she can leave because everyone is looking for her. Nick ends up giving her the keys to a car and a gun but she decides to stay, and they have sex. In a flashback, after the attack on the Capitol Building and the White House, Emily is told by her boss, Professor Dan, that she will not be teaching the following semester at the university, giving her a lower profile to avoid attracting criticism for her sexual orientation. Professor Dan is later seen hanged at the university with the word "faggot" spray painted underneath him. While Emily, along with her wife Sylvia and son Oliver, attempt to emigrate to Canada, she is unable to leave the country because their same-sex marriage is no longer recognized, and it becomes known that she is the biological mother of Oliver. June makes a memorial for The Boston Globe employees who were executed at the newspaper's former headquarters and prays to God to send an angel to watch over it.[25]

13
3
"Baggage"
Kari Skogland
Dorothy Fortenberry
May 2, 2018 (2018-05-02)

Having spent two months at The Boston Globe offices, June has found evidence in their archives of the early emergence of the Gilead movement. Nick visits occasionally. She is abruptly moved to a place where she meets Omar, who tells her he is bringing her to another safe house near an airstrip to fly to Canada. He receives a message that the safe house has been compromised, and tries to leave without her, but she stands in front of his van to make him take her. He takes her to his apartment, where she meets his wife, Heather, and their son, Adam. Left alone when his family goes to church, June finds a hidden Qur'an and prayer rug under the bedsprings; Omar and his family do not return. She dons Heather's Econowife outfit and gets out of the apartment, blending in with other Econowives. After a train ride, June runs into the woods. She realizes she has no way of rescuing Hannah and advances to the airstrip that Omar had told her of; however, the plane is intercepted before take-off, the pilot is executed, and June and another fugitive are apprehended by the Guardians. Meanwhile, Moira, now living with Luke and Erin (who is no longer mute) in Canada, gives a tour to a new co-worker but he has a breakdown, traumatized by what he did as a Guardian. In a flashback, June as a child is taken to a Take Back the Night rally by her mother, Holly. When she grew up, Holly was disappointed at June's career choices and plan to marry Luke, hoping that she would have been an activist. Moira and June learned during their training at the Red Center that Holly had been declared an Unwoman and was sent to the Colonies to be worked to death.

14
4
"Other Women"
Kari Skogland
Yahlin Chang
May 9, 2018 (2018-05-09)

June is taken back and chained in a room where Aunt Lydia explains that if she must choose between this imprisonment, followed by execution after the birth of her child, and return as a handmaid to the Waterfords. She chooses the latter and is under close supervision from Lydia. The Waterfords, who still employ Nick, publicly treat Offred's disappearance as a kidnapping, but privately Serena is furious and grabs Offred by the throat. Rita returns the letters she found and tells Offred that she will no longer be involved. A baby shower is held Serena, incorporating prayer and a ritual binding of Offred to Serena. Offred learns from Alma that Ofglen's tongue was removed for speaking up to save Ofwarren (Janine) as she was about to be stoned and that Mayday has now gone silent. Aunt Lydia takes Offred out to show her what is presumed to be Omar's hanging corpse. She tells June that Omar's wife, Heather, is now a handmaid and that their child, Adam, was given away to another family. Aunt Lydia tells Offred that this was her fault, and Offred accepts the blame. Aunt Lydia encourages June to distinguish between Offred's person and June's. In a flashback, June sees Luke's first wife Annie, who tells her that they made wedding vows before God, but Luke rejects her attempts to come between him and June; a few years later, Annie sees Luke and June in a restaurant with their child, Hannah. Offred has collapsed emotionally under the knowledge of Omar's family's fate. June prays that Hannah might forget her, and ignoring Nick, appears to be conforming to the expectations of a handmaid.

15
5
"Seeds"
Mike Barker
Kira Snyder
May 16, 2018 (2018-05-16)

Offred is very subdued, and starts to burn the letters she had been keeping for Mayday. She notices vaginal bleeding, which continues and gets worse but does not inform anyone, although Rita notices her unsteadiness. Nick notices Offred's apparent depression and lets Mrs. Waterford know about it. Mrs. Waterford becomes alarmed at Nick's interest in Offred and informs Commander Waterford, who arranges for him to be married at a Prayvaganza where loyal Guardians are issued a wife as a reward for their work. Nick's new bride, Eden, moves into his room. Nick later finds Offred unconscious and drenched in the bushes outside the Waterfords' house and she is taken to the hospital. Offred, still pregnant, promises to her baby that they both will escape Gilead. Meanwhile, in the Colonies, Janine assures Emily that God is protecting them through their struggles in Gilead, and helps to arrange a small wedding for a dying worker, officiated by another Unwoman who is a rabbi. Emily, who has begun to lose her teeth, argues with her over her faith and her wishes to bring brightness to a place that otherwise seems so bleak. When the newlywed Unwoman dies, the rabbi officiates at the burial as she is lowered into her grave in a cemetery adorned with crosses.

16
6
"First Blood"
Mike Barker
Eric Tuchman
May 23, 2018 (2018-05-23)

Offred and Serena seem to be bonding when Serena gathers several handmaids and hosts lunch in Offred's honor. Serena offers her airy sitting room to Offred to use as a bedroom and shows Offred the nursery for the baby. Offred asks to see Hannah, which angers Serena. Eden reveals to Offred that she fears Nick may be a "gender traitor" due to his reluctance to have sex with her so Offred warns him and he has sex with Eden to avoid suspicion. Fred visits Offred in secret and gives her a photograph of Hannah. Nick asks Commander Pryce to be reassigned. Ofglen goes rogue at the opening of the Rachel and Leah Center and detonates a bomb. Flashbacks show Serena promoting her book tour A Woman's Place and being verbally attacked and shot by a protester, as well as Fred's efforts in punishing those who threatened Serena.

17
7
"After"
Kari Skogland
Lynn Renee Maxcy
May 30, 2018 (2018-05-30)

Wearing mourning veils, the handmaids and aunts attend a funeral for all of the 31 handmaids who perished in the bomb blast carried out by Ofglen. Twenty-six commanders were also killed in the attack on the Rachel and Leah Center, including Commander Pryce, while others, such as Commander Waterford, were seriously injured. Following the attack, Commander Cushing takes Commander Pryce's role and tightens security in Gilead, instituting an increased number of checkpoints and having numerous civilians summarily executed. He questions Offred, asking who aided her when she tried to flee the country. Offred responds that she was kidnapped, an answer that Commander Cushing does not believe. Mrs. Waterford is alarmed at the possibility of her household being targeted, and is angry at his heavy-handed response to the bombing. She forges orders from her husband to have Commander Cushing arrested. Because so many handmaids were killed at the Rachel and Leah Center during Ofglen's attack, some fertile women are taken back from the Colonies and are made to serve as handmaids once again, including Janine and Emily. Both reunite with Offred in the grocery store, with Janine happily telling her that it was God's plan that she be rescued. Offred tells her real name, June, to Emily and another handmaid and following this, several of the handmaids whisper their real names to one another. Later, Mrs. Waterford enlists Offred's help in illicitly performing the Commander's work for him while he is in the hospital. At the refugee center, Moira looks through countless records to try to confirm whether her fiancée, Odette, has died. Through flashbacks Moira is revealed to have been a voluntary surrogate for a couple before the war. She met Odette, a doctor, during this process. In the present, Moira eventually finds photographs showing Odette was killed.

18
8
"Women's Work"
Kari Skogland
Nina Fiore & John Herrera
June 6, 2018 (2018-06-06)

Offred helps Serena to complete Fred's work while he is too ill from his bomb injuries to do so himself. Serena tells Offred that the Putnams' child, Angela (called Charlotte by Janine, who is her biological mother) is sick. Offred advocates for Janine to be able to see the baby, and Serena agrees to ask about it for the baby's sake. Naomi Putnam dislikes the idea, but she is overruled by her husband, Warren. Serena petitions Fred to allow the sick child to be seen by a Martha who, prior to the Sons of Jacob coup, was one of the nation's top neonatologists. Fred denies the request, saying that whatever happens to the child must now be left to God's will. A dismayed Serena forges Fred's signature to a written order that transfers the Martha to the hospital for a day. Aunt Lydia tells June that she will hold her personally responsible if anything goes wrong with Janine's visit to the hospital. Offred, with true concern, tells Aunt Lydia that she will hold herself responsible too. The neonatologist can find nothing physically wrong with the child, and she advises them to simply unplug the baby from all of the machines and help her to feel safe and warm. When Fred discovers that Serena forged his signature on an order to temporarily transfer the physician/Martha, he beats Serena with his belt as Offred is forced to watch. Meanwhile, Eden is working hard to please Nick, but after rearranging his garret and uncovering the bundle of handmaids' letters he is keeping safe for Offred, he becomes aggressive towards her, demanding that she never touch his belongings. The episode ends with Janine singing "I Only Want to Be with You" to her child and bouncing her as her baby gurgles happily. Janine is in a state of undress, paying tribute to the theory that skin-to-skin maternal contact can solve a variety of infant maladies.

19
9
"Smart Power"
Jeremy Podeswa
Dorothy Fortenberry
June 13, 2018 (2018-06-13)

Fred orders Serena to travel with him on a diplomatic mission to Canada, despite the baby's birth is so close,saying that outsiders need to see "a strong Gilead wife." Serena punishes Offred by telling her she'll be kicked out of the house as soon as the baby is born. Offred is disturbed to learn that she won't be permitted to nurse and then wean the baby, as is customary, but tries to hide her dismay by agreeing with Serena that they've all had enough of one another. As Serena and Fred are driven through the streets of Toronto, Serena is reminded of what normalcy used to look like in the US. The Waterfords are officially greeted by a contingent of Canadian government officials, with a gay male government official pointedly telling Fred that he used to enjoy visiting the US with "his husband." Fred then diplomatically attempts to whitewash Gilead's anti-gay stance. An aide hands Serena a schedule of activities that consists of pictures rather than words. Feeling ambivalent about all of the reminders of open society surrounding her in Toronto and embarrassed by her welcome, Serena goes to a bar and orders a glass of wine. She is soon approached by a handsome man named Mark, who reveals he's a spy working for the remnant of the US government in Hawaii. Mark offers to help Serena defect and denounce Gilead and her husband in exchange for her freedom. Serena declines even after Mark offers to arrange fertility treatment so Serena can have a baby of her own. US refugees stand in protest at the entrance to Fred and Serena's hotel. One of the protesters is Luke, who accosts the Waterfords as their limo pulls up. Luke, holding an enlarged, sign-sized photo of himself, June, and their daughter Hannah, accuses Waterford of raping his wife. Serena and Nick are visibly disquieted by the photo. Afterwards, Nick quietly finds Luke at a bar and tells him June is pregnant but safe, and gives him the bundle of letters from handmaids who are enslaved in Gilead. Luke, Moira, and Erin release the letters on the Web, causing a huge public outcry that prompts the Canadians to cancel the summit. At the airport, as the Waterfords are surrounded by more protesters, Moira angrily bangs on the Waterfords' car and holds up a sign that says "My name is Moira." Fred learns that Moira (who he knew as "Ruby" at Jezebel's) successfully escaped from Gilead. Offred pleads with Rita, and then with Aunt Lydia, to protect the child from the Waterfords after Offred is expelled from the house. Offred is able to extract a somewhat grudging promise to do so from Rita and a tearful promise to do so from Aunt Lydia. Serena burns the Hawaiian tiki bar matches Mark gave her to remind her that a United States still exists beyond the borders of Gilead, with some apparent regret. Meanwhile, Nick gives Offred news of Luke and Moira, which lifts her spirits and reignites her will to fight.

20
10
"The Last Ceremony"[27]
TBA
TBA
June 20, 2018 (2018-06-20)

text: Production[edit]

text: A straight-to-series order by Hulu of The Handmaid's Tale was announced in April 2016, with Elisabeth Moss set to star.[28] Based on the 1985 novel of the same name by Margaret Atwood, the series was created by Bruce Miller, who is also an executive producer with Daniel Wilson, Fran Sears, and Warren Littlefield.[28] Atwood serves as consulting producer, giving feedback on some of the areas where the series expands upon or modernizes the book.[28][29] She also played a small cameo role in the first episode.[30] Moss is also a producer.[31] In June 2016, Reed Morano was announced as director of the series.[32] Samira Wiley, Max Minghella, and Ann Dowd joined the cast in July 2016.[33][34][35] Joseph Fiennes, Madeline Brewer, and Yvonne Strahovski were cast in August 2016,[36][37][38] followed by O. T. Fagbenle and Amanda Brugel in September 2016.[39][40] In October 2016, Ever Carradine joined the cast,[41] and Alexis Bledel was added in January 2017.[42]

text: Filming on the series took place in Toronto, Mississauga, Hamilton, Oakville, and Cambridge, Ontario, from September 2016 to February 2017.[43][44] The first full trailer of the TV series was released by Hulu on YouTube on March 23, 2017.[45] The series premiered on April 26, 2017.[46]

text: On May 3, 2017, The Handmaid's Tale was renewed for a second season to premiere in 2018.[47] Moss told the news media that the subsequent episodes would cover further developments in the story, filling in some of the unanswered questions and continuing the narrative already "finished" in the book.[48] The second season consists of 13 episodes and began filming in fall 2017. Alexis Bledel returned as a series regular.[49] Showrunner Bruce Miller stated that he envisioned 10 seasons of the show, stating, "Well, you know, honestly, when I started, I tried to game out in my head what would ten seasons be like? If you hit a home run, you want energy to go around the bases, you want enough story to keep going, if you can hook the audience to care about these people enough that they're actually crying at the finale."[50]

text: Broadcast and release[edit]

text: The first three episodes of the series premiered on April 26, 2017; the subsequent seven episodes were released on a weekly basis.[46][51] In Canada, the series is broadcast by Bravo; the first two episodes premiered on April 30, 2017.[52] In Scandinavia, the series is available on HBO Nordic.[53] In the United Kingdom, the series premiered on May 28, 2017, on Channel 4.[54] In Ireland, the series premiered on February 5, 2018 on RTÉ2, with a showing of the first two episodes.[55] RTÉ also became the first broadcaster in Europe to debut Season 2 following its broadcast in the US and Canada.[56]

text: In New Zealand, the series was released on the subscription video on demand service Lightbox on June 8, 2017.[57] In Australia, the series premiered on the TV channel SBS's video streaming service SBS on Demand, on July 6, 2017.[58]

text: The first season was released on Blu-ray and DVD on March 13, 2018.[59]

text: Reception[edit]

text: Critical response[edit]

text:
Season
Critical response

Rotten Tomatoes
Metacritic

1
95% (106 reviews)
92 (41 reviews)

2
94% (69 reviews)
86 (28 reviews)

text: Season 1[edit]

text: On Rotten Tomatoes, the first season has an approval rating of 95% based on 106 reviews, with an average rating of 8.7/10. The site's critical consensus reads, "Haunting and vivid, The Handmaid's Tale is an endlessly engrossing adaptation of Margaret Atwood's dystopian novel that's anchored by a terrific central performance from Elisabeth Moss."[60] On Metacritic, it has a weighted average score of 92 out of 100 based on 41 critics, indicating "universal acclaim".[61]

text: Daniel Fienberg of The Hollywood Reporter called it "probably the spring's best new show".[62] Jen Chaney of Vulture gave it a highly positive review, and wrote that it is "A faithful adaptation of the book that also brings new layers to Atwood's totalitarian, sexist world of forced surrogate motherhood" and that "this series is meticulously paced, brutal, visually stunning, and so suspenseful from moment to moment that only at the end of each hour will you feel fully at liberty to exhale".[63]

text: There was much debate on whether parallels could be drawn between the series (and by extension, the book it is based on) and American society following Donald Trump and Mike Pence's elections as President and Vice President of the United States, respectively. [64] [65] A comparison has also been made to the Salafi/Wahabbi extremism of ISIL, under which enslaved women of religious minorities are passed around and utilized as sex objects and vessels to bear new jihadis.[66][67]

text: Season 2[edit]

text: On Rotten Tomatoes, the second season has an approval rating of 94% based on 69 reviews, with an average rating of 8.35/10. The site's critical consensus reads, "Beautifully shot but dishearteningly relevant, The Handmaid's Tale centers its sophomore season tightly around its compelling cast of characters, making room for broader social commentary through more intimate lenses."[68] On Metacritic, it has a weighted average score of 86 out of 100 based on 28 critics, indicating "universal acclaim".[69]

text: Accolades[edit]

text:
Year
Award
Category
Nominee(s)
Result
Ref.

2017
Primetime Emmy Awards
Outstanding Drama Series
Bruce Miller, Warren Littlefield, Daniel Wilson, Fran Sears, Ilene Chaiken, Sheila Hockin, Eric Tuchman, Frank Siracusa, John Weber, Kira Snyder, Elisabeth Moss, Joseph Boccia, and Leila Gerstein
Won
[70]

Outstanding Lead Actress in a Drama Series
Elisabeth Moss (for "Night")
Won

Outstanding Supporting Actress in a Drama Series
Ann Dowd (for "Offred")
Won

Samira Wiley (for "Night")
Nominated

Outstanding Directing for a Drama Series
Reed Morano (for "Offred")
Won

Kate Dennis (for "The Bridge")
Nominated

Outstanding Writing for a Drama Series
Bruce Miller (for "Offred")
Won

Primetime Creative Arts Emmy Awards
Outstanding Guest Actress in a Drama Series
Alexis Bledel (for "Late")
Won

Outstanding Casting for a Drama Series
Russell Scott, Sharon Bialy, and Sherry Thomas
Nominated

Outstanding Cinematography for a Single-Camera Series (One Hour)
Colin Watkinson (for "Offred")
Won

Outstanding Period/Fantasy Costumes for a Series, Limited Series, or Movie
Ane Crabtree and Sheena Wichary (for "Offred")
Nominated

Outstanding Production Design for a Narrative Contemporary or Fantasy Program (One Hour or More)
Julie Berghoff, Evan Webber, and Sophie Neudorfer (for "Offred")
Won

Outstanding Special Visual Effects in a Supporting Role
Brendan Taylor, Stephen Lebed, Leo Bovell, Martin O'Brien, Winston Lee, Kelly Knauff, Zach Dembinski, Mike Suta, and Cameron Kerr (for "Birth Day")
Nominated

Peabody Award
Entertainment, children's and youth honoree
The Handmaid's Tale
Won
[71]

Gold Derby TV Awards
Drama Series
The Handmaid's Tale
Nominated
[72]

Drama Actress
Elisabeth Moss
Won

Drama Guest Actress
Alexis Bledel
Won

TCA Awards
Program of the Year
The Handmaid's Tale
Won
[73]

Outstanding Achievement in Drama
Won

Outstanding New Program
Nominated

Individual Achievement in Drama
Elisabeth Moss
Nominated

American Film Institute Awards
Top 10 TV Programs of the Year
The Handmaid's Tale
Won
[74]

2018
American Cinema Editors Awards
Best Edited Drama Series for Non-Commercial Television
Julian Clarke and Wendy Hallam Martin (for "Offred")
Won
[75]

Art Directors Guild Awards
One-Hour Contemporary Single-Camera Television Series
Julie Berghoff (for "Offred", "Birth Day", "Nolite Te Bastardes Carborundorum")
Won
[76]

Andrew Stearn (for "The Bridge")
Nominated

Casting Society of America
Television Pilot and First Season – Drama
Sharon Bialy, Sherry Thomas, Russell Scott, Robin D. Cook, and Jonathan Oliveira
Won
[77]

Cinema Audio Society Awards
Outstanding Achievement in Sound Mixing for Television Series – One Hour
John J. Thomson, Lou Solakofski, Joe Morrow, and Don White (for "Offred")
Nominated
[78]

Costume Designers Guild Awards
Excellence in Contemporary Television Series
Ane Crabtree
Won
[79]

Critics' Choice Television Awards
Best Drama Series
The Handmaid's Tale
Won
[80]

Best Actress in a Drama Series
Elisabeth Moss
Won

Best Supporting Actress in a Drama Series
Ann Dowd
Won

Directors Guild of America Awards
Outstanding Directorial Achievement for a Drama Series
Reed Morano (for "Offred")
Won
[81]

Golden Globe Awards
Best Television Series – Drama
The Handmaid's Tale
Won
[82]

Best Actress – Television Series Drama
Elisabeth Moss
Won

Best Supporting Actress – Series, Miniseries or Television Film
Ann Dowd
Nominated

Location Managers Guild Awards
Outstanding Locations in Contemporary Television
John Musikka and Geoffrey Smither
Nominated
[83]

Producers Guild of America Awards
Outstanding Producer of Episodic Television, Drama
The Handmaid's Tale
Won
[84]

Satellite Awards
Best Drama Series
The Handmaid's Tale
Nominated
[85]

Best Actress in a Drama / Genre Series
Elisabeth Moss
Won

Best Supporting Actress in a Series, Miniseries or TV Film
Ann Dowd
Won

Saturn Awards
Best New Media Television Series
The Handmaid's Tale
Pending
[86]

Screen Actors Guild Awards
Outstanding Performance by an Ensemble in a Drama Series
Madeline Brewer, Amanda Brugel, Ann Dowd, O. T. Fagbenle, Joseph Fiennes, Tattiawna Jones, Max Minghella, Elisabeth Moss, Yvonne Strahovski, and Samira Wiley
Nominated
[87]

Outstanding Performance by a Female Actor in a Drama Series
Elisabeth Moss
Nominated

USC Scripter Awards
Best Adapted TV Screenplay
Bruce Miller and Margaret Atwood (for "Offred")
Won
[88]

Writers Guild of America Awards
Dramatic Series
Ilene Chaiken, Nina Fiore, Dorothy Fortenberry, Leila Gerstein, John Herrera, Lynn Maxcy, Bruce Miller, Kira Snyder, Wendy Straker Hauser, and Eric Tuchman
Won
[89]

New Series
Won


document_title: Thalidomide

question_text: who discovered the link between thalidomide and birth defects

root

text: Thalidomide

text: Medical uses[edit]

text: Thalidomide is used as a first line treatment in multiple myeloma in combination with dexamethasone or with melphalan and prednisone, to treat acute episodes of erythema nodosum leprosum and for maintenance therapy.[7][8]

tag: p

text: Thalidomide is used off-label in several ways.

text: The bacterium that causes tuberculosis is related to leprosy. Thalidomide may be helpful in some cases where standard TB drugs and corticosteroids are not sufficient to resolve severe inflammation in the brain.[9][10]

text: It is used as a second-line treatment to manage graft versus host disease and aphthous stomatitis in children and has been prescribed for other conditions in children including actinic prurigo and epidermolysis bullosa pruriginosa; the evidence for these uses is weak.[11] It is recommended only as a third line treatment in graft versus host disease in adults, based on lack of efficacy and side effects observed in clinical trials.[12][13]

text: Contraindications[edit]

text: Thalidomide should not be used by people who are breast feeding or pregnant, trying to conceive a child, or cannot or will not follow the risk management program to prevent pregnancies. The prescribing doctor is required to ensure that contraception is being used, and regularly pregnancy tests must be administered. Some people are allergic to thalidomide and should not take it. It should be used with caution in people with chronic infections like HIV or hepatitis B.[8][7]

text: Adverse effects[edit]

text: Thalidomide causes birth defects.[8][7][14] The FDA and other regulatory agencies have approved marketing of the drug only with an auditable risk evaluation and mitigation strategy that ensures that people using the drug are aware of the risks and avoid pregnancy; this applies to men and women both, as the drug can be transmitted in sperm.[14]

text: There is a high risk that thalidomide can cause excessive blood clots. There is also a high risk that thalidomide can interfere with formation of various kinds of new blood cells, creating a risk of infection via neutropenia, leukopenia, and lymphopenia, and risks that blood will not clot via thrombocytopenia. There is also a risk of anemia via lack of red blood cells. The drug can also damage nerves, causing peripheral neuropathy that may be irreversible.[8][7]

text: Thalidomide has several cardiovascular adverse effects, including risk of heart attacks, pulmonary hypertension, and changes in heart rhythm including syncope, bradycardia and atrioventricular block.[8][7]

text: It can cause liver damage and severe skin reactions like Stevens-Johnson Syndrome. It tends to make people sleepy, which creates risk for driving and operating other machinery. As it kills cancer cells, it can cause tumor lysis syndrome. Thalidomide can prevent menstruation.[8][7]

text: Other than the above, very common (reported in more than 10% of people) adverse effects include tremor, dizziness, tingling, numbness, constipation, and peripheral edema.[8][7]

text: Common (reported by 1-10% of people) adverse effects include confusion, depressed mood, reduced coordination, heart failure, difficulty breathing, interstitial lung disease, lung inflammation, vomiting, dry mouth, rashes, dry skin, fever, weakness, and a sense of unwellness.[8][7]

text: Interactions[edit]

text: There are no expected pharmacokinetic interactions between thalidomide and other medicines due to its neutral effects on p-glycoprotein and P450 cytochromes. It may interact with sedatives due to its sedative action. It may also interact with bradycardic agents due to its bradycardia-inducing effects. The risk of peripheral neuropathy may be increased by concomitant treatment with other agents known to cause peripheral neuropathy.[15] The risk of venous thromboembolisms with thalidomide seems to be increased when patients are treated with oral contraceptives or other cytotoxic agents (including doxorubicin and melphalan) concurrently. Thalidomide may interfere with the contraceptive effects of various contraceptives and hence it is advised that women of reproductive age use at least two different means of contraception to ensure that no child will be conceived while they are receiving thalidomide.[15][8][7]

text: Overdose[edit]

text: As of 2013 eighteen cases of overdoses had been reported with doses of up to 14.4 g without any reported fatalities.[15] No specific antidote for overdoses exists and treatment is purely supportive.[15]

text: Pharmacology[edit]

text: The precise mechanism of action for thalidomide is unknown although efforts to identify thalidomide's teratogenic action generated 2000 research papers and the proposal of 15 or 16 plausible mechanisms by 2000.[16] As of 2015 the main theories were inhibition of the process of angiogenesis, its inhibition of cereblon, a ubiquitin ligase, and its ability to generate reactive oxygen species which in turn kill cells.[17][18]

text: Thalidomide also binds to and acts as an antagonist of the androgen receptor (AR) and hence is a nonsteroidal antiandrogen (NSAA) of some capacity.[19] In accordance, it can produce gynecomastia and sexual dysfunction as side effects in men.[20]

text: Thalidomide is provided as a racemic mixture of two enantiomers; while there are reports that only one of the enantiomers may cause birth defects, the body converts each enantiomer into the other through mechanisms that are not well understood.[14]

text: Chemistry[edit]

text: Thalidomide is racemic; while the S-thalidomide is the bioactive form of the molecule, the individual enantiomers can racemize to each other due to the acidic hydrogen at the chiral centre, which is the carbon of the glutarimide ring bonded to the phthalimide substituent. The racemization process can occur in vivo.[2][21][22][23]

text: Celgene Corporation originally synthesized thalidomide using a three-step sequence starting with L-glutamic acid treatment, but this has since been reformed by the use of L-glutamine.[24] As shown in the image below, N-carbethoxyphtalimide (1) can react with L-glutamine to yield N-Phthaloyl-L-glutamine (2). Cyclization of N-Phthaloyl-L-glutamine occurs using carbonyldiimidazole, which then yields thalidomide (3).[24] Celegne Corporation's original method resulted in a 31% yield of S-thalidomide, whereas the two-step synthesis yields 85-93% product that is 99% pure.

text: History[edit]

text: Thalidomide was discovered by scientists at the German pharmaceutical company Chemie Grünenthal (now Grünenthal GmbH) around 1953. The company had been set up as a soap maker just after WWII ended, to address the urgent market need for antibiotics. Heinrich Mueckter was appointed to head the discovery program based on his experience working with the German army's antiviral research program. In the course of preparing reagents for the work, Mueckter's assistant Wilhelm Kunz isolated a by-product, that was in turn recognized by pharmacologist Herbert Keller as an analog of glutethimide, a sedative, and the medicinal chemistry work turned to improving the lead compound into a suitable drug; the result was thalidomide. The toxicity was examined in several animals, and the drug was introduced in 1956 as a sedative.[25]

text: Researchers at Chemie Grünenthal also found that thalidomide was a particularly effective antiemetic that had an inhibitory effect on morning sickness.[26] Hence, on October 1, 1957, the company launched thalidomide and began aggressively marketing it under the trade name Contergan.[27][better source needed] It was proclaimed a "wonder drug" for insomnia, coughs, colds and headaches.[citation needed]

text: During this time period, the use of medications during pregnancy was not strictly controlled, and drugs were not thoroughly tested for potential harm to the fetus.[26] Thousands of pregnant women took the drug to relieve their symptoms. At the time of the drug's development, scientists did not believe any drug taken by a pregnant woman could pass across the placental barrier and harm the developing fetus,[6] even though the effect of alcohol on fetal development had been documented by case studies on alcoholic mothers since at least 1957.[28] There soon appeared reports of findings of abnormalities in children being born, traced back to the use of the drug thalidomide. In late 1959, it was noticed that peripheral neuritis developed in patients who took the drug over a period of time, and it was only after this point that thalidomide ceased to be provided over the counter.[29]

text: Hence, while initially considered safe, the drug was responsible for teratogenic deformities in children born after their mothers used it during pregnancies, prior to the third trimester. In November 1961, thalidomide was taken off the market due to massive pressure from the press and public.[30] Experts estimate that the drug thalidomide led to the death of approximately 2,000 children and serious birth defects in more than 10,000 children, about 5,000 of them in West Germany.[citation needed] The regulatory authorities in East Germany did not approve thalidomide.[4][dead link] One reason for the initially unobserved side effects of the drug and the subsequent approval in West Germany was that at that time drugs did not have to be tested for teratogenic effects. They had been tested on rodents only, as was usual at the time.[31]

text: In the UK, the British pharmaceutical company The Distillers Company (Biochemicals) Ltd, a subsidiary of Distillers Co. Ltd. (now part of Diageo plc), marketed thalidomide under the brand name Distaval as a remedy for morning sickness throughout the United Kingdom, Australia and New Zealand. Their advertisement claimed that "Distaval can be given with complete safety to pregnant women and nursing mothers without adverse effect on mother or child...Outstandingly safe Distaval has been prescribed for nearly three years in this country."[4][dead link] Around the world, more and more pharmaceutical companies started to produce and market the drug under license from Chemie Grünenthal. By the mid 1950s, 14 pharmaceutical companies were marketing thalidomide in 46 countries under 37 (some reports suggest 51) different trade names.

text: In the U.S., representatives from Chemie Grünenthal approached Smith, Kline & French (SKF), now GlaxoSmithKline (GSK) with a request to market and distribute the drug in North America. A memorandum rediscovered in 2010 in the archives of the U.S. Food and Drug Administration (FDA) shows that, as part of its in-licensing approach, Smith, Kline and French conducted animal tests and ran a clinical trial of the drug in the United States involving 875 people, including pregnant women, in 1956–57.[citation needed] In 1956, researchers at SKF involved in clinical trials noted that even when used in very high doses, thalidomide could not induce sleep in mice.[citation needed] And when administered at doses 50 to 650 times larger than that claimed by Chemie Grünenthal to be "sleep inducing", the researchers could still not achieve the hypnotic effect in animals that it had on humans.[citation needed] After completion of the trial, and based on reasons kept hidden for decades, SKF declined to commercialize the drug. Later, Chemie Grünenthal, in 1958, reached an agreement with William S Merrell Company in Cincinnati, Ohio, (later Richardson-Merrell, now part of Sanofi), to market and distribute thalidomide throughout the United States.[4][dead link]

text: The U.S. FDA refused to approve thalidomide for marketing and distribution. However, the drug was distributed in large quantities for testing purposes, after the American distributor and manufacturer Richardson-Merrell had applied for its approval in September 1960.[citation needed] The official in charge of the FDA review, Frances Oldham Kelsey, did not rely on information from the company, which did not include any test results. Richardson-Merrell was called on to perform tests and report the results. The company demanded approval six times, and was refused each time. Nevertheless, a total of 17 children with thalidomide-induced malformations were born in the U.S.[32]

text: In Canada, the history of the drug thalidomide dates back to April 1, 1961. There were many different forms sold, with the most common variant being Talimol.[33] Two months after Talimol went on sale, pharmaceutical companies sent physicians letters warning about the risk of birth defects.[33] It was not until March 2, 1962, that both drugs were banned from the Canadian market by the FDD, and soon afterward physicians were warned to destroy their supplies.[33]

text: Leprosy treatment[edit]

text: In 1964, Israeli physician Jacob Sheskin administered thalidomide to a patient critically ill with leprosy. The patient exhibited erythema nodosum leprosum (ENL), a painful skin condition, one of the complications of leprosy. This was attempted despite the ban on thalidomide's use, but results were favourable: the patient slept for hours and was able to get out of bed without aid upon awakening. A clinical trial studying the use of thalidomide in leprosy soon followed.[34]

text: Thalidomide has been used by Brazilian physicians as the drug of choice for the treatment of severe ENL since 1965, and by 1996, at least 33 cases of thalidomide embryopathy were recorded in people born in Brazil after 1965.[35] Since 1994, the production, dispensing, and prescription of thalidomide have been strictly controlled, requiring women to use two forms of birth control and submit to regular pregnancy tests. Despite this, cases of thalidomide embryopathy continue,[36][37] with at least 100 cases identified in Brazil between 2005 and 2010.[38] 5.8 million thalidomide pills were distributed throughout Brazil in this time period, largely to poor Brazilians in areas with poor access to healthcare, and these cases have occurred despite the controls.

text: In 1998 the FDA approved the drug's use in the treatment of ENL.[39] Because of thalidomide's potential for causing birth defects, the drug may be distributed only under tightly controlled conditions. The FDA required that Celgene Corporation, which planned to market thalidomide under the brand name Thalomid, establish a system for thalidomide education and prescribing safety (STEPS) oversight program. The conditions required under the program include limiting prescription and dispensing rights to authorized prescribers and pharmacies only, keeping a registry of all patients prescribed thalidomide, providing extensive patient education about the risks associated with the drug, and providing periodic pregnancy tests for women who take the drug.[39]

text: In 2010, the World Health Organisation (WHO) stated that it did not recommend thalidomide due the difficulty of adequately controlling its use, and due to the availability of clofazimine.[40]

text: Cancer treatment[edit]

text: Shortly after the teratogenic properties of thalidomide were recognized in the mid-1960s, its anti-cancer potential was explored and two clinical trials were conducted in people with advanced cancer, including some people with multiple myeloma; the trials were inconclusive.[41]

text: Little further work was done with thalidomide in cancer until the 1990s.[41]

text: Judah Folkman pioneered studies into the role of angiogenesis (the proliferation and growth of blood vessels) in the development of cancer, and in the early 1970s had shown that solid tumors could not expand without it.[42][43] In 1993 he surprised the scientific world by hypothesizing the same was true of blood cancers,[44] and the next year he published work showing that a biomarker of angiogenesis was higher in all people with cancer, but especially high in people with blood cancers, and other evidence emerged as well.[44] Meanwhile, a member of his lab, Robert D'Amato, was looking for angiogenesis inhibitors, and discovered in 1994 that thalidomide inhibited angiogenesis.[45] Around that time, the wife of a man who was dying of multiple myeloma and whom standard treatments had failed, called Folkman asking him about his anti-angiogenesis ideas.[43] Folkman convinced the patient's doctor to try thalidomide, and that doctor conducted a clinical trial of thalidomide for people with multiple myeloma in which about a third of the subjects responded to the treatment.[43] The results of that trial were published in the New England Journal of Medicine in 1999.[43][46]

text: After further work was done by Celgene and others, in 2006 the U.S. Food and Drug Administration granted accelerated approval for thalidomide in combination with dexamethasone for the treatment of newly diagnosed multiple myeloma patients.[43][47]

text: Society and culture[edit]

text: Birth defects crisis[edit]

text: In the late 1950s and early 1960s, more than 10,000 children in 46 countries were born with deformities such as phocomelia as a consequence of thalidomide use.[48] The severity and location of the deformities depended on how many days into the pregnancy the mother was before beginning treatment; thalidomide taken on the 20th day of pregnancy caused central brain damage, day 21 would damage the eyes, day 22 the ears and face, day 24 the arms, and leg damage would occur if taken up to day 28. Thalidomide did not damage the foetus if taken after 42 days gestation.[30]

text: It is not known exactly how many worldwide victims of the drug there have been, although estimates range from 10,000 to 20,000[49] to 100,000.[30] Despite the side effects, thalidomide was sold in pharmacies in Canada until 1962.[33][50]

text: In the United Kingdom, the drug was licensed in 1958 and withdrawn in 1961. Of the approximately 2,000 babies born with defects, around half died within a few months and 466 survived to at least 2010.[51]

text: In Spain, thalidomide was widely available throughout the 1970s, perhaps even into the 1980s. There were two reasons for this. First, state controls and safeguarding were poor; indeed, it was not until 2008 that the government even admitted the country had ever imported thalidomide. Second, Grünenthal failed to insist that its sister company in Madrid warn Spanish doctors, and permitted it to not warn them. The Spanish advocacy group for victims of thalidomide estimates that in 2015, there were 250–300 living victims of thalidomide in Spain.[52]

text: The Australian obstetrician William McBride and the German paediatrician Widukind Lenz suspected a link between birth defects and the drug, a theory Lenz proved in 1961.[53][54] McBride was later awarded a number of honors, including a medal and prize money by L'Institut de la Vie in Paris.[55] Further animal tests were conducted by Dr George Somers, Chief Pharmacologist of Distillers Company in Britain, which showed foetal abnormalities in rabbits.[56] Similar results were also published showing these effects in rats[57][58] and other species.[59]

text: In East Germany, the head of the central pharmacy control commission, Friedrich Jung, suspected an antivitaminic effect of thalidomide as derivative of glutamic acid.[60] Meanwhile, in West Germany, it took some time before the increase in dysmelia at the end of the 1950s was connected with thalidomide. In 1958 Karl Beck, a former pediatric doctor in Bayreuth wrote an article in a local newspaper claiming a relationship between nuclear weapons testing and cases of dysmelia in children.[61] Based on this, FDP whip Erich Mende requested an official statement from the federal government.[61] For statistical reasons, the main data series used to research dysmelia cases started by chance at the same time as the approval date for thalidomide.[61] After the Nazi regime with its Law for the Prevention of Hereditarily Diseased Offspring used mandatory statistical monitoring to commit various crimes, western Germany had been very reluctant to monitor congenital disorders in a similarly strict way.[62] The parliamentary report rejected any relation with radioactivity and the abnormal increase of dysmelia.[61] Also the DFG research project installed after the Mende request was not helpful. The project was led by pathologist Franz Büchner who ran the project to propagate his teratological theory. Büchner saw lack of healthy nutrition and behavior of the mothers as being more important than genetic reasons.[62] Furthermore, it took a while to install a Surgeon General in Germany; the Federal Ministry of Health (Germany) was not founded until 1962, some months after thalidomide was banned from the market.[61] In Germany approximately 2,500 thalidomide babies were born.[54]

text: Several countries either restricted the drug's use or never approved it. Ingeborg Eichler, a member of the Austrian pharmaceutical admission conference, enforced thalidomide (tradename Softenon) being sold under the rules of prescription medication and as a result relatively few affected children were born in Austria and Switzerland.[63] In the United States, pharmacologist Frances Oldham Kelsey M.D. withstood pressure from the Richardson-Merrell company and refused Food and Drug Administration (FDA) approval to market thalidomide, saying further studies were needed.[48] This reduced the impact of thalidomide in United States patients. Although thalidomide was never approved for sale in the United States at the time, millions of tablets had been distributed to physicians during a clinical testing program. It was impossible to know how many pregnant women had been given the drug to help alleviate morning sickness or as a sedative.[64]

text: Aftermath of scandal[edit]

text: The numerous reports of malformations in babies brought about the awareness of the side effects of the drug on pregnant women. The birth defects caused by the drug thalidomide can range from moderate malformation to more severe forms. Possible birth defects include phocomelia, dysmelia, amelia, bone hypoplasticity, and other congenital defects affecting the ear, heart, or internal organs.[26] Franks et al. looked at how the drug affected newborn babies, the severity of their deformities, and reviewed the drug in its early years. Webb in 1963 also reviewed the history of the drug and the different forms of birth defects it had caused. "The most common form of birth defects from thalidomide is shortened limbs, with the arms being more frequently affected. This syndrome is the presence of deformities of the long bones of the limbs resulting in shortening and other abnormalities."[33]

text: Germany[edit]

text: In 1968, a large criminal trial began in Germany, charging several Grünenthal officials with negligent homicide and injury. After Grünenthal settled with the victims in April 1970, the trial ended in December 1970 with no finding of guilt. As part of the settlement, Grünenthal paid 100 million DM into a special foundation; the German government added 320 million DM. The foundation paid victims a one-time sum of 2,500-25,000 DM (depending on severity of disability) and a monthly stipend of 100-450 DM. The monthly stipends have since been raised substantially and are now paid entirely by the government (as the foundation had run out of money). Grünenthal paid another 50 million Euros into the foundation in 2008.

text: On 31 August 2012, Grünenthal chief executive Harald F. Stock, PhD, who served as the Chief Executive Officer of Grünenthal GmbH from January 2009 to May 28, 2013 and was also a Member of Executive Board until May 28, 2013, apologized for the first time for producing the drug and remaining silent about the birth defects.[65] At a ceremony, Stock unveiled a statue of a disabled child to symbolize those harmed by thalidomide and apologized for not trying to reach out to victims for over 50 years. At the time of the apology, there were 5,000 to 6,000 sufferers still alive. Victim advocates called the apology "insulting" and "too little, too late", and criticized the company for not compensating victims. They also criticized the company for their claim that no one could have known the harm the drug caused, arguing that there were plenty of red flags at the time.[66]

text: United Kingdom[edit]

text: In 1968, after a long campaign by The Sunday Times, a compensation settlement for the UK victims was reached with Distillers Company (now part of Diageo), which had distributed the drug in the UK.[67][68] This compensation, which is distributed by the Thalidomide Trust in the UK, was substantially increased by Diageo in 2005.[69] The UK Government gave survivors a grant of £20 million, to be distributed through the Thalidomide Trust, in December 2009.[70]

text: Australia[edit]

text: Melbourne woman Lynette Rowe, who was born without limbs, led an Australian class action lawsuit against the drug's manufacturer, Grünenthal, which fought to have the case heard in Germany. The Supreme Court of Victoria dismissed Grünenthal's application in 2012, and the case was heard in Australia.[71] On 17 July 2012, Rowe was awarded an out-of-court settlement, believed to be in the millions of dollars and paving the way for class action victims to receive further compensation.[72] In February 2014, the Supreme Court of Victoria endorsed the settlement of $89 million AUD to 107 victims of the drug in Australia and New Zealand.[73][74]

text: Canada[edit]

text: The drug thalidomide's birth defects in children affected many people's lives, and from these events came the formation of the group called The Thalidomide Victims Association of Canada, a group of 120 Canadian survivors.[75][76] Their goal was to prevent future usage of drugs that could be of potential harm to mothers and babies. The members from the thalidomide victims association were involved in the STEPS program, which aimed to prevent teratogenicity.[26]

text: The effects of thalidomide increased fears regarding the safety of pharmaceutical drugs. The Society of Toxicology of Canada was formed after the effects of thalidomide were made public, focusing on toxicology as a discipline separate from pharmacology.[77] The need for the testing and approval of the toxins in certain pharmaceutical drugs became more important after the disaster. The Society of Toxicology of Canada is responsible for the Conservation Environment Protection Act, focusing on researching the impact to human health of chemical substances.[77] Thalidomide brought on changes in the way drugs are tested, what type of drugs are used during pregnancy, and increased the awareness of potential side effects of drugs.

text: According to Canadian news magazine program W5, most, but not all, victims of thalidomide receive annual benefits as compensation from the Government of Canada. Excluded are those who cannot provide the documentation the government requires.[78]

text: United States[edit]

text: For correctly denying the application despite the pressure from Richardson-Merrell, Kelsey eventually received the President's Award for Distinguished Federal Civilian Service at a 1962 ceremony with President John F. Kennedy. In September 2010, the FDA honored Kelsey with the first Kelsey award. The award, given annually to an FDA staff member, came 50 years after Kelsey, then a new medical officer at the agency, first reviewed the application from the William S. Merrell Company of Cincinnati.[79] Cardiologist Helen B. Taussig learned of the damaging effects of the drug thalidomide on newborns and in 1967, testified before Congress on this matter after a trip to Germany where she worked with infants with phocomelia (severe limb deformities). As a result of her efforts, thalidomide was banned in the United States and Europe.[citation needed]

text: Notable cases[edit]

text:
Lorraine Mercer MBE of the United Kingdom, born with phocomelia of both arms and legs, is the only thalidomide survivor to carry the Olympic Torch.[80]
Thomas Quasthoff, an internationally acclaimed bass-baritone, who describes himself: "1.34 meters tall, short arms, seven fingers — four right, three left — large, relatively well-formed head, brown eyes, distinctive lips; profession: singer".[81]
Niko von Glasow produced a documentary called NoBody's Perfect, based on the lives of 12 people affected by the drug, which was released in 2008.[82][83]
Mercédes Benegbi, born with phocomelia of both arms, drove the successful campaign for compensation from her government for Canadians who were affected by thalidomide.[84]

text: Change in drug regulations[edit]

text: The disaster prompted many countries to introduce tougher rules for the testing and licensing of drugs, such as the Kefauver Harris Amendment[85] (U.S.), Directive 65/65/EEC1 (E.U.),[86] and the Medicines Act 1968.[87][88] In the United States, the new regulations strengthened the FDA, among other ways, by requiring applicants to prove efficacy and to disclose all side effects encountered in testing.[48] The FDA subsequently initiated the Drug Efficacy Study Implementation to reclassify drugs already on the market.

text: Research[edit]

text: Research efforts have been focused on determination how thalidomide causes birth defects and its other activities in the human body, efforts to develop safer analogs, and efforts to find further uses for thalidomide.

text: Thalidomide analogs[edit]

text: The exploration of the antiangiogenic and immunomodulatory activities of thalidomide has led to the study and creation of thalidomide analogs.[89][90] Celgene has sponsored numerous clinical trials with analogues to thalidomide, such as lenalidomide, that are substantially more powerful and have fewer side effects — except for greater myelosuppression.[91] In 2005, Celgene received FDA approval for lenalidomide (Revlimid) as the first commercially useful derivative. Revlimid is available only in a restricted distribution setting to avoid its use during pregnancy. Further studies are being conducted to find safer compounds with useful qualities. Another more potent analog, pomalidomide, is now FDA approved.[92] Additionally, apremilast was approved by the FDA in March 2014. These thalidomide analogs can be used to treat different diseases, or used in a regimen to fight two conditions.[93]

text: Interest turned to pomalidomide, a derivative of thalidomide marketed by Celgene. It is a very active anti-angiogenic agent [90] and also acts as an immunomodulator. Pomalidomide was approved in February 2013 by the U.S. Food and Drug Administration (FDA) as a treatment for relapsed and refractory multiple myeloma.[94] It received a similar approval from the European Commission in August 2013, and is expected to be marketed in Europe under the brand name Imnovid.[95]

text: Clinical research[edit]

text: There is no conclusive evidence that thalidomide or lenalidomide is useful to bring about or maintain remission in Crohn's disease.[96][97]

text: Thalidomide was studied in a Phase II trial for Kaposi's sarcoma, a rare soft tissue cancer most commonly seen in the immunocompromised, that is caused by the Kaposi's sarcoma-associated herpesvirus (KSHV).[98][99]

text:
AIDS wasting syndrome,[100] associated diarrhoea[101]
Renal cell carcinoma (RCC)[99][102]
Glioblastoma multiforme[99]
Prostate cancer[99]
Melanoma[99]
Colorectal cancer[99]
Crohn's disease[99]
Rheumatoid arthritis[99]
Behcet's syndrome[103]
Breast cancer[99]
Head and neck cancer[99]
Ovarian cancer[99]
Chronic heart failure[99]
Graft-versus-host disease[99]
Tuberculous meningitis[104]