Hi I’m Wendy Zukerman, and you’re listening to Science Vs from Gimlet. This is the show that pits facts against fertilization. On today’s show: the fertility cliff ...  whether you want a kid right now… or you’re thinking… maybe… some day… you might have wondered ... is it a problem if you wait too long? How much harder does it really get to make a baby if you leave it until you’re a little older?

And this worry is especially personal for one of our producers on Science Vs-- Meryl Horn and her husband Chris. They’re in their mid 30s… and they’ve been busy focusing on their careers…. But recently they decided they’d start trying to have kids...  I talked to them about it at their Brooklyn apartment…

Hello! Hi Hello Bark Bark

Woof woof!

Once their dog, Penny, settled down ... We got to chatting about Meryl and Chris’ origin story. Turns out they first met on a dating site about five years ago… Chris was immediately taken.

CS Yeah I had actually just seen her profile and thought she looked amazing. And you know she had this like nice black and white picture of her playing her guitar. I was like oh she seems great  And then a couple of days later she messaged me.  

One message led to another, and the two started dating. And the topic of kids popped up quite early on.

 

MH I mentioned it super casually and it was like the third date or something and then I felt really awkward about it. Do you remember that.

CS I sort of remember that we had like an awkwardly early kids conversation.

MH I was like what did I say. It was like “Oh when we have kids. Something something something.”

WZ Oh you went for that. When we have kids.  

MH I think I did, I don't know why I would have said that early.

WZ I'm so embarrassed for you

hahaha

MH But I meant it in the royal ‘we’ somehow like in my head.  It wasn't going to be about us. It was just in general. And then Chris just made a joke of it and it was like ‘Oh honey what will we call them’ so that diffused the tension.

Dropping the “kid” bomb on the 3rd date didn’t throw Chris off because he always knew he'd want kids someday. And so after dating for a few years Meryl and Chris got married - and they started trying to have a baby pretty much straight away… . And Meryl figured this would be easy!

MH at that time I was like we could get pregnant immediately and that felt super scary and

 I was already kind of worried about what it would mean for my career because I was switching jobs, I was switching careers and was like applying for science versus actually.

Science Vs- that’s us! So yeah- we ended up hiring Meryl…  Months went by… and she still wasn’t pregnant. At first it was a bit of a relief - after all she’d just started this new job with us… but then…at one point… she was like, wait a sec. Do we have a problem?

MH so I think I like it took a while for it to really sink in that like oh but now it's been a long time. I think we might be one of those couples that's infertile. Like it made me feel kind of like I was like defective or something.

After about a year… Meryl and Chris went to the doctor… and have started to get checked out. And so far, there’s nothing obviously wrong with either of them… So why weren’t they pregnant yet?  

One thing that crossed Meryl's mind at this point was this idea of the fertility cliff... That once women hit their 30s it gets really hard to have a baby...Could this be what’s going on for Meryl and Chris? She’s 34 ... [1]

MH I was a little confused about it actually. Cos I had it in my consciousness somewhere like biological clock is ticking but then I had also heard that ‘oh no like you don't actually need to worry about that’ ... That's just this kind of old sexist idea. That women have to be worried about having kids, when really you can relax.

WZ Yeah that is what I had heard as well

MH Also my mum had me when she was 40! So I guess that’s on my mind too! That maybe it will be fine for me.

Even gynecologists can’t seem to agree about when a woman’s fertility starts to drop. Surveys of gynnies find that a few say it happens in your 20s, while some go for the 30s or even 40s[2] [3] And then, of course, there’s the other half of the equation: the dude. Maybe the problem is Chris? He’s 36… could that be the issue? We keep hearing stories of older men having kids - like… according to the gossip mags -  guys like Steve Martin and Jeff Goldblum had babies well into their 60s[4]....  I guess life found a way for them… but what about the average Joe or Chris...?  We wondered… can men really have babies forever…

Today, we’re going to get to the bottom of the following questions.

  1. Is the fertility cliff real for women? And, if it is,  is there anything you can do about it?
  2. What about men - is it harder for them to make babies as they get older?

When it comes to fertility, there’s lots of

Oh honey what will we call them

But then there’s science.

AHHH

And by the way- some of what we’ll be looking at in today’s episode focuses on cis, straight couples, but a lot of the research is relevant if you’re in the LGBT community as well.

Science Vs the Fertility Cliff is coming up after the break.

BREAK

Welcome back. Today, we’re looking at the fertility cliff… More and more people in the US are waiting until their 30s to have kids...[5][6] We want our careers in order, good partner in check!… and literally a decade of partying before we have to deal with babies crying and crapping all day. But by waiting are we actually jeopardizing our shot at having a biological kid? Let’s start with the potential issues of waiting… for people with ovaries.

This idea that women in their 30s struggle to get pregnant has been in the scientific literature for decades ...[7]… and was being taught in universities as scientific fact … which is where Lauren Wise first remembers seeing it…

LS there was a cliff happening at around age 30.

WZ 30! And was it pretty cliffy?

LW  It was pretty cliffy. [8] it was like a straight line from you know age 18 to 30 and then this amazing drop almost looks like a ski hill type drop. but yeah it looked like a pretty big cliff.

WZ Oh man I can just imagine you guys learning about that in school, I mean it’s making my heart drop in to my stomach

LW: yes

Lauren is now[9] a professor of epidemiology at Boston University. And she told us that a few years ago[10]. one academic ….. started questioning the science behind the fertility cliff..

LW the criticism that was raised was that this cliff, the idea of the cliff, is based on really poor data.

It turned out that some of the first studies describing the fertility cliff were using data from the 1600s![11][12][13]  While other studies were finding the cliff after looking at Amish couples…  who had pumped out kiddos when they were younger... and the researchers were now tracking to see if they had less bubs in their 30s[14] 

But, for decades, what was missing in the research were modern couples like Meryl and Chris … who had never tried to have a baby until they were older…  [15] [16] 

LW So for the women who want to know can I wait until I’m in my thirties? There were no data

WZ no data

LW no data.  

WZ Wow

 

These criticisms of the fertility cliff started to get a lot of media attention. And in the last few years we’ve seen more and more think pieces were coming out saying this whole cliff thing is bunk[17] [18] [19] [20]. 

You know, if you don’t have fertility issues, can have a baby later than you think- age doesn’t affect fertility until your 40s.

So, what is going on? Is the fertility cliff real? Or not?

Luckily Lauren and her team have dug into this. They recruited around 3000 couples who were trying to get pregnant… [21][22] and tracked them to see who was the most likely to have a bun in the oven after a year. So what did she find? 

LW you still see evidence of a rapid decline in the chances of pregnancy after around age 33.

WZ So that cliff was still right

LW the cliff was still there

WZ was it as cliffy?

LW I would say it was as cliffy as what the previous data showed but at a slightly later age 

Back in school, Lauren had seen that women’s fertility starts dropping at 30…. While her new research found the cliff really started at around 33. And that matched what she personally had gone through

LW  so it wasn’t surprising to me because I was living that experience.  I had trouble trying to conceive my own child conceiving my child at age 32, was feeling that age was already catching up to me, and maybe it was having an impact on my own fertility

Meanwhile, another study came out showing the same thing:[23] the fertility cliff is real. And it starts at around 33.[24] 

So for Meryl… who is 34… how dire is this? Once  you hit your mid 30s… do you fall off the edge of the cliff, like that chick reaching for the cup of christ in Indiana Jones?  [25] Well, not exactly. It just gets harder, on average, for women to get pregnant.  For example: let’s take a group of women trying to have a baby in their mid 30’s - 34 to 36 - how many get knocked up after a year?

 

Over a 12 month period, it’s about 75%[26]

WZ 75% - it’s not too bad

LW It’s not it’s not terrible.

So within a year, 3 out of 4 women in their mid 30s will be pregnant… The problem is that after your mid 30s with each passing year… your chances of getting pregnant get lower and lower… So when you’re 40 -- around half of women will get pregnant after a year[27]…  So that’s where some of the confusion about whether the cliff exists might be coming from… it’s not like no women get pregnant after their mid 30s, but on average, it does get harder… So rather than a cliff, it really is more like a Fertility-ski-slope.

Meryl, our producer who’s struggling with this right now, was here all through this conversation with Lauren … and knowing about the ski slope kind of changed how she felt about her own situation …

MH If it could just be sort of normal aging it kind of makes me feel a little bit better on the one hand, it’s nothing it’s not like I’m defective, it’s part of the natural process, but then it’s hard to know how worried i should be

LW: It’s hard to tell, I mean I think it’s a normal process and it makes sense that women in their 30s are going to start having problems conceiving, and so yes I can see how that’s somewhat reassuring. I know it’s hard to hear when you’re in the middle of it, but I wish you the best of luck

So now that we know that this Fertility-ski slope exists .. we wanted to know what’s causing it. Like, what is going on in our bodies to make it so much harder to get a kit in the caboodle?   

To find out we spoke to a bona fide egg-spert…

MS So my name is Mary Sabatini, I’m a reproductive endocrinologist and infertility expert and I work at the Massachusetts General Hospital.[28] 

Mary told us that there’s this idea out there… that women have a harder time getting preggers in their 30s because they start to run out of eggs… But she says, that’s actually not what’s going on.

MS  So this is this is  one of my I think the biggest misconception that's out there

It is true that women are born with lots of eggs - millions-[29]  and the number goes down and down  but by the time you’re in your 30s, you still have around 50,000 [30] [31] [32]. And you know what they say, you only need one egg, to make a small omelette.  

… Ok so, there is a test that tells you whether your egg supply is running low - it looks at your so called: ovarian reserve[33], but a recent study found that this doesn’t do a good job of predicting who will get pregnant naturally[34] [35][36]

MS So there are great studies that show women with great ovarian reserve who can’t get pregnant, there are people with terrible reserve who get pregnant easily.

So it doesn’t look like the number of eggs is problem here… So Meryl wanted to know ... if that’s not the problem, what is?

MH So what's going? on what's happening? Why are my eggs less likely to end up turning into a baby.

MS So, It's the quality the egg that changes.

Yeah. The eggs themselves are getting worse over time...

MS It's much like buying eggs and putting in your refrigerator. You can't just leave them there forever.

And the best evidence we have that aging eggs that are the problem here is because of research done on people who’ve had IVF. This is a process where you take a sperm and an egg, combine it in a petri dish and then pop the embryo into a uterus.

And through the magic of science and capitalism - you can now do with all kinds of combinations … so you can mix and match …using a donor sperm, or donor egg, or donor uterus, like with a surrogate…[37] And because of this, scientists have now figured out a lot of what really matters for baby making… 

MS One of the things that IVF has taught is that the age of the uterus is irrelevant.

That is, If you use a younger woman’s egg … in combo with an older uterus… it has a high chance of eventually working. [38] [39] [40]

WZ so we really know it’s the eggs, they’re the ones getting older in this process

MS unfortunately yes, that’s what’s hard about reproduction and women in today’s world, it really is about time.

And what’s happening in that time is that it gets trickier for your eggs to do this critical thing. So… to make a baby…. Your egg has to chuck out some of its DNA … so it can make room for the DNA in the sperm. And that process can go wrong, especially as we get older.

So you start to see more mistakes in the DNA. And those can lead to issues like miscarriages, Down Syndrome, and other genetic conditions [41] [42] [43] [44] [45] [46] [47] [48] [49] 

Okay - so if you’re on the edge of the Fertility ski slope... and you’re not ready to have kids… this can sound pretty scary…is there anything we can do about it? Well one idea that’s been getting a lot of attention recently… is that to stop the biological clock… women should be freezing their eggs. It’s been in the news a bit that some tech companies - like Google - now covering the cost of this for their employees.[50] and lots of fertility start-ups are popping up offering to put your eggs on ice.[51] [52]

<<Freezing your eggs is empowering choice because you truly are taking control of your life... We truly can have it all>>[53] 

Egg freezing is becoming more and more popular,[54] But,  when we asked Mary about it, she talked a little less about empowerment and a little more about the unpleasant realities of egg freezing. She ran us through the steps.

<<It takes about two weeks from start to finish of taking daily injections.  …  light anesthesia, transvaginal ultrasound Needle pokes through vaginal wall into the ovaries. Light suction used for egg extraction.>>[55]

And sometimes you’ll need to go through this more than once because you won’t get enough eggs in one round...[56] on top of all that... it’s really expensive, if you’re insurance doesn’t cover it - it can cost tens of thousands of dollars[57]So, egg freezing is a helluva process...   But, after all that… does it actually work? I asked Mary, if this can really keep your eggs young and fresh.

WZ is that a way to increase their shelf life?

MS 10 years ago, I probably would have said no, but I think the technologies for freezing eggs have become so good that I do think it's a viable opportunity for women

We’re in the early days of this egg freezing frontier…[58] But a couple[59][60] studies have estimated that a woman in her mid 30s who does all this…has about a 70%[61]  chance of eventually walking away with a baby! So it’s not bad… The thing is, if you wait too long before you freeze your eggs… the success rate drops pretty quickly. [62] [63] 

Conclusion: Women do have a fertility cliff,  well it’s more of a fertility ski slope… and it’s because their eggs age over time and the DNA can get messed up. If you can afford it, it’s not a bad idea to think about freezing those eggs, though it’s kind of an ordeal. 

And by the way… one thing Meryl had heard a lot is that if you really want to boost your fertility, it's best to cut out all alcohol, and caffeine from your life...But we looked into this, there’s no need to go cold turkey. Studies found you can swig one glass of booze and up to 4 cups of coffee a day[64][65][66][67][68]… and it won’t affect your fertility… so it’s not all bad news.

Ok that’s the story with the eggs… After the break… sperm. There’s been fears in the news recently that we’re in the midst of a sperm-pocalypse… with sperm counts plummeting across the United States…  is this true? And we go back to our couple…  to find out ... are Chris’ swimmers OK?

<<Low motility- I don’t know what you do about that.

Motivational talks?

C’mon get it together boys! >> 

That’s coming up after the break.

BREAK

Welcome back. We’ve just learned that - for women - the fertility cliff is pretty much real. At around the mid 30s it starts getting harder and harder for a woman to get pregnant. Now we’re  talking about the other side of this: people with testicles. Cause even though the focus of getting knocked up has historically been on the women…  when you look at everyone, regardless of age… for half of all infertile couples, it’s the men who have the problem.[69] And funnily enough, early on -- our producer Meryl Horn and her husband Chris actually had the same idea about who was the source of their troubles…

 

MH This is gonna sound mean but I always just kind of felt like my body is good because I've been able to track my ovulation and it looks so good, Yeah I think part of me does it assumes it's Chris.

CS No. I mean I think I've generally assumed that if something was wrong with one of us it was probably me.  

 WZ Really?

CS Yeah, yeah

Chris went to the doc for some initial testing, and they didn’t find any obvious problems with his plumbing.

<<MH your testicles look good!>>>

So that brought us to a broader question … could Chris have just fallen off his own fertility cliff? Do men even have one?

For this, we had to talk to Allan Pacey. He’s a professor of andrology at the University of Sheffield and has been studying all kinds of sperm for decades… .[70] 

AP So my P H D was on a little worm that lived in the sand

WZ so like the sperm of a sperm really

AP: So the sperm of a worm. It was really stressful but interesting… So this is a worm that only breeds once a year OK. And not only that all of the males ejaculate in the same half hour. [71] 

WZ Oh my Gosh.

It seems to be synchronised with the moon or the tides or something.

After a surprisingly long chat about worm sperm

and see the white patches appear

 we got onto the topic of the male fertility cliff ... and Allan says that a lot of people have this assumption that men that can go on having babies until they’re decrepit.

AP and you get that impression from rock stars Mick Jagger[72] people like Charlie Chaplin who was 72 when he had his 11th child to his fourth wife[73].

Right… but are these men anomalies.. For the average guy out there… do they have to worry about a fertility cliff?

AP I wouldn't say that men, men older men face a reproductive cliff edge. They kind of have a like a rolling slope. Things happen slowly. 

MH So if you compared it to like the female fertility cliff is it as scary?

AP No I don't think it is. I don’t think it’s as steep in a man as it is in a woman. 

Yeah, so there’s not a cliff, per se, it’s more like a fertility grassy knoll… several studies suggest that as a guy gets older it takes more time to get a woman pregnant. But when it comes to  exactly how much more time… well, the studies are all over the map[74] [75] [76][77]…  It’s also not clear when men start rolling down their fertility grass knoll …but Allan puts it at roughly around 40. And why is that? 

AP So men by the age of 40 have been making sperm for gosh 25 years or more. Um, the engine is getting a little bit tired at that point.

That tired engine starts to affect spermand it means that men don’t make as many good swimmers as they used to.[78] [79][80] 

 So does this mean for Meryl and Chris? He’s 36… Has he been affected by the fertility grassy knoll?? Allen told us there was a home test you could do.  

AP Sitting on my kitchen table at home is a device that you can clip to an iPhone and a little chamber where you can put a drop of your sperm and it will use the iPhone to make the measurement for you.

 Sounds super dinky, but it’s actually FDA approved …  to basically tell you if your swimmers can swim.[81] [82] 

I think that's fantastic.  

So Meryl and Chris decided… why not give it a go themselves?

MH Should we get this thing started?

CS Yep

<< opening package..

CS Turn your phone into a sperm testing device. 

To start… Chris mixes some of his semen with a special little powder that turns the semen pink…[83]  but it can be a little tricky to use…

<<MH oh I think you put the wrong end in the bottle 

CS did I? I tried to ask you but I needed a scientist.

MH Ohh Chris put the wrong end of the pipette into the bottle.

CS So now I’ll have sperm juice on my hand. >>

They put the sperm juice onto a plastic slide… which slots into a device so that your camera acts like a tiny microscope.

<<CS And like what else can you put in this thing? Oh we should go to park later and collect pond water and look at little paramecium!>>

What a nerd. No wonder we hired Meryl. The results pop up, telling you how many swimmers you’ve got and whether it’s low, or normal.[84] And while the whole thing started a little jokey… it started to hit home… that this could explain why Meryl and Chris were having trouble…and they both got a little anxious.  

<<MH LIke I just got a flutter in my chest. Um, yeah hope it’s good.

CS We’ll see. >>.

One minute and 5 seconds. Whoa it’s so precise. One minute 5 seconds. 

MH  High range of normal

CS I passed. 

MH Wow!

CS My boys can swim!

Later they got this checked by a real doctor too .. and those results matched up with this dinky DIY kit.

MH Yeah are you happy now?

CS I guess, I don’t know, why aren’t we pregnant then?

 So Chris's sperm doesn't seem to be the reason that Meryl isn’t pregnant, And, at 36, Chris probably isn’t rolling down his fertility grassy knoll…  

But zooming out here… the research is showing that it’s not just about whether your boys can swim. There’s another concern.  As men get older, you start to see an uptick in certain medical conditions in their kids.[85] Here’s Allan

AP You see more disorders like achondroplasia which is when someone has short stature, you see mutations related to autism.[86] [87] [88] [89] [90] So the risks are actually quite small but they're statistically significant.

So for example, one big study found, if a chap is in his 30s, the risk his child will have autism is 1.2%. That risk goes up to about 1.4% if he's in his 40s, and it keeps creeping up.[91] [92] [93] And to understand WHY we think older dads are more likely to have kids with various conditions we have to tell you about your granddad’s jizz kinda.

OK, here we go. So testicles ...will pump out fresh sperm throughout a man’s life.[94] That means even 90 year olds are making new sperm every day. And by now - their gear is getting clumsy. And starts making mistakes. Genetic mistakes. [95] [96] [97] [98] [99]

AP So many different genetic errors would be evident in the sperm of a 40 year old in comparison to a 20-25 year old.

Scientists actually mapped the genome of different aged father’s … And their kids…  And they could SEE that as men get older, their children had more genetic mutations[100] [101] [102] Allan had an analogy for what seems to be going on here... he’s like, think of the sperm-making machinery as a kind of mould, like for a waffle iron.  Year after year you use that same waffle iron to make sperm. Over time, it might get a little damaged.

AP But if somebody scratches the inside of the mould

WZ in this case is that the testicles in that. Yeah that's that's what I RIght

AP and then forevermore the thing you're making will be defective.

It’s that defective sperm making machinery that passes little genetic mistakes onto kids… noow a lot of the time it’s not a big deal, but it does up the chances of kids having some genetic conditions.

Conclusion: Men’s fertility goes down a little as they age - but it’s not like a cliff… it’s more of a gentle slope…

But our final question is this…  could there be another threat lurking around the corner for male fertility? Because some studies are reporting that men's sperm counts have been dropping dramatically  And that we could be heading into a fertility crisis soon…

A health alert tonight regarding sperm counts. A new study showing they’re plummeting

So Sperm count in men in declined by 50-60%

If this continues, we’re doomed.>>

These scary reports are based on real science. A big review came out a couple years ago, which seemed to show that since the 1970s sperm counts in North America, Europe, Australia and New Zealand had dropped [103] on average, by more than 50%. And while we’re not at the point where it’s affecting fertility now, some are saying if things keep going this same way - this will cause a massive fertility crisis in a few decades.[104] [105] [106] [107] 

Currently it’s not clear what might be causing the sperm-pocalypse… but one clue is that the drop didn’t seem to be happening everywhere. This study didn’t find it in South America, Africa or Asia…  Which is making some think that something about our Western lives is killing the sperm. Here’s Allan

AP People always gravitate to kind of Western habits be it pesticides be processed food or what have you. But really we don't know.

But before we prepare ourselves to live in a Handmaid's Tale[108]… Allan says there is actually a huge debate going on amongst sperm counting boffins [109] [110] [111]  [112] [113] as to whether the spermageddon is happening at all. ... And a big reason for this is because of the difficulties of counting sperm… While you can roughly tell if you’ve got enough swimmers on an iPhone like Meryl and Chris did… you need to be a lot more precise to do these kinds of studies… which is tough because sperm are tiny and they… wiggles and jiggles inside a sticky, gooey liquid[114] [115].  Allan explained it like this …

AP But you know semen is a is a viscous substance even picking it up in a in a defined way. You know I want to measure a hundred micro liters of semen and I want to see how many sperm is in that you can't even pick it up in a good way because it's really viscous. It's like the cheese on the top of pizza it will keep on going.[116]

WZ thanks for that image, by the way

AP wonderful. So when you’re trying to count, that’s just one potential source of error 

There are so many tricky things with counting sperm… and such a lack of consistency from lab to lab; country to country,[117] in fact…  the World Health Organization publishes[118] a guide to examining human semen. The latest edition was 271 pages long. 

So for now… Allan and others that we spoke to say this really could be a huge counting error… [119] [120][121]

AP I'm skeptical on the fact that the sperm counts are declining on the basis of the data that I've seen.

WZ so when will we know if sperm counts really are dropping?  

AP: Well one answer to that is if they are dropping we might know when we finally get infertility and men don't have any sperm left. But that's probably too late.  

Allan is kind of joking here… but also kind of not. Because if it is true - and sperm counts do keep dropping …  to the point where they start affecting fertility…. this  really could open up a whole can of sperms for humanity… particularly… if you couple this with the fact that lots of people are having babies later and later …

AP Is this age at which couples are wanting to have their children going to carry on increasing? And if it does, the two together are a perfect storm.

Conclusion: There’s some scary research suggesting that sperm counts are dropping…. But scientists are still fighting over this. So it doesn't look like it's time to panic yet.  Just try to enjoy your next slice of cheesy pizza.

So when it comes to the fertility cliff, does it stack up?

  1.  Is the fertility cliff real for women? Yes, kind of. It’s more like a ski slope. While many women get pregnant later in life, on average, fertility does start to drop off in their mid 30s and just keeps falling.  The reason this happens is that our eggs start to get older… which can mess up their DNA … and that can cause genetic conditions in the bub. 
  2. What about men - are their swimmers healthy forever? No. While men don’t have a fertility cliff --  they do have to worry about genetic mutations in their sperm, which can increase their baby’s risk of some medical conditions.  

Last beat: MERYL AND CHRIS TAKE A PREGNANCY TEST

As for Meryl and Chris? Well… Meryl’s only 34… she’s on the fertility slope, but she’s not skiing down a black diamond run just yet … and Chris’ swimmers, as best as we can tell, look good… So that shouldn’t really explain what’s going on. With that out of the way, they figured- let’s keep trying to have a baby and maybe it will happen. On a recent evening, in their Brooklyn apartment, Meryl took another pregnancy test.

MH Feels like maybe it will actually be positive this time. Because now we know there’s nothing wrong so there’s no reason it shouldn’t be positive.  

CS Right,

MH Alright, do you want to look at it? Yeah. Alright we’re going to go look at the test.

So, Chris has his phone out and is I guess recording a video. Why are you recording this video?

I don’t know just in case

It’s going to be sad when we turn it over and it’s negative.

CS we dont have to do anything with the video...

No it’s okay lets just do it.

click

MH It’s only one line, which means it’s negative.

MH It’s just one pink line.  Well. I’m kind of sad. 

MH Sigh

I dunno I just don’t know what else I could be doing.

CS It’s not your fault.

MH So it’s your fault

CS It’s nobody’s fault.

MH Just hasn’t happened yet. Yeah…  It’s not all happy endings.

CS It might be a happy ending, it’s just an unhappy middle.

MH Yeah

Right now we don’t know why Meryl and Chris are having trouble making a baby -- and whether this would have been easier, if they had started trying years ago. And that’s the thing about stats like the fertility - ski slope…  you can’t know ahead of time whether it’s actually going to be a problem for you… And while that may be scary and anxiety provoking...  Meryl and Chris feel better about all of it now that they’re armed with a tonne of facts. They decided to start treatment next month. They’re feeling pretty good about it.

That’s Science Vs The Fertility cliff.

<<CITATIONS>>

And by the way… Gimlet has just released a new show you should check out … it’s hosted by reproductive psychiatrist Alexandra Sacks… and each episode is kinda like therapy for women struggling with all kinds of issues… It’s called Motherhood Sessions.  In one of their episodes, Alexandra talks to Toni...about facing the fertility cliff as a single woman.

MOTHERHOOD SESSIONS PROMO

That’s Motherhood Sessions… find it on Spotify or wherever you listen to podcasts.

We’re taking a week to work on more stories… and then we’ll be back with the Placebo effect… does your mind have the power to heal you?

CREDITS

This episode was produced by Meryl Horn, with help from me, Wendy Zukerman, as well as Rose Rimler and Michelle Dang. Our senior producer is Kaitlyn Sawrey. We’re edited by Blythe Terrell. Fact checking by Diane Kelley. Editing help from Caitlin Kenney. Mix and sound design by Peter Leonard. Music by Peter Leonard, Emma Munger and Bobby Lord. Recording assistance from Mary Dooe and Andy Short. A huge thanks to all the scientists we got in touch with for this episode, including Dr. Richard Lea, Dr. Hagai Levine, Professor Jens Peter Ellekilde Bond, and others. And special thanks to everyone at Gimet who listened to the episode, the Zukerman family, and Joseph Lavelle Wilson.  And a huge thanks to Chris Suter, we couldn’t have done this without you.


[1] E.g. Janet Jackson https://www.elitedaily.com/entertainment/janet-jackson-baby-at-50-asked-expert/1741825 (Jackson born 5-16-1966: https://www.britannica.com/biography/Janet-Jackson; birth announced 1-3-2017: https://www.bbc.com/news/world-us-canada-38503168)

[2] https://sci-hub.tw/10.1093/humrep/dev308 

[3] http://sci-hub.tw/10.1007/s10815-018-1273-7 another survey, of American College of Obstetricians and Gynecologists fellows, asked “A significant decline in fertility occurs during which age range?” most said early or late 30s

[4] https://people.com/parents/jeff-goldblum-older-dad-kids-waited-math/; https://www.biography.com/actor/jeff-goldblum; (Alec Baldwin squeaks in - his youngest was born 1 month after his 60th birthday) https://www.biography.com/actor/alec-baldwin; https://www.biography.com/actor/steve-martin

[5] https://www.cdc.gov/nchs/data/nvsr/nvsr51/nvsr51_01.pdf Table 1: Mean age of 1st birth: 21.4, in 1970 https://www.cdc.gov/nchs/data/databriefs/db232.pdf “The mean age of first-time mothers increased 1.4 years, from 24.9 in 2000 to 26.3 in 2014” 26.3-21.4 = 4.9

Latest data (for 2017): https://www.cdc.gov/nchs/data/nvsr/nvsr67/nvsr67_08-508.pdf: “In 2017, the mean age of mothers at first birth was 26.8 years, an increase from 26.6 in 2016, and another record high for the country”

[6] https://academic.oup.com/humrep/article/32/10/2110/4096427 Mean paternal age has increased over the past 44 years from 27.4 to 30.9 years… Indeed, births to fathers over 40, a definition many researchers suggest constitutes an ‘older father’ has more than doubled over the past 4 decades and now comprises nearly 9% of all births in the USA; also see CDC data from 2015: https://www.cdc.gov/nchs/data/nvsr/nvsr66/nvsr66_01.pdf  “(birth) Rates for men aged 15–19 (10.4), 20–24 (51.6), and 25–29 (87.4) were once more at record lows in 2015, whereas the rates for men aged 35–39 (69.1), 40–44 (28.6), and 45–49 (9.6) were the highest in more than 40 years (17).”

[7] "it was popping up in the scientific literature by the '70s". There seem to be mentions of declines in human fecundity with age in demographic/population control papers from the 1960s, though those aren't focused on the health/medical aspects of the event. Sample source: https://www.tandfonline.com/doi/abs/10.1080/19485565.1961.9987465?journalCode=hsbi18

[8] http://sci-hub.tw/10.1210/er.2009-0006 figure 2 (Data from 2 Dutch fertility clinics 1973-mid 1980s)

[9] https://www.bu.edu/sph/profile/lauren-wise/; also verified with fact emails 

[10] https://www.theatlantic.com/magazine/archive/2013/07/how-long-can-you-wait-to-have-a-baby/309374/ : Jean Twenge, psychology professor; 3 kids after age 35

[11] https://www.theatlantic.com/magazine/archive/2013/07/how-long-can-you-wait-to-have-a-baby/309374/ Rarely mentioned is the source of the data: French birth records from 1670 to 1830.

[12] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4389129/pdf/deu056.pdf see “results” - breakdown of many populations living in the 1600s

[13] https://sci-hub.tw/10.1126/science.3755843 All data predates 1950, with the earliest: Geneva bourgeoisie, husbands born before 1600, and born 1600-49 in fig 1

[14] http://sci-hub.tw/10.1080/03014460110075684 the fertility patterns and consequent population growth rates of the Old Order Amish have long been studied by demo- graphers, particularly those with an interest in natural fertility (Espinshade 1971, Markle and Pasco 1977, Ericksen, Ericksen, Hostetler et al. 1979, Henry 1980, Wood, Holman, Yashin et al. 1994, Wasao and Donnermeyer 1996, Hewner 1997).

[15] From Lauren’s paper http://sci-hub.tw/10.1016/j.fertnstert.2013.02.040 “No study has examined the age-related decline in fecundability in a population-based prospective cohort study of women trying to conceive, while controlling for volitional factors.”

[16] https://sci-hub.tw/10.1097/01.AOG.0000100153.24061.45 This study looks at couples at European family planning centers, not the Amish group, and controls for frequency of intercourse. However, it didn’t collect data from couples who waiting until later in life to try to conceive “No data were collected on the couple’s desire to conceive”

[17] https://slate.com/human-interest/2013/06/fertility-after-35-everything-you-thought-you-knew-was-wrong-says-new-atlantic-article.html Everything You Thought You Knew About Age and Fertility Was Wrong...A jaw-dropping new article by Jean Twenge in the Atlantic shows that a lot of what we’ve been told about the fertility plunge that happens to women in their 30s has been highly oversold.

[18] https://www.dailymail.co.uk/femail/article-2377056/A-controversial-new-book-claims-getting-pregnant-35-far-easier-doctors-say.html Is everything we thought we knew about older women and fertility WRONG? A controversial new book claims getting pregnant after 35 is far easier than doctors say

[19] https://www.washingtonpost.com/posteverything/wp/2014/07/22/no-womens-fertility-doesnt-drop-off-a-cliff-at-35/?utm_term=.92084a2c2cd1 No, women's fertility doesn't 'drop off a cliff' at 35

[20] https://www.newstatesman.com/lifestyle/2015/06/whats-wrong-older-mothers-nothing-time-dispel-fertility-cliff-myth What's wrong with older mothers? Nothing. Time to dispel the "fertility cliff" myth

[21] http://sci-hub.tw/10.1016/j.fertnstert.2013.02.040 Danish study

[22] https://sci-hub.tw/10.1016/j.ajog.2017.09.002 NORTH AMERICAN STUDY

[23] http://sci-hub.tw/10.1016/j.fertnstert.2016.02.028 see table 2

[24]  https://sci-hub.tw/10.1016/j.ajog.2017.09.002 ; This also is backed up by older studies done on women with IUI and IVF http://sci-hub.tw/10.1056/NEJM198202183060706 data from IUI also shows slight decline after 30, followed by steeper decline after 35

[25] https://www.rogerebert.com/reviews/indiana-jones-and-the-last-crusade-1989; search youtube indiana jones elsa death for scene

[26] https://sci-hub.tw/10.1016/j.ajog.2017.09.002 table 2

[27]  Compared with women 21e24 ½F1 years old, FRs for women aged 25e27, 28e30, 31e33, 34e36, 37e39, and 40e45 years were 1.06 (95% CI, 0.88e1.28), 1.08 (95% CI, 0.91e1.29), 1.06 (95% CI, 0.88e1.26), 1.02 (95% CI, 0.83e1.25), 0.75 (95% CI, 0.58e0.98), and 0.48 (95% CI, 0.27e0.85),

[28] https://www.massgeneral.org/doctors/doctor.aspx?id=18315 

[29] Jones and Lopez 2014 Human Reproductive Biology p 27 (verifies millions of eggs in ovaries at birth)

[30] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3276943/ figure 2

[31] http://sci-hub.tw/10.1016/j.ijrobp.2004.11.038 see figure 1, at age 30, less than 10^5 remaining oocytes. Also mention “around age 37 years when approximately 25,000 primordial oocytes remain,”; by the same authors: https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0008772 “We estimate that for 95% of women by the age of 30 years only 12% of their maximum pre-birth NGF population is present and by the age of 40 years only 3% remains. “ Fig 1 in shows that though the Wallace-Kelsey model's average is comfortably less than 100,000 when women are in their 30s, their upper limits shows some individuals had numbers like 500,000. So atypical, but possible for some people.

[32] http://sci-hub.tw/10.1159/000140595 diagram 1 on page 115,

[33] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3276943/ review of the role of measuring ovarian reserve in achieving pregnancy following any treatment in subfertile women (not spontaneous conception)

[34] https://jamanetwork.com/journals/jama/article-abstract/2656811 Among women attempting to conceive naturally, diminished ovarian reserve was not associated with infertility; women should be cautioned against using AMH levels to assess their current fertility… Three other publications examined AMH and fecundability in women attempting to conceive naturally and none reported significant associations.19-21

[35] Study 20 above is a secondary cohort analysis of a clinical trial  http://sci-hub.tw/10.1210/jc.2015-2474 “Lower and higher AMH values were not associated with fecundability in unassisted conceptions in a cohort of fecund women with a history of one or two prior losses. Our data do not support routine AMH testing for preconception counseling in young, fecund women”

[36] https://www.fertstert.org/article/S0015-0282(17)31938-6/fulltext “There was no association between live birth and ovarian reserve among pregnant IVF patients under the age of 35 years.”;

[37] https://www.bbc.com/news/uk-england-bristol-44940929

[38] https://www.sartcorsonline.com/rptCSR_PublicMultYear.aspx?reportingYear=2015#patient-cumulative stat for >42 “live birth” is 3.9% for “patient’s own eggs”- very low. For “donor eggs” for all ages (not separated by age) - 36.5% but this is just for 1 cycle. If you calculate the chances after 3 cycles based on this, (.63*.63*.63 = .25 chance of not having a baby, so chance of having a baby ~75% - MH calculations)

[39]  https://www.cdc.gov/art/ART2010/PDFs/ART_2010_Clinic_Report-Full.pdf also not separated by patient, apparently “Success rates shown in this report are presented in terms of cycles, as required by law, rather than in terms of patients.” older data- says chances of success after 1 donor egg cycle is either 55.8% or 34.9% depending on frozen or fresh (see table 21) Also see table for stats on over 40 year olds using their own eggs; 2016 cdc clinic report has similar statistics: pregnancies from 65% for fresh, 54.7% frozen donor eggs.

[40]https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(18)31766-5/fulltext; but also surrogate births

[41] https://ovarianresearch.biomedcentral.com/articles/10.1186/s13048-018-0438-4 there is also a qualitative decline primarily attributed to an increase in aneuploidy amongst aging oocytes. 

[42] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3313661/Most of the human autosomal trisomies result from a maternal meiotic error, which preferentially occurs during the first meiotic division .. A positive relationship was found between maternal age and the global rate of aneuploidy, in agreement with the findings of epidemiological studies… [see Fig. 1a–c]

[43] http://sci-hub.tw/10.1136/bmj.320.7251.1708 figure 1

[44] https://sci-hub.tw/10.1093/humrep/den135 figure 1, for IVF spontaneous abortions.

[45] https://www.aafp.org/afp/2000/0815/p825.html see figure 1: downs syndrome rates mirror cliff

[46] https://www.ndss.org/about-down-syndrome/down-syndrome/ 

[47] Still born:

https://www.ncbi.nlm.nih.gov/pubmed/30946794

Advanced maternal age women had higher rates of perinatal mortality and stillbirth.

https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0186287

AMA increased the risk of stillbirth (OR 1.75, 95%CI 1.62 to 1.89) with a population attributable risk of 4.7%.

[48] Autism:

https://www.nature.com/articles/mp201570

Advancing paternal and maternal age were each associated with increased RR of ASD after adjusting for confounding and the other parent's age

https://onlinelibrary.wiley.com/doi/abs/10.1111/acps.12666

ORs 1.41 (95% CI 1.29–1.55) and 1.55 (95% CI 1.39–1.73) for mother and father respectively

sci-hub.tw/10.1016/j.jaac.2012.02.018

The results of this meta-analysis support an association between advancing maternal age and risk of autism. The RR increased monotonically with increasing maternal age.

[49] Chromosome anomalies:

https://sci-hub.tw/10.1159/000086889"It was previously shown that more than half of the human oocytes obtained from IVF patients of advanced reproductive age are aneuploid, due to meiosis I and meiosis II errors. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6033961/

Maternal age is the main cause of embryonic aneuploidies (4, 13, 17). More than 90% of these imbalances are indeed of maternal origin caused by chromosomal missegregation during oogenesis

http://sci-hub.tw/10.1056/NEJMp048087 See table.

[50] https://www.wired.co.uk/article/work-smarter-productivity-perks; https://www.theguardian.com/technology/2014/oct/15/apple-facebook-offer-freeze-eggs-female-employees

[51] https://www.ovaeggfreezing.com/video/ “kaitlyn bristow”

[52] https://www.cbsnews.com/news/egg-freezing-growing-crop-of-companies-suggest-young-women-protect-themselves-against-infertility/ 

[53] https://www.ovaeggfreezing.com/video/ “kaitlyn bristow”

[54] https://www.cdc.gov/art/pdf/2015-report/ART-2015-National-Summary-Report.pdf figure 45; increased even more in 2016: https://www.cdc.gov/art/pdf/2016-report/ART-2016-National-Summary-Report.pdf

[55] https://www.mayoclinic.org/tests-procedures/egg-freezing/about/pac-20384556

[56] Number of eggs harvested per cycle varies a lot among individuals: https://link.springer.com/article/10.1007/s10815-008-9274-6

[57] https://www.fertilityiq.com/egg-freezing/the-costs-of-egg-freezing#treatment-and-medication ; Mary confirms costs

[58] http://sci-hub.tw/10.1016/j.fertnstert.2012.09.028 on one hand: “There are not yet sufficient data to recommend oocyte cryopreservation for the sole purpose of circumventing reproductive aging in healthy women” , on the other hand, they note the success rates seem to similar to IVF, which we do have a lot of data for “ These studies and a recent meta-analysis (5) suggest that fertilization and pregnancy rates are similar to IVF/ICSI with fresh oocytes when vitrified/warmed oocytes are used as part of IVF/ICSI.”

[59] http://sci-hub.tw/10.1016/j.fertnstert.2015.10.026 

[60] http://sci-hub.tw/10.1093/humrep/dex008 

[61] This is assuming they froze ~14 mature eggs, which is the mean number according to this http://sci-hub.tw/10.1093/humrep/dex008 (table 1), According to this paper (2015) it’s about 70% for 30-34 yo, or a little under 70% for 35-70 yo for 1 child, while according to this (2017) it’s more like 80% at 35 or younger, but then drops quickly [Note: possible that change in statistics reflects improvements in techniques for thawing eggs]

[62] http://sci-hub.tw/10.1016/j.fertnstert.2015.10.026 figure 1 “Vitrifying oocytes at an earlier age may benefit in terms of maximizing oocyte quality and minimizing the number of cycles necessary to accumulate the recommended number of oocytes, but the cryopreserved oocytes are less likely to be needed. On the other hand, cryopreserving at a later age requires that more oocytes of a lower quality be stored to achieve comparable pregnancy rates.”

[63] http://sci-hub.tw/10.1093/humrep/dex008 figure 1- less than 50% chance if 40 or older, and average number of mature eggs for a 40+ year old from 1 cycle is about 8-10

[64] http://sci-hub.tw/10.1016/j.fertnstert.2016.09.029

High levels of caffeine consumption (500 mg; >5 cups of coffee/day or its equivalent) have been associated with decreased fertility (OR 1.45; 95% CI, 1.03–2.04) Overall, moderate caffeine consumption (1 to 2 cups of coffee per day or its equivalent) before or during pregnancy has no apparent adverse effects on fertility or pregnancy outcomes. In men caffeine consumption has no effect on semen parameters (55).

[65] https://www.ncbi.nlm.nih.gov/pubmed/9054236

significantly increased odds ratio (OR) of 1.45 (95% confidence interval (CI) 1.03-2.04) for subfecundity in the first pregnancy was observed for women drinking more than 500 mg of caffeine per day … Women in the highest level of consumption had an increase in the time leading to the first pregnancy of 11% (hazard ratio = 0.90, 95% CI 0.78-1.03). … The authors conclude that high levels of caffeine intake may delay conception among fertile women.

[66] http://sci-hub.tw/10.1016/j.fertnstert.2016.09.029

Higher levels of alcohol consumption (>2 drinks/day, with 1 drink >10 g of ethanol) probably are best avoided when attempting pregnancy, but there is limited evidence to indicate that more moderate alcohol consumption adversely affects fertility

[67] http://sci-hub.tw/10.1016/j.ajog.2017.08.010 While concerns regarding adverse effects of maternal alcohol intake on fetal development are warranted, as are also concerns of increased risk of pregnancy loss with caffeine intake, whether intake of these substances have a deleterious effect on the ability to become pregnant is questionable.

[68] http://sci-hub.tw/10.1136/bmj.i4262. Alcohol: for women, doesn’t matter if it’s 2 or less drinks/day. 6120 female Danish residents. More than that, and it goes down to .82.

[69] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4691969/ “Male factor” infertility is seen as an alteration in sperm concentration and/or motility and/or morphology in at least one sample of two sperm analyzes, collected 1 and 4 weeks apart.[20] In humans, it accounts for 40-50% of infertility[21,22,23]”; Agreement from American Urological Association: https://www.auajournals.org/doi/abs/10.1016/j.juro.2012.08.239 “A male factor contributes to 50% of cases”

[70] https://www.sheffield.ac.uk/oncology-metabolism/staff/pacey 

[71] https://www.sheffield.ac.uk/oncology-metabolism/staff/pacey “I was awarded my PhD in 1991”- where he studied sperm in worms; early work on Arenicola marina (lugworms) https://www.tandfonline.com/doi/abs/10.1080/07924259.1989.9672045; and lugworms are synchronous spawners: https://www.marlin.ac.uk/species/detail/1402 

[72] https://ultimateclassicrock.com/mick-jagger-kids-children-photos/: most recent child Deveraux Octavian Basil Jagger was born in early December 2016”; Jagger born 7-26-43 so was 73 : https://www.history.com/this-day-in-history/entertainer-mick-jagger-born

[73] https://www.charliechaplin.com/en/articles/291-Chaplin-Children-and-Grandchildren?category=biography; child #11 = Christopher James Chaplin was born July 6, 1962; Charles Spencer Chaplin was born in London, England, on April 16th, 1889

[74] http://sci-hub.tw/10.1016/j.fertnstert.2013.02.040 found a drop- table 3

[75] https://sci-hub.tw/10.1016/j.ajog.2017.09.002 did not find a drop

[76] http://sci-hub.se/10.1093/humrep/15.8.1703 took longer for older men - FACT: but since the data is from a longitudinal study of couples, unclear whether older men are also paired with older women.

[77] https://www.fertstert.org/article/S0015-0282(12)02436-3/pdf  “Hassan et al. (12) also found that increasing male age was associated with an increased time to pregnancy in a cohort study of 2,112 consecutive pregnancies. Males >45 years were 4.6 times and 12.5 times more likely to have had a time to pregnancy of >1 year or >2 years respectively relative to men [less than or equal to ]25 years.Dunson et al. (13) reported similar findings in a study of 782 healthy couples in whom natural fertility was  significantly reduced for men over age 35 years. These authors controlled for both maternal age as well as sexual behavior (Table 1).” [Also see table 1 for good summary of IVF and IUI data- most studies show effects from age (especially those where they control for maternal age) but many do not.]

[78] http://sci-hub.tw/10.1016/j.arr.2014.10.007 Age-associated declines in semen volume, percentage motility, progressive motility, normal morphology and unfragmented cells were statistically significant and results generally seemed to be robust against confounding factors…. We conclude that paternal aging results in significant reduction in semen parameters values, which likely need to be given more recognition as potential contributors to the negative pregnancy outcomes and reduced offspring health associated with delayed reproduction

[79] http://sci-hub.tw/10.1002/pd.5402 The American College of Medical Genetics (ACMG) has defined APA [advanced paternal age] as 40 years or older at the time of conception.3 The American Society for Reproductive Medicine has established age 40 as the upper age limit for sperm donors.; In a cohort of 17 000 intrauterine insemination cycles, and also controlling for maternal age, partners of men older than 35 years had miscarriage rates of 32.4% compared with 13.7% in men younger than 35 years (P < 0.001).- n 2005, Thomas et al found that 72% of the de novo unbal- anced chromosomal rearrangements are of paternal origin.51 When dividing them by class and chromosome, 70% of terminal deletions, 84% of interstitial deletions, 58% of small duplications, and 62% of unbalanced translocations originated from the paternal side.51

[80] http://sci-hub.tw/10.1016/j.fertnstert.2018.03.016 table 3: percent motility, before and after 40 “A negative correlation was found between age and routine semen parameters: volume, sperm count, motility, vitality, total motile spermatozoa and normal-motile spermatozoa, round cell concentration, and hypo-osmotic swelling test values. Several CASA variables (straight-line velocity, curvilinear velocity, average path velocity, beat cross frequency, amplitude of lateral head displacement, and mean angular displacement) were also negatively affected. FACT: nice things about this study - large sample size, and standardized collection and anaysis

[81] https://www.accessdata.fda.gov/cdrh_docs/pdf16/K161493.pdf the company submitted the device to the FDA as a 510(K) Premarket Notification -- saying that it's not substantially different from other already-FDA-approved devices that are on the market. The FDA agreed on 11-2016: https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfIVD/Detail.cfm?ID=5872 ;

[82] From FDA media affairs: Thank you for checking. The FDA clears products for very specific indications for use, as in this case. It’s more accurate to note that it is a test for assessing the motility of sperm, which you could also refer to as the mobility of sperm. Specific indications: The YO™ Home Sperm Test is a smartphone based home test which provides a qualitative assessment of motile sperm concentration (MSC) in human semen. MSC is one aspect of a male semen examination. The YO™ Home Sperm Test does not provide a comprehensive evaluation of a male’s fertility status and is intended for over-the-counter, in vitro use only.

[83] https://www.accessdata.fda.gov/cdrh_docs/reviews/K161493.pdf “The seminal fluid collected in the semen sample cup is liquefied with the addition of chymotrypsin with eosin.”

[84] https://www.yospermtest.com/blog/understanding-your-yo-score/ 

[85] http://sci-hub.tw/10.1016/j.fertnstert.2016.12.019 

[86] http://sci-hub.tw/10.1038/nature11011. . The small increase in the rate of de novo events, when

taken together with the protein interaction results, are consistent with an important but limited role for de novo point mutations in ASD,... From analyses of secondary phenotypes (Supplementary Tables 2

and 3), the most striking result is that paternal and maternal age, themselves highly correlated (r 2 5 0.679, P-value ,0.0001), each strongly predicts the number of de novo events per offspring (paternal age, P 5 0.0013; maternal age, P 5 0.000365), consistent with aggregating mutations in germ cells in the paternal line

[87] http://sci-hub.tw/10.1038/nrg3585 see “Contribution of de novo mutations”

[88] http://sci-hub.tw/10.1038/nature10989. Here we show that de novo point mutations are overwhelmingly paternal in origin (4:1 bias) and positively correlated with paternal age, consistent with the modest increased risk for children of older fathers to develop ASD5; Moreover, 39% (49 of 126) of the most severe or disruptive de novo mutations map to a highly interconnected β-catenin/chromatin remodelling protein network ranked significantly for autism candidate genes.

Association with achondroplasia: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4854094/

[89]  http://sci-hub.tw/10.1038/nature10945. We found that the rate of de novo SNVs indeed increases with paternal age (

[90] Table S1. Categories of parental age group and relative risks of autism in the included studies http://sci-hub.tw/10.1111/acps.12666 

[91] https://academic.oup.com/ije/article/43/1/107/736982  see table 2 paternal age, total ASD ranges from 11.62-12.36 out of 1000 for men in their 30s. For 40s, ranges from 13.24-14.16 out of 1000

[92] http://sci-hub.tw/10.1001/archpsyc.63.9.1026 see table 1. paternal age 30-39: 0.09 risk 40-49: 0.32 risk.  But this study’s baseline rate seems much lower than what the global population is, and

[93] http://sci-hub.tw/10.1038/nrg3585  ASDs afflict ~1% of the human population

[94] https://rep.bioscientifica.com/view/journals/rep/70/1/jrf_70_1_028.xml & https://books.google.com/books?hl=en&lr=&id=hakvCgAAQBAJ&oi=fnd&pg=PA33&dq=geriatric+sperm+production&ots=5G5r-9LrgM&sig=2xRrEdN3BI2PvzQXTveUKgEUzlI#v=onepage&q=sperm&f=false pg 394

[95] https://www.nature.com/articles/nature11396 After accounting for random Poisson variation, father’s age is estimated to explain nearly all of the remaining variation in the de novo mutation counts. These observations shed light on the importance of the father’s age on the risk of diseases such as schizophrenia and autism.

[96] https://fohs.bgu.ac.il/develop/DB2/Where%20are%20the%20genes/Crow,%202000.pdf : explanation of how larger number of germ cell divisions build into sperm development increases number of mutations in those cells over time.

[97] http://sci-hub.tw/10.1016/j.fertnstert.2016.12.019 A number of rare, well-defined syndromes have for a long time been known to be more frequent if the father was of advanced age. These are, for example, severe types of affected growth (achondroplasia,...The most robust finding in the neurodevelopmental areas is that advanced paternal age is associated with ASD…. In conclusion, the vast majority of studies support that risk of schizophrenia and ASDs is increased in offspring of older fathers,...

[98] https://jamanetwork.com/journals/jamapsychiatry/fullarticle/1833092  Compared with offspring born to fathers 20 to 24 years old, offspring of fathers 45 years and older were at heightened risk of autism (hazard ratio [HR] = 3.45; 95% CI, 1.62-7.33),...

[99] http://sci-hub.tw/10.1111/acps.12666 Advanced parental age was associated with an increased

risk of autism in the offspring. More mechanistic studies are needed to further explain this positive association….  Increased rates of de novo mutations and epigenetic alternations with increasing age are the most frequently proposed mechanisms underlie paternal age effects

[100] http://sci-hub.tw//10.1038/ng.3629 [Kong et al. showed that] each newborn carries 30–100 (average of 60) sequence alterations, also known as DNMs, that are not present in the DNA of their parents. Because DNMs arise in the parental germ line (sperm or egg) before fertilization, their occurrence is intimately linked to the biology of germ cells. ...  The strength of the study by Goldmann et al. is undoubtedly its size, as these authors report the analysis of whole-genome data from 816 family trios …  the authors validated some previous findings, including the male-biased origin of DNMs— with ~80% of mutations originating during spermatogenesis—and the paternal age effect of ~1 new mutation per additional year of father’s age.

[101] https://www.nature.com/articles/nature11396 Kong et al. - The effect is an increase of about two mutations per year. An exponential model estimates paternal mutations doubling every 16.5 years.

[102] http://sci-hub.tw/10.1038/ng.3597 Goldmann et al. - Our results show that the number of DNMs in offspring increases not only with paternal age, but also with maternal age

[103] 2017:This comprehensive meta-regression analysis reports a significant decline in sperm counts (as measured by SC and TSC) between 1973 and 2011, driven by a 50–60% decline among men unselected by fertility from North America, Europe, Australia and New Zealand.

https://sci-hub.tw/10.1093/humupd/dmx022  ;  but some meta-analyses foundsperm number decline in African populations 1965-2015: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5637027/; another sees it in Asia as well: https://journals.sagepub.com/doi/full/10.1177/1557988316643383 But: these papers don’t mention controlling for many of the variables the 2017 meta-analysis did, e.g. not using samples from infertility clinics, adjusting for days of abstinence before giving sample, only including studies which used hemocytometers, etc. (see figure 3 for long list of things the 2017 paper adjusts for)

[104]  Original paper said “There was no sign of ‘leveling off’ of the decline” and according to this news story, Dr Levine [the lead author], an epidemiologist, told the BBC that if the trend continued humans would become extinct.”

[105]https://sci-hub.tw/10.1111/j.1365-2605.2007.00853.x . adverse trends in male reproductive health: we may have reached a crucial ‘tipping point’ …. Consequently, we must face the possibility of more infertile couples and lower fertility rates in the future…. We have no time to waste in our efforts to identify the causes of these health problems.

[106] https://sci-hub.tw/10.1152/physrev.00017.2015 and it’s not just sperm counts- some researchers are linking the sperm drop to an increase in other male reproductive issues. That’s a good review of that evidence. Also has pretty graphs of fertility rates dropping. And they conclude “it seems a more likely scenario that fertility rates significantly below replacement level have become “chronic” in those areas of the world, where they have virtually been unchanged for more than a generation. If they persist at the current level, our grandchildren and their children will face a different world.”

[107] http://sci-hub.tw/10.1136/bmj.j4517 We have already waited too long. As New York Times columnist

Nicholas Kristof recently wrote: “Our human future will only be as healthy as our sperm.”

[108] http://cbhandmaidstale.wikifoundry.com/page/Historical+Notes The backstory of Margaret Atwood's A Handmaid's Tale involves increasing infertility, in both men and women. Source: A Handmaid's Tale, endnotes

[109] https://sci-hub.tw/10.1038/nrurol.2017.153   “the authors ignore the severe methodological limitations that apply to all retrospective sperm trend studies using antecedent data collected for other purposes,

such as high nonresponse in semen studies, large variation in sperm counting between laboratories, and geographical variation.”

[110] http://sci-hub.tw/10.1097/OGX.0000000000000599 there’s still a debate, authors mention variability in terms of accuracy and type of technique used for semen analysis being a problem, but also mention most studies do show a downward trend

[111] https://apps.who.int/iris/bitstream/handle/10665/44261/9789241547789_eng.pdf;jsessionid=599623C312962D5F7B0B5BE8364E0431?sequence=1 The WHO has been publishing a guide for semen analysis, "in response to a growing need for the standardization of procedures for the examination of human semen. "

[112] http://sci-hub.tw/10.1530/jrf.0.0080149 Marked variation was found in counts among technicians and in duplicate counts by the same technician…(DK: 6% of variance due to individual technicians; another 4% between pipettings of a single sample; 60% between samples from a single individual...) The variance associated with the haemocytometer technique is large and must be considered in the design and analysis of studies of semen.

[113] http://sci-hub.tw/10.1016/0890-6238(88)90020-2 Sperm count, percent motile sperm, and semen volume each had large coefficients of variation (both between and within subjects). These variables, especially count, had relatively poor precision.

[114] Semen viscosity: https://www.ncbi.nlm.nih.gov/pubmed/1358311

[115] See page 33 for section on viscosity in the “Handbook of the Laboratory Diagnosis and Treatment of Infertility” says “hyperviscosity can, however, cause technical problems for semen analysis” “https://books.google.com/books?hl=en&lr=&id=rfaDfk19pHcC&oi=fnd&pg=PA27&dq=semen+viscosity+hemocytometer&ots=1WDdgzRwZY&sig=bON6p5EBpZXqPh3suSOnIdF0Ma0#v=onepage&q&f=false

[116] WHO manual “The viscosity should be recorded as abnormal when the thread exceeds 2 cm”

[117] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3739166/ This made results obtained from different laboratories and even from the same laboratory difficult to compare, which became strikingly evident when the World Health Organization (WHO) started to perform worldwide multicentre trials for male contraception and for male infertility treatment.  

[118] https://apps.who.int/iris/bitstream/handle/10665/44261/9789241547789_eng.pdf;jsessionid=599623C312962D5F7B0B5BE8364E0431?sequence=1   "In order to make global comparisons easier, this edition of the manual therefore includes much greater detail, and the rationale is explained when alternative methods of analysis are presented. It is recommended that, when reporting results in published articles, laboratories should indicate which specific method was used when they refer to this manual."

[119] http://sci-hub.tw/10.1097/OGX.0000000000000599 More prospective, large-scale, population based studies are needed in order to provide sound evidence of possible global trends in sperm count. https://www.ncbi.nlm.nih.gov/pubmed/18423235 lays out many confounding variables that make it difficult to compare semen samples

[120] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3739166/ critical review which outlines some of the issues with the older studies showing the drop.

[121] the 2017 study did try to control for some issues the older meta-analyses did not, like: not selecting for infertility and only using studies which used hemocytometers, but there have been differences between types of hemocytometers used, and some of the papers they used did not report which type they used, whether they followed the WHO guidelines, or the details of their analysis (whether they counted only sperm with normal tails, e.g.)